RARE DISEASE
PTEN hamartoma tumor syndrome
PTEN hamartoma tumor syndrome
PTEN hamartoma tumor syndrome
Synonyms: PHTS
Synonyms: PHTS
Synonyms: PHTS
Drug discovery
0
drugs
With orphan designations
Overview
PTEN Hamartoma Tumor Syndrome (PHTS) is an autosomal dominant disorder caused by germline PTEN mutations, leading to dysregulated cell growth. It encompasses Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, and related disorders. PHTS is characterized by macrocephaly, hamartomas (skin, thyroid, GI tract), and elevated cancer risks, particularly breast (up to 85%), thyroid (up to 35%), and endometrial cancers (up to 28%). Early diagnosis enables proactive cancer surveillance and management.
Burden
High lifetime cancer risks (breast: 67–85%, thyroid: 6–35%, endometrial: 19–28%) requiring lifelong monitoring [2][11][16].
Psychosocial impact: Developmental delays (47–89% with autism/intellectual disability) and cosmetic/functional challenges from hamartomas [6][15][19].
Economic strain: Frequent screenings, surgeries, and interdisciplinary care increase healthcare utilization [17][18].
Therapies
Surveillance: Annual thyroid ultrasound (from adolescence), breast MRI/mammography (age 30–35+), endometrial biopsies, and dermatologic exams [2][11][16].
Surgical Intervention: Tumor resection (e.g., thyroidectomy, mastectomy) for malignancy or symptomatic benign growths [12][16].
Targeted Therapy: mTOR inhibitors (sirolimus, everolimus) show promise in trials for symptom control and tumor reduction [3][8][17].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare neoplastic diseases, rare skin diseases
Research Papers
177 drug discovery papers about PTEN hamartoma tumor syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
177 drug discovery papers about PTEN hamartoma tumor syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-05-19 | Treatment of Vascular Anomalies With Sirolimus: An Updated Comprehensive Review.
Sirolimus, an mTOR inhibitor, has transformed the management of complex slow- flow vascular malformations (VAMs), particularly those driven by PI3K/AKT/mTOR pathway activation. Evidence from prospective trials and real- world cohorts supports its use in venous, lymphatic and combined malformations, as well as in PIK3CA- related overgrowth spectrum (PROS) and PTEN hamartoma tumor syndrome (PHTS). However, sirolimus shows poor or absent benefit in fast- flow lesions such as arteriovenous malformations (AVMs). This narrative review of the recent literature (2020- 2025) was performed using PubMed, focusing on molecular mechanisms, clinical efficacy, safety, quality of life, therapeutic drug monitoring (TDM) and cost- utility of sirolimus in vascular anomalies. Sirolimus demonstrates high response rates in slow- flow malformations, with partial responses in approximately 60-85%60-85% of patients and clinically meaningful improvements in health- related quality of life (HRQoL). Lower trough levels (4- 10 ng/mL) provide comparable efficacy with reduced toxicity. Adverse effects include oral mucositis, dyslipidemia, fatigue and infections. In contrast, fast- flow malformations show negligible benefit, consistent with their distinct genetic architecture, which predominantly activates RAS/MAPK rather than PI3K/AKT/mTOR signalling. Sirolimus is an effective targeted therapy for refractory slow- flow vascular malformations but should not be considered a universal treatment for all vascular anomalies. Future directions include molecularly guided therapy, rational combination regimens and integration with PI3K- and AKT- directed agents.
2026-05-12 | Management and outcomes of fertility preservation in rare Cowden syndrome-associated endometrial carcinoma: a case series.
Cowden syndrome-associated endometrial carcinoma (CS-EC) is rare, and data on fertility-preserving treatment for young patients remain limited. This series describes the diagnosis and management of three patients with CS-EC who underwent fertility-sparing treatment. We also report the subsequent pregnancy outcome for one of these individuals. These cases provide a clinical reference for the individualized management of such patients. Three patients (aged 29, 31, and 28 years) with germline Phosphatase and tensin homolog (PTEN) pathogenic variants and stage IA endometrial carcinoma underwent individualized fertility-sparing treatment. Case 1 (PTEN p.R189Qfs*9) failed levonorgestrel-releasing intrauterine system (LNG-IUS) treatment at 19 months. Eight cycles of GnRH agonist (GnRH-a) plus letrozole (LE) subsequently induced a complete response. A recurrence was successfully managed with twelve additional cycles of this regimen. Case 2 (PTEN p.R173C) attained remission after six months of megestrol acetate (MA). Case 3 (PTEN p.R335*) responded to MA over nine months, then developed complex mucinous papillary metaplasia during LNG-IUS maintenance, which resolved with ethinylestradiol/cyproterone acetate (EE/CPA). She subsequently conceived and delivered a live birth through Intracytoplasmic sperm injection (ICSI). During the follow-up period, all patients were administered maintenance therapy using a LNG-IUD. Fertility-sparing therapy may serve as a potentially feasible option for highly selected patients with stage IA CS-EC, and could lead to relatively favorable pregnancy outcomes. The clinical feasibility of this strategy relies heavily on strict patient selection, timely molecular diagnosis, and standardized continuous multidisciplinary management.
2026-04-29 | Pleiotropic germline PTEN mutations influence gastrulation through dysregulated AKT activation.
PTEN hamartoma tumor syndrome (PHTS), caused by germline PTEN mutations, exhibits pleiotropic manifestations, including hamartomas, cancers, and neurodevelopmental disorders, posing challenges in patient management. We hypothesized that mutant PTEN allele-dependent alterations during gastrulation impact PHTS pleiotropism. We generated gastruloids from isogenic human induced pluripotent stem cells with clinically relevant heterozygous PTEN mutations, PTENG132D/WT found in PHTS patients with cancer, hamartoma, and autism spectrum disorder, and PTENM134R/WT associated with cancer-only patients. PTENG132D/WTgastruloids exhibited axial over-elongation driven by AKT hyperactivation, upregulation of Snail, a key regulator of epithelial-to-mesenchymal transition (EMT), and enrichments in mesoderm and endoderm-related gene signatures, compared to those with PTENM134R/WT or PTENWT/WT. Our machine-learning algorithm accurately recognized the over-elongated PTENG132D/WT gastruloids and morphological reversal with AKT inhibitor treatment. Our data suggest a potential link between the mutant PTEN allele-specific early developmental alterations and the clinical outcomes of PHTS, and provide a platform for pathogenic mutation and drug screening.
2026-04-20 | Repurposing drugs for treating the neurobehavioral manifestations of PTEN hamartoma tumor syndrome.
PTEN hamartoma tumor syndrome (PHTS) is caused by mutation of PTEN and patients suffer from an increased risk of cancer and neurodevelopmental disorders. While treatment with mTOR inhibitors can alleviate some aspects, there remains a significant need for treatment of neurobehavioral symptoms in PHTS. Here, we describe a drug-repurposing program, screening >60 compounds targeting the PI3K/AKT/mTOR pathway. First, we interrogated altered signaling and morphology in a cell-line and primary neurons with PTEN-dysfunction, before further refining our compound selection using multielectrode recordings and MDCK assays. A final number of six compounds, with promising potency and propensity to cross the blood-brain-barrier, were tested in vivo in pharmacokinetic and proof-of-principle pharmacodynamic studies, and we observed that dual PI3K/mTOR inhibitors achieve effects comparable to or even surpassing those of standard mTOR inhibitors. In summary, our study showcases a combination of in vitro models providing a valid strategy for identifying drug-repurposing candidates to treat PHTS patients.
2026-04-17 | Sirolimus for Extracranial Arteriovenous Malformations: A Scoping Review of the Evidence in Syndromic and Non-Syndromic Cases.
Arteriovenous malformations (AVMs) are rare, high-flow, vascular anomalies that can occur either sporadically or as part of a genetic syndrome. AVMs can progress with serious morbidity and even mortality if left unchecked. Sirolimus is an mTOR inhibitor that is effective in low-flow vascular malformations; however, its role in AVMs is unclear. This scoping review investigates the current evidence base around the use of sirolimus for AVMs. Twenty-one reports encompassing a total of 60 patients with AVMs treated with systemic sirolimus were included. Sirolimus was predominantly used as an adjunct or salvage therapy. Response was variable overall; however, there was a more consistent benefit in patients with PTEN hamartoma syndrome (PHTS)-associated AVMs, where PI3K/AKT/mTOR pathway dysregulation provides a molecular basis for sirolimus efficacy. Standardised outcome reporting, routine molecular profiling, and larger multicentre collaboration are needed to better define the role of sirolimus for AVMs, particularly as part of multimodal care.
gene therapies
2026-05-06 | Generation of two induced pluripotent stem cell lines from patients carrying heterozygous PTEN mutations associated with PTEN Hamartoma Tumor Syndrome.
PTEN Hamartoma Tumor Syndrome (PHTS) is an inherited condition caused by germline mutations in PTEN, characterized by abnormal development and an elevated cancer risk driven by altered PI3K-AKT signaling. To model this disease in vitro, we derived human induced pluripotent stem cell (iPSC) lines SCVIi142-A and SCVIi143-A from two male donors clinically diagnosed with PHTS carrying heterozygous PTEN mutations. Both lines displayed undifferentiated iPSC morphology, robust expression of undifferentiated iPSC state markers, trilineage differentiation capacity, normal karyotypes, and validated PTEN variants. These iPSC lines provide a patient-specific platform for studying PTEN-associated developmental and signaling abnormalities.
2026-01-02 | Population-based Characterization of PTEN Hamartoma Tumor Syndrome.
PTEN hamartoma tumor syndrome (PHTS) is a cancer predisposition disorder caused by germline PTEN variants, yet its full clinical spectrum remains poorly defined due to reliance on highly selected cohorts. Accordingly, PHTS is underrecognized and its prevalence underestimated. Leveraging genomic and electronic health record data from 414,830 participants in the All of Us (AoU) Research Program, we identified 55 individuals with pathogenic or likely pathogenic PTEN variants, the majority of whom lacked a prior PHTS diagnosis, underscoring underrecognition in the general population. PHTS affects ~1/7500 individuals in this US cohort, which is about 26-folds higher than historical estimates for PTEN-related disorder. Compared with carriers of other cancer-related gene variants and noncarriers, PTEN variant carriers exhibited the highest cancer prevalence and significantly younger ages at first cancer diagnosis. Phenotype enrichment revealed expected overgrowth-related features as well as previously unreported associations, including adenotonsillar hypertrophy, sleep apnea, acanthosis nigricans, and extreme obesity, suggesting broader systemic involvement than classically appreciated. Variant spectra were consistent across the population-based and clinically-ascertained PHTS cohorts. These findings demonstrate that PHTS is more prevalent, more heterogeneous, and more often undiagnosed than current clinical practice reflects, emphasizing the value of population-scale genomics for comprehensive characterization and earlier detection of PHTS.
2017-05-02 | Correction of PTEN mutations in glioblastoma cell lines via AAV-mediated gene editing
PTEN is among the most commonly mutated tumor suppressor genes in human cancer. However, studying the role of PTEN in the pathogenesis of cancer has been limited, in part, by the paucity of human cell-based isogenic systems that faithfully model PTEN loss. In an effort to remedy this problem, gene editing was used to correct an endogenous mutant allele of PTEN in two human glioblastoma multiforme (GBM) cell lines- 42MGBA and T98G. PTEN correction resulted in reduced cellular proliferation that was Akt-dependent in 42MGBA cells and Akt-independent in T98G cells. This is the first report of human cancer cell lines in which mutant PTEN has been corrected by gene editing. The isogenic sets of gene edited cell lines reported here will likely prove useful for further study of PTEN mutations in the pathogenesis of cancer, and for the discovery and validation of novel therapeutics targeting the PTEN pathway.
2005-01-27 | Akt: a potential target for thyroid cancer therapy.
Thyroid cancer is a heterogeneous disorder characterized by gene mutations that activate signaling pathways, and also by abnormalities in tumor suppressor genes and cell cycle proteins. Activation of the Akt/PKB signaling pathway appears to be an important event in thyroid tumorigenesis and, perhaps, in tumor progression too. Akt is activated in Cowden's syndrome through inactivation of PTEN, a negative regulator of Akt. Cowden's syndrome is an autosomal dominant multiorgan hamartoma syndrome characterized by benign and malignant thyroid tumors, breast cancers, and colon cancers. In addition, the Akt pathway appears to be activated in a significant proportion of sporadic thyroid cancers through activation of growth factor pathways by thyroid oncogenes and/or receptor overexpression. Disruption of PI3-kinase activity pharmacologically or disruption of Akt signaling using dominant negative cDNA expression have demonstrated salutary effects on several cancer models in vitro. Therefore, Akt represents an attractive target for pharmaceutical development for a variety of malignancies, including thyroid cancer.
proteins
2021-12-03 | PTEN regulates adipose progenitor cell growth, differentiation, and replicative aging.
The tumor suppressor phosphatase and tensin homolog (PTEN) negatively regulates the insulin signaling pathway. Germline PTEN pathogenic variants cause PTEN hamartoma tumor syndrome (PHTS), associated with lipoma development in children. Adipose progenitor cells (APCs) lose their capacity to differentiate into adipocytes during continuous culture, whereas APCs from lipomas of patients with PHTS retain their adipogenic potential over a prolonged period. It remains unclear which mechanisms trigger this aberrant adipose tissue growth. To investigate the role of PTEN in adipose tissue development, we performed functional assays and RNA-Seq of control and PTEN knockdown APCs. Reduction of PTEN levels using siRNA or CRISPR led to enhanced proliferation and differentiation of APCs. Forkhead box protein O1 (FOXO1) transcriptional activity is known to be regulated by insulin signaling, and FOXO1 was downregulated at the mRNA level while its inactivation through phosphorylation increased. FOXO1 phosphorylation initiates the expression of the lipogenesis-activating transcription factor sterol regulatory element-binding protein 1 (SREBP1). SREBP1 levels were higher after PTEN knockdown and may account for the observed enhanced adipogenesis. To validate this, we overexpressed constitutively active FOXO1 in PTEN CRISPR cells and found reduced adipogenesis, accompanied by SREBP1 downregulation. We observed that PTEN CRISPR cells showed less senescence compared with controls and the senescence marker CDKN1A (p21) was downregulated in PTEN knockdown cells. Cellular senescence was the most significantly enriched pathway found in RNA-Seq of PTEN knockdown versus control cells. These results provide evidence that PTEN is involved in the regulation of APC proliferation, differentiation, and senescence, thereby contributing to aberrant adipose tissue growth in patients with PHTS.
2021-10-14 | Integrating thousands of PTEN variant activity and abundance measurements reveals variant subgroups and new dominant negatives in cancers
PTEN is a multi-functional tumor suppressor protein regulating cell growth, immune signaling, neuronal function, and genome stability. Experimental characterization can help guide the clinical interpretation of the thousands of germline or somatic PTEN variants observed in patients. Two large-scale mutational datasets, one for PTEN variant intracellular abundance encompassing 4112 missense variants and one for lipid phosphatase activity encompassing 7244 variants, were recently published. The combined information from these datasets can reveal variant-specific phenotypes that may underlie various clinical presentations, but this has not been comprehensively examined, particularly for somatic PTEN variants observed in cancers.Here, we add to these efforts by measuring the intracellular abundance of 764 new PTEN variants and refining abundance measurements for 3351 previously studied variants. We use this expanded and refined PTEN abundance dataset to explore the mutational patterns governing PTEN intracellular abundance, and then incorporate the phosphatase activity data to subdivide PTEN variants into four functionally distinct groups.This analysis revealed a set of highly abundant but lipid phosphatase defective variants that could act in a dominant-negative fashion to suppress PTEN activity. Two of these variants were, indeed, capable of dysregulating Akt signaling in cells harboring a WT PTEN allele. Both variants were observed in multiple breast or uterine tumors, demonstrating the disease relevance of these high abundance, inactive variants.We show that multidimensional, large-scale variant functional data, when paired with public cancer genomics datasets and follow-up assays, can improve understanding of uncharacterized cancer-associated variants, and provide better insights into how they contribute to oncogenesis.
2021-01-07 | PTEN regulates adipocyte progenitor growth, differentiation and replicative aging
Abstract The tumor suppressor phosphatase and tensin homolog (PTEN) negatively regulates the insulin signaling pathway. Germline PTEN pathogenic variants cause PTEN Hamartoma Tumor Syndrome (PHTS), associated with lipoma development in children. It remains unclear which mechanisms trigger this aberrant adipose tissue growth. Adipocyte progenitor cells (APCs) lose their capacity to differentiate into adipocytes during continuous culture, while APCs from PHTS patients’ lipomas retain their adipogenic potential over a prolonged period. To investigate the role of PTEN in adipose tissue development we performed functional assays and RNA sequencing of control and PTEN knockdown APCs. Reduction of PTEN levels using siRNA or CRISPR lead to an enhanced proliferation and differentiation of APCs. FOXO1 was downregulated on the mRNA level while inactivation through phosphorylation increased. FOXO1 phosphorylation initiates the expression of the lipogenesis activating transcription factor SREBP1. SREBP1 levels were higher after PTEN knockdown and may account for the enhanced adipogenesis. To validate this we overexpressed constitutively active FOXO1 in PTEN CRISPR cells and found reduced adipogenesis, accompanied by a SREBP1 downregulation. We observed that PTEN levels were upregulated during long term culture of wild type APCs. PTEN CRISPR cells showed less senescence compared to controls and the senescence marker CDKN1A (p21) was downregulated in PTEN knockdown cells. Cellular senescence was the most significantly enriched pathway found in RNA sequencing of PTEN knockdown vs. control cells. These results provide evidence that PTEN is involved in the regulation of APCs proliferation, differentiation and senescence, thereby contributing to aberrant adipose tissue growth in PHTS patients.
2020-12-23 | Recent advances in PTEN signalling axes in cancer
In over two decades since the discovery of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), nearly 18,000 publications have attempted to elucidate its functions and roles in normal physiology and disease. The frequent disruption of PTEN in cancer cells was a strong indication that it had critical roles in tumour suppression. Germline PTEN mutations have been identified in patients with heterogeneous tumour syndromic diseases, known as PTEN hamartoma tumour syndrome (PHTS), and in some individuals with autism spectrum disorders (ASD). Today we know that by limiting oncogenic signalling through the phosphoinositide 3-kinase (PI3K) pathway, PTEN governs a number of processes including survival, proliferation, energy metabolism, and cellular architecture. Some of the most exciting recent advances in the understanding of PTEN biology and signalling have revisited its unappreciated roles as a protein phosphatase, identified non-enzymatic scaffold functions, and unravelled its nuclear function. These discoveries are certain to provide a new perspective on its full tumour suppressor potential, and knowledge from this work will lead to new anti-cancer strategies that exploit PTEN biology. In this review, we will highlight some outstanding questions and some of the very latest advances in the understanding of the tumour suppressor PTEN.
2019-06-22 | Analyzing aggregation propensities of clinically relevant PTEN mutants: a new culprit in pathogenesis of cancer and other PTENopathies
While studies on pathological protein aggregation are largely limited to neurodegenerative disease, emerging evidence suggests that other diseases are also associated with pathogenic protein aggregation. For example, tumor suppressor protein p53, and its mutant conformers, undergo protein aggregation, exacerbating the cancer phenotype. These findings raise the possibility that inactivation of tumor suppressors via protein aggregation may participate in cancer and other disease pathologies. Since tumor suppressor protein PTEN has similar functions to p53, and is mutated in multiple diseases, we examined the aggregation propensity of PTEN wild-type and 1523 clinically relevant PTEN mutants. Applying computational tools to PTEN mutation databases revealed that PTEN wild-type protein can aggregate under physiological conditions, and 274 distinct PTEN mutants had increased aggregation propensity. To understand the mechanism underlying PTEN conformer aggregation, we analyzed the physicochemical properties of these 274 PTEN mutants and defined their aggregation potential. We conclude that increased aggregation propensity of select PTEN mutants may contribute to disease phenotypes. Our studies have built the foundation for interrogating the aggregation potential of these select mutants in cancers and in PTENopathies. Elucidating the pathogenic mechanisms associated with aggregation-prone PTEN conformers will aid in developing therapies that target PTEN-aggregates in multiple diseases.Communicated by Ramaswamy H. Sarma
oligonucleotides
2023-08-10 | Small integral membrane protein 10 like 1 downregulation enhances differentiation of adipose progenitor cells.
Small integral membrane protein 10 like 1 (SMIM10L1) was identified by RNA sequencing as the most significantly downregulated gene in Phosphatase and Tensin Homologue (PTEN) knockdown adipose progenitor cells (APCs). PTEN is a tumor suppressor that antagonizes the growth promoting Phosphoinositide 3-kinase (PI3K)/AKT/mechanistic Target of Rapamycin (mTOR) cascade. Diseases caused by germline pathogenic variants in PTEN are summarized as PTEN Hamartoma Tumor Syndrome (PHTS). This overgrowth syndrome is associated with lipoma formation, especially in pediatric patients. The mechanisms underlying this adipose tissue dysfunction remain elusive. We observed that SMIM10L1 downregulation in APCs led to an enhanced adipocyte differentiation in two- and three-dimensional cell culture and increased expression of adipogenesis markers. Furthermore, SMIM10L1 knockdown cells showed a decreased expression of PTEN, pointing to a mutual crosstalk between PTEN and SMIM10L1. In line with these observations, SMIM10L1 knockdown cells showed increased activation of PI3K/AKT/mTOR signaling and concomitantly increased expression of the adipogenic transcription factor SREBP1. We computationally predicted an α-helical structure and membrane association of SMIM10L1. These results support a specific role for SMIM10L1 in regulating adipogenesis, potentially by increasing PI3K/AKT/mTOR signaling, which might be conducive to lipoma formation in pediatric patients with PHTS.
2007-08-20 | Comparative genomic and functional analyses reveal a novel cis-acting PTEN regulatory element as a highly conserved functional E-box motif deleted in Cowden syndrome.
Germline mutations in PTEN, encoding a phosphatase on 10q23, cause Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS). Approximately, 10% of CS-related PTEN mutations occur in the PTEN promoter and 11% of BRRS-related mutations include large deletions, often favoring the gene's 5' end (exon 1, promoter). In order to better understand the mechanism(s) underlying the deregulation of PTEN in these syndromes, it is important that functional cis-regulatory elements be identified. We employed a comparative genomic approach combined with molecular genetic techniques to identify a highly conserved sequence upstream of the PTEN promoter, sharing 80% sequence identity among Homo sapiens, Mus musculus and Rattus norvegicus. Within this region, we identified a canonical E-box sequence (CACGTG) located at position -2181 to -2176, approximately 800 bp upstream of the PTEN core promoter and more than 1.1 kb upstream of its minimal promoter region (located at -958 to -821). In vitro assays suggest that this motif is recognized by members of the basic region-helix-loop-helix-leucine-zipper (bHLH-LZ) transcription factor family, USF1 and USF2, and reporter assays indicate that this novel E-box is involved in mediating PTEN transcriptional activation. Four of 30 CS/CS-like patients, without previously identified PTEN mutations, were found with germline deletions of the E-box element. Of the four, three had deletions stretching to exon 1, but not 3' of it; importantly, one classic CS patient harbored a germline deletion localizing to this E-box region, further affirming the role of this element in PTEN's regulation and deregulation, and its contribution to the pathogenesis of CS.
other
2023-08-01 | Novel anti-PTEN C2 domain monoclonal antibodies to analyse the expression and function of PTEN isoform variants
PTEN is a major tumor suppressor gene frequently mutated in human tumors, and germline PTEN gene mutations are the molecular diagnostic of PTEN Hamartoma Tumor Syndrome (PHTS), a heterogeneous disorder that manifests with multiple hamartomas, cancer predisposition, and neurodevelopmental alterations. A diversity of translational and splicing PTEN isoforms exist, as well as PTEN C-terminal truncated variants generated by disease-associated nonsense mutations. However, most of the available anti-PTEN monoclonal antibodies (mAb) recognize epitopes at the PTEN C-terminal tail, which may introduce a bias in the analysis of the expression of PTEN isoforms and variants. We here describe the generation and precise characterization of anti-PTEN mAb recognizing the PTEN C2-domain, and their use to monitor the expression and function of PTEN isoforms and PTEN missense and nonsense mutations associated to disease. These anti-PTEN C2 domain mAb are suitable to study the pathogenicity of PTEN C-terminal truncations that retain stability and function but have lost the PTEN C-terminal epitopes. The use of well-defined anti-PTEN mAb recognizing distinct PTEN regions, as the ones here described, will help to understand the deleterious effects of specific PTEN mutations in human disease.
2022-08-29 | Phospholipid Scramblase 4 (PLSCR4) Regulates Adipocyte Differentiation via PIP3-Mediated AKT Activation
Phospholipid scramblase 4 (PLSCR4) is a member of a conserved enzyme family with high relevance for the remodeling of phospholipid distribution in the plasma membrane and the regulation of cellular signaling. While PLSCR1 and -3 are involved in the regulation of adipose-tissue expansion, the role of PLSCR4 is so far unknown. PLSCR4 is significantly downregulated in an adipose-progenitor-cell model of deficiency for phosphatase and tensin homolog (PTEN). PTEN acts as a tumor suppressor and antagonist of the growth and survival signaling phosphoinositide 3-kinase (PI3K)/AKT cascade by dephosphorylating phosphatidylinositol-3,4,5-trisphosphate (PIP3). Patients with PTEN germline deletion frequently develop lipomas. The underlying mechanism for this aberrant adipose-tissue growth is incompletely understood. PLSCR4 is most highly expressed in human adipose tissue, compared with other phospholipid scramblases, suggesting a specific role of PLSCR4 in adipose-tissue biology. In cell and mouse models of lipid accumulation, we found PLSCR4 to be downregulated. We observed increased adipogenesis in PLSCR4-knockdown adipose progenitor cells, while PLSCR4 overexpression attenuated lipid accumulation. PLSCR4 knockdown was associated with increased PIP3 levels and the activation of AKT. Our results indicated that PLSCR4 is a regulator of PI3K/AKT signaling and adipogenesis and may play a role in PTEN-associated adipose-tissue overgrowth and lipoma formation.
small molecules
2026-05-19 | Treatment of Vascular Anomalies With Sirolimus: An Updated Comprehensive Review.
Sirolimus, an mTOR inhibitor, has transformed the management of complex slow- flow vascular malformations (VAMs), particularly those driven by PI3K/AKT/mTOR pathway activation. Evidence from prospective trials and real- world cohorts supports its use in venous, lymphatic and combined malformations, as well as in PIK3CA- related overgrowth spectrum (PROS) and PTEN hamartoma tumor syndrome (PHTS). However, sirolimus shows poor or absent benefit in fast- flow lesions such as arteriovenous malformations (AVMs). This narrative review of the recent literature (2020- 2025) was performed using PubMed, focusing on molecular mechanisms, clinical efficacy, safety, quality of life, therapeutic drug monitoring (TDM) and cost- utility of sirolimus in vascular anomalies. Sirolimus demonstrates high response rates in slow- flow malformations, with partial responses in approximately 60-85%60-85% of patients and clinically meaningful improvements in health- related quality of life (HRQoL). Lower trough levels (4- 10 ng/mL) provide comparable efficacy with reduced toxicity. Adverse effects include oral mucositis, dyslipidemia, fatigue and infections. In contrast, fast- flow malformations show negligible benefit, consistent with their distinct genetic architecture, which predominantly activates RAS/MAPK rather than PI3K/AKT/mTOR signalling. Sirolimus is an effective targeted therapy for refractory slow- flow vascular malformations but should not be considered a universal treatment for all vascular anomalies. Future directions include molecularly guided therapy, rational combination regimens and integration with PI3K- and AKT- directed agents.
2026-05-12 | Management and outcomes of fertility preservation in rare Cowden syndrome-associated endometrial carcinoma: a case series.
Cowden syndrome-associated endometrial carcinoma (CS-EC) is rare, and data on fertility-preserving treatment for young patients remain limited. This series describes the diagnosis and management of three patients with CS-EC who underwent fertility-sparing treatment. We also report the subsequent pregnancy outcome for one of these individuals. These cases provide a clinical reference for the individualized management of such patients. Three patients (aged 29, 31, and 28 years) with germline Phosphatase and tensin homolog (PTEN) pathogenic variants and stage IA endometrial carcinoma underwent individualized fertility-sparing treatment. Case 1 (PTEN p.R189Qfs*9) failed levonorgestrel-releasing intrauterine system (LNG-IUS) treatment at 19 months. Eight cycles of GnRH agonist (GnRH-a) plus letrozole (LE) subsequently induced a complete response. A recurrence was successfully managed with twelve additional cycles of this regimen. Case 2 (PTEN p.R173C) attained remission after six months of megestrol acetate (MA). Case 3 (PTEN p.R335*) responded to MA over nine months, then developed complex mucinous papillary metaplasia during LNG-IUS maintenance, which resolved with ethinylestradiol/cyproterone acetate (EE/CPA). She subsequently conceived and delivered a live birth through Intracytoplasmic sperm injection (ICSI). During the follow-up period, all patients were administered maintenance therapy using a LNG-IUD. Fertility-sparing therapy may serve as a potentially feasible option for highly selected patients with stage IA CS-EC, and could lead to relatively favorable pregnancy outcomes. The clinical feasibility of this strategy relies heavily on strict patient selection, timely molecular diagnosis, and standardized continuous multidisciplinary management.
2026-04-29 | Pleiotropic germline PTEN mutations influence gastrulation through dysregulated AKT activation.
PTEN hamartoma tumor syndrome (PHTS), caused by germline PTEN mutations, exhibits pleiotropic manifestations, including hamartomas, cancers, and neurodevelopmental disorders, posing challenges in patient management. We hypothesized that mutant PTEN allele-dependent alterations during gastrulation impact PHTS pleiotropism. We generated gastruloids from isogenic human induced pluripotent stem cells with clinically relevant heterozygous PTEN mutations, PTENG132D/WT found in PHTS patients with cancer, hamartoma, and autism spectrum disorder, and PTENM134R/WT associated with cancer-only patients. PTENG132D/WTgastruloids exhibited axial over-elongation driven by AKT hyperactivation, upregulation of Snail, a key regulator of epithelial-to-mesenchymal transition (EMT), and enrichments in mesoderm and endoderm-related gene signatures, compared to those with PTENM134R/WT or PTENWT/WT. Our machine-learning algorithm accurately recognized the over-elongated PTENG132D/WT gastruloids and morphological reversal with AKT inhibitor treatment. Our data suggest a potential link between the mutant PTEN allele-specific early developmental alterations and the clinical outcomes of PHTS, and provide a platform for pathogenic mutation and drug screening.
2026-04-20 | Repurposing drugs for treating the neurobehavioral manifestations of PTEN hamartoma tumor syndrome.
PTEN hamartoma tumor syndrome (PHTS) is caused by mutation of PTEN and patients suffer from an increased risk of cancer and neurodevelopmental disorders. While treatment with mTOR inhibitors can alleviate some aspects, there remains a significant need for treatment of neurobehavioral symptoms in PHTS. Here, we describe a drug-repurposing program, screening >60 compounds targeting the PI3K/AKT/mTOR pathway. First, we interrogated altered signaling and morphology in a cell-line and primary neurons with PTEN-dysfunction, before further refining our compound selection using multielectrode recordings and MDCK assays. A final number of six compounds, with promising potency and propensity to cross the blood-brain-barrier, were tested in vivo in pharmacokinetic and proof-of-principle pharmacodynamic studies, and we observed that dual PI3K/mTOR inhibitors achieve effects comparable to or even surpassing those of standard mTOR inhibitors. In summary, our study showcases a combination of in vitro models providing a valid strategy for identifying drug-repurposing candidates to treat PHTS patients.
2026-04-17 | Sirolimus for Extracranial Arteriovenous Malformations: A Scoping Review of the Evidence in Syndromic and Non-Syndromic Cases.
Arteriovenous malformations (AVMs) are rare, high-flow, vascular anomalies that can occur either sporadically or as part of a genetic syndrome. AVMs can progress with serious morbidity and even mortality if left unchecked. Sirolimus is an mTOR inhibitor that is effective in low-flow vascular malformations; however, its role in AVMs is unclear. This scoping review investigates the current evidence base around the use of sirolimus for AVMs. Twenty-one reports encompassing a total of 60 patients with AVMs treated with systemic sirolimus were included. Sirolimus was predominantly used as an adjunct or salvage therapy. Response was variable overall; however, there was a more consistent benefit in patients with PTEN hamartoma syndrome (PHTS)-associated AVMs, where PI3K/AKT/mTOR pathway dysregulation provides a molecular basis for sirolimus efficacy. Standardised outcome reporting, routine molecular profiling, and larger multicentre collaboration are needed to better define the role of sirolimus for AVMs, particularly as part of multimodal care.
gene therapies
2026-05-06 | Generation of two induced pluripotent stem cell lines from patients carrying heterozygous PTEN mutations associated with PTEN Hamartoma Tumor Syndrome.
PTEN Hamartoma Tumor Syndrome (PHTS) is an inherited condition caused by germline mutations in PTEN, characterized by abnormal development and an elevated cancer risk driven by altered PI3K-AKT signaling. To model this disease in vitro, we derived human induced pluripotent stem cell (iPSC) lines SCVIi142-A and SCVIi143-A from two male donors clinically diagnosed with PHTS carrying heterozygous PTEN mutations. Both lines displayed undifferentiated iPSC morphology, robust expression of undifferentiated iPSC state markers, trilineage differentiation capacity, normal karyotypes, and validated PTEN variants. These iPSC lines provide a patient-specific platform for studying PTEN-associated developmental and signaling abnormalities.
2026-01-02 | Population-based Characterization of PTEN Hamartoma Tumor Syndrome.
PTEN hamartoma tumor syndrome (PHTS) is a cancer predisposition disorder caused by germline PTEN variants, yet its full clinical spectrum remains poorly defined due to reliance on highly selected cohorts. Accordingly, PHTS is underrecognized and its prevalence underestimated. Leveraging genomic and electronic health record data from 414,830 participants in the All of Us (AoU) Research Program, we identified 55 individuals with pathogenic or likely pathogenic PTEN variants, the majority of whom lacked a prior PHTS diagnosis, underscoring underrecognition in the general population. PHTS affects ~1/7500 individuals in this US cohort, which is about 26-folds higher than historical estimates for PTEN-related disorder. Compared with carriers of other cancer-related gene variants and noncarriers, PTEN variant carriers exhibited the highest cancer prevalence and significantly younger ages at first cancer diagnosis. Phenotype enrichment revealed expected overgrowth-related features as well as previously unreported associations, including adenotonsillar hypertrophy, sleep apnea, acanthosis nigricans, and extreme obesity, suggesting broader systemic involvement than classically appreciated. Variant spectra were consistent across the population-based and clinically-ascertained PHTS cohorts. These findings demonstrate that PHTS is more prevalent, more heterogeneous, and more often undiagnosed than current clinical practice reflects, emphasizing the value of population-scale genomics for comprehensive characterization and earlier detection of PHTS.
2017-05-02 | Correction of PTEN mutations in glioblastoma cell lines via AAV-mediated gene editing
PTEN is among the most commonly mutated tumor suppressor genes in human cancer. However, studying the role of PTEN in the pathogenesis of cancer has been limited, in part, by the paucity of human cell-based isogenic systems that faithfully model PTEN loss. In an effort to remedy this problem, gene editing was used to correct an endogenous mutant allele of PTEN in two human glioblastoma multiforme (GBM) cell lines- 42MGBA and T98G. PTEN correction resulted in reduced cellular proliferation that was Akt-dependent in 42MGBA cells and Akt-independent in T98G cells. This is the first report of human cancer cell lines in which mutant PTEN has been corrected by gene editing. The isogenic sets of gene edited cell lines reported here will likely prove useful for further study of PTEN mutations in the pathogenesis of cancer, and for the discovery and validation of novel therapeutics targeting the PTEN pathway.
2005-01-27 | Akt: a potential target for thyroid cancer therapy.
Thyroid cancer is a heterogeneous disorder characterized by gene mutations that activate signaling pathways, and also by abnormalities in tumor suppressor genes and cell cycle proteins. Activation of the Akt/PKB signaling pathway appears to be an important event in thyroid tumorigenesis and, perhaps, in tumor progression too. Akt is activated in Cowden's syndrome through inactivation of PTEN, a negative regulator of Akt. Cowden's syndrome is an autosomal dominant multiorgan hamartoma syndrome characterized by benign and malignant thyroid tumors, breast cancers, and colon cancers. In addition, the Akt pathway appears to be activated in a significant proportion of sporadic thyroid cancers through activation of growth factor pathways by thyroid oncogenes and/or receptor overexpression. Disruption of PI3-kinase activity pharmacologically or disruption of Akt signaling using dominant negative cDNA expression have demonstrated salutary effects on several cancer models in vitro. Therefore, Akt represents an attractive target for pharmaceutical development for a variety of malignancies, including thyroid cancer.
proteins
2021-12-03 | PTEN regulates adipose progenitor cell growth, differentiation, and replicative aging.
The tumor suppressor phosphatase and tensin homolog (PTEN) negatively regulates the insulin signaling pathway. Germline PTEN pathogenic variants cause PTEN hamartoma tumor syndrome (PHTS), associated with lipoma development in children. Adipose progenitor cells (APCs) lose their capacity to differentiate into adipocytes during continuous culture, whereas APCs from lipomas of patients with PHTS retain their adipogenic potential over a prolonged period. It remains unclear which mechanisms trigger this aberrant adipose tissue growth. To investigate the role of PTEN in adipose tissue development, we performed functional assays and RNA-Seq of control and PTEN knockdown APCs. Reduction of PTEN levels using siRNA or CRISPR led to enhanced proliferation and differentiation of APCs. Forkhead box protein O1 (FOXO1) transcriptional activity is known to be regulated by insulin signaling, and FOXO1 was downregulated at the mRNA level while its inactivation through phosphorylation increased. FOXO1 phosphorylation initiates the expression of the lipogenesis-activating transcription factor sterol regulatory element-binding protein 1 (SREBP1). SREBP1 levels were higher after PTEN knockdown and may account for the observed enhanced adipogenesis. To validate this, we overexpressed constitutively active FOXO1 in PTEN CRISPR cells and found reduced adipogenesis, accompanied by SREBP1 downregulation. We observed that PTEN CRISPR cells showed less senescence compared with controls and the senescence marker CDKN1A (p21) was downregulated in PTEN knockdown cells. Cellular senescence was the most significantly enriched pathway found in RNA-Seq of PTEN knockdown versus control cells. These results provide evidence that PTEN is involved in the regulation of APC proliferation, differentiation, and senescence, thereby contributing to aberrant adipose tissue growth in patients with PHTS.
2021-10-14 | Integrating thousands of PTEN variant activity and abundance measurements reveals variant subgroups and new dominant negatives in cancers
PTEN is a multi-functional tumor suppressor protein regulating cell growth, immune signaling, neuronal function, and genome stability. Experimental characterization can help guide the clinical interpretation of the thousands of germline or somatic PTEN variants observed in patients. Two large-scale mutational datasets, one for PTEN variant intracellular abundance encompassing 4112 missense variants and one for lipid phosphatase activity encompassing 7244 variants, were recently published. The combined information from these datasets can reveal variant-specific phenotypes that may underlie various clinical presentations, but this has not been comprehensively examined, particularly for somatic PTEN variants observed in cancers.Here, we add to these efforts by measuring the intracellular abundance of 764 new PTEN variants and refining abundance measurements for 3351 previously studied variants. We use this expanded and refined PTEN abundance dataset to explore the mutational patterns governing PTEN intracellular abundance, and then incorporate the phosphatase activity data to subdivide PTEN variants into four functionally distinct groups.This analysis revealed a set of highly abundant but lipid phosphatase defective variants that could act in a dominant-negative fashion to suppress PTEN activity. Two of these variants were, indeed, capable of dysregulating Akt signaling in cells harboring a WT PTEN allele. Both variants were observed in multiple breast or uterine tumors, demonstrating the disease relevance of these high abundance, inactive variants.We show that multidimensional, large-scale variant functional data, when paired with public cancer genomics datasets and follow-up assays, can improve understanding of uncharacterized cancer-associated variants, and provide better insights into how they contribute to oncogenesis.
2021-01-07 | PTEN regulates adipocyte progenitor growth, differentiation and replicative aging
Abstract The tumor suppressor phosphatase and tensin homolog (PTEN) negatively regulates the insulin signaling pathway. Germline PTEN pathogenic variants cause PTEN Hamartoma Tumor Syndrome (PHTS), associated with lipoma development in children. It remains unclear which mechanisms trigger this aberrant adipose tissue growth. Adipocyte progenitor cells (APCs) lose their capacity to differentiate into adipocytes during continuous culture, while APCs from PHTS patients’ lipomas retain their adipogenic potential over a prolonged period. To investigate the role of PTEN in adipose tissue development we performed functional assays and RNA sequencing of control and PTEN knockdown APCs. Reduction of PTEN levels using siRNA or CRISPR lead to an enhanced proliferation and differentiation of APCs. FOXO1 was downregulated on the mRNA level while inactivation through phosphorylation increased. FOXO1 phosphorylation initiates the expression of the lipogenesis activating transcription factor SREBP1. SREBP1 levels were higher after PTEN knockdown and may account for the enhanced adipogenesis. To validate this we overexpressed constitutively active FOXO1 in PTEN CRISPR cells and found reduced adipogenesis, accompanied by a SREBP1 downregulation. We observed that PTEN levels were upregulated during long term culture of wild type APCs. PTEN CRISPR cells showed less senescence compared to controls and the senescence marker CDKN1A (p21) was downregulated in PTEN knockdown cells. Cellular senescence was the most significantly enriched pathway found in RNA sequencing of PTEN knockdown vs. control cells. These results provide evidence that PTEN is involved in the regulation of APCs proliferation, differentiation and senescence, thereby contributing to aberrant adipose tissue growth in PHTS patients.
2020-12-23 | Recent advances in PTEN signalling axes in cancer
In over two decades since the discovery of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), nearly 18,000 publications have attempted to elucidate its functions and roles in normal physiology and disease. The frequent disruption of PTEN in cancer cells was a strong indication that it had critical roles in tumour suppression. Germline PTEN mutations have been identified in patients with heterogeneous tumour syndromic diseases, known as PTEN hamartoma tumour syndrome (PHTS), and in some individuals with autism spectrum disorders (ASD). Today we know that by limiting oncogenic signalling through the phosphoinositide 3-kinase (PI3K) pathway, PTEN governs a number of processes including survival, proliferation, energy metabolism, and cellular architecture. Some of the most exciting recent advances in the understanding of PTEN biology and signalling have revisited its unappreciated roles as a protein phosphatase, identified non-enzymatic scaffold functions, and unravelled its nuclear function. These discoveries are certain to provide a new perspective on its full tumour suppressor potential, and knowledge from this work will lead to new anti-cancer strategies that exploit PTEN biology. In this review, we will highlight some outstanding questions and some of the very latest advances in the understanding of the tumour suppressor PTEN.
2019-06-22 | Analyzing aggregation propensities of clinically relevant PTEN mutants: a new culprit in pathogenesis of cancer and other PTENopathies
While studies on pathological protein aggregation are largely limited to neurodegenerative disease, emerging evidence suggests that other diseases are also associated with pathogenic protein aggregation. For example, tumor suppressor protein p53, and its mutant conformers, undergo protein aggregation, exacerbating the cancer phenotype. These findings raise the possibility that inactivation of tumor suppressors via protein aggregation may participate in cancer and other disease pathologies. Since tumor suppressor protein PTEN has similar functions to p53, and is mutated in multiple diseases, we examined the aggregation propensity of PTEN wild-type and 1523 clinically relevant PTEN mutants. Applying computational tools to PTEN mutation databases revealed that PTEN wild-type protein can aggregate under physiological conditions, and 274 distinct PTEN mutants had increased aggregation propensity. To understand the mechanism underlying PTEN conformer aggregation, we analyzed the physicochemical properties of these 274 PTEN mutants and defined their aggregation potential. We conclude that increased aggregation propensity of select PTEN mutants may contribute to disease phenotypes. Our studies have built the foundation for interrogating the aggregation potential of these select mutants in cancers and in PTENopathies. Elucidating the pathogenic mechanisms associated with aggregation-prone PTEN conformers will aid in developing therapies that target PTEN-aggregates in multiple diseases.Communicated by Ramaswamy H. Sarma
oligonucleotides
2023-08-10 | Small integral membrane protein 10 like 1 downregulation enhances differentiation of adipose progenitor cells.
Small integral membrane protein 10 like 1 (SMIM10L1) was identified by RNA sequencing as the most significantly downregulated gene in Phosphatase and Tensin Homologue (PTEN) knockdown adipose progenitor cells (APCs). PTEN is a tumor suppressor that antagonizes the growth promoting Phosphoinositide 3-kinase (PI3K)/AKT/mechanistic Target of Rapamycin (mTOR) cascade. Diseases caused by germline pathogenic variants in PTEN are summarized as PTEN Hamartoma Tumor Syndrome (PHTS). This overgrowth syndrome is associated with lipoma formation, especially in pediatric patients. The mechanisms underlying this adipose tissue dysfunction remain elusive. We observed that SMIM10L1 downregulation in APCs led to an enhanced adipocyte differentiation in two- and three-dimensional cell culture and increased expression of adipogenesis markers. Furthermore, SMIM10L1 knockdown cells showed a decreased expression of PTEN, pointing to a mutual crosstalk between PTEN and SMIM10L1. In line with these observations, SMIM10L1 knockdown cells showed increased activation of PI3K/AKT/mTOR signaling and concomitantly increased expression of the adipogenic transcription factor SREBP1. We computationally predicted an α-helical structure and membrane association of SMIM10L1. These results support a specific role for SMIM10L1 in regulating adipogenesis, potentially by increasing PI3K/AKT/mTOR signaling, which might be conducive to lipoma formation in pediatric patients with PHTS.
2007-08-20 | Comparative genomic and functional analyses reveal a novel cis-acting PTEN regulatory element as a highly conserved functional E-box motif deleted in Cowden syndrome.
Germline mutations in PTEN, encoding a phosphatase on 10q23, cause Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS). Approximately, 10% of CS-related PTEN mutations occur in the PTEN promoter and 11% of BRRS-related mutations include large deletions, often favoring the gene's 5' end (exon 1, promoter). In order to better understand the mechanism(s) underlying the deregulation of PTEN in these syndromes, it is important that functional cis-regulatory elements be identified. We employed a comparative genomic approach combined with molecular genetic techniques to identify a highly conserved sequence upstream of the PTEN promoter, sharing 80% sequence identity among Homo sapiens, Mus musculus and Rattus norvegicus. Within this region, we identified a canonical E-box sequence (CACGTG) located at position -2181 to -2176, approximately 800 bp upstream of the PTEN core promoter and more than 1.1 kb upstream of its minimal promoter region (located at -958 to -821). In vitro assays suggest that this motif is recognized by members of the basic region-helix-loop-helix-leucine-zipper (bHLH-LZ) transcription factor family, USF1 and USF2, and reporter assays indicate that this novel E-box is involved in mediating PTEN transcriptional activation. Four of 30 CS/CS-like patients, without previously identified PTEN mutations, were found with germline deletions of the E-box element. Of the four, three had deletions stretching to exon 1, but not 3' of it; importantly, one classic CS patient harbored a germline deletion localizing to this E-box region, further affirming the role of this element in PTEN's regulation and deregulation, and its contribution to the pathogenesis of CS.
other
2023-08-01 | Novel anti-PTEN C2 domain monoclonal antibodies to analyse the expression and function of PTEN isoform variants
PTEN is a major tumor suppressor gene frequently mutated in human tumors, and germline PTEN gene mutations are the molecular diagnostic of PTEN Hamartoma Tumor Syndrome (PHTS), a heterogeneous disorder that manifests with multiple hamartomas, cancer predisposition, and neurodevelopmental alterations. A diversity of translational and splicing PTEN isoforms exist, as well as PTEN C-terminal truncated variants generated by disease-associated nonsense mutations. However, most of the available anti-PTEN monoclonal antibodies (mAb) recognize epitopes at the PTEN C-terminal tail, which may introduce a bias in the analysis of the expression of PTEN isoforms and variants. We here describe the generation and precise characterization of anti-PTEN mAb recognizing the PTEN C2-domain, and their use to monitor the expression and function of PTEN isoforms and PTEN missense and nonsense mutations associated to disease. These anti-PTEN C2 domain mAb are suitable to study the pathogenicity of PTEN C-terminal truncations that retain stability and function but have lost the PTEN C-terminal epitopes. The use of well-defined anti-PTEN mAb recognizing distinct PTEN regions, as the ones here described, will help to understand the deleterious effects of specific PTEN mutations in human disease.
2022-08-29 | Phospholipid Scramblase 4 (PLSCR4) Regulates Adipocyte Differentiation via PIP3-Mediated AKT Activation
Phospholipid scramblase 4 (PLSCR4) is a member of a conserved enzyme family with high relevance for the remodeling of phospholipid distribution in the plasma membrane and the regulation of cellular signaling. While PLSCR1 and -3 are involved in the regulation of adipose-tissue expansion, the role of PLSCR4 is so far unknown. PLSCR4 is significantly downregulated in an adipose-progenitor-cell model of deficiency for phosphatase and tensin homolog (PTEN). PTEN acts as a tumor suppressor and antagonist of the growth and survival signaling phosphoinositide 3-kinase (PI3K)/AKT cascade by dephosphorylating phosphatidylinositol-3,4,5-trisphosphate (PIP3). Patients with PTEN germline deletion frequently develop lipomas. The underlying mechanism for this aberrant adipose-tissue growth is incompletely understood. PLSCR4 is most highly expressed in human adipose tissue, compared with other phospholipid scramblases, suggesting a specific role of PLSCR4 in adipose-tissue biology. In cell and mouse models of lipid accumulation, we found PLSCR4 to be downregulated. We observed increased adipogenesis in PLSCR4-knockdown adipose progenitor cells, while PLSCR4 overexpression attenuated lipid accumulation. PLSCR4 knockdown was associated with increased PIP3 levels and the activation of AKT. Our results indicated that PLSCR4 is a regulator of PI3K/AKT signaling and adipogenesis and may play a role in PTEN-associated adipose-tissue overgrowth and lipoma formation.
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