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  • br Introduction br Phosphatase and


    Phosphatase and tensin homolog deleted on chromosome ten (PTEN [MIM: 601728]) is a multi-functional tumor-suppressor gene found to be mutated in the germline of in-dividuals with Cowden syndrome (CS [MIM: 158350]) and related cancer-predisposition syndromes or somatically in a diverse range of solid tumors.1–3 Individuals, regardless of clinical presentation, with germline PTEN mutations are molecularly diagnosed with PTEN hamartoma tumor syndrome (PHTS). PHTS is typically an autosomal-domi-nant disorder variably characterized by macrocephaly, hamartomatous overgrowths, and malignant neoplasia, especially of the breast and thyroid.4–6 The phenotypically diverse clinical manifestations encompassed by PHTS often share overlapping clinical features but have great variability, making clinical outcomes difficult to predict. Paradoxically, approximately one-fifth of PHTS-affected in-dividuals also present with autism spectrum disorder (ASD), raising an intriguing question about how two seem-ingly disparate clinical outcomes can result from germline mutations in one gene when there are no obvious geno-type-phenotype associations.5,7 Current clinical manage-ment guidelines assign enhanced clinical surveillance for component cancers in all individuals with PHTS and a low threshold to evaluate for ASD in children. It would enhance precision practice if clinicians could predict ahead 
    of time which PHTS-affected individual would develop ASD only, cancer only, or both.
    PTEN functions as a dual-specificity phosphatase that an-tagonizes both the PI3K/AKT/mTOR signaling pathway8–10 and the mitogen-activated protein kinase (MAPK) path-way.11 The critical ability of PTEN to catalyze the dephos-phorylation of phosphatidylinositol (3,4,5)-triphosphate (PIP3) restrains pro-growth, pro-survival, and pro-prolifera-tion signaling, guarding against tumorigenesis.10,12–14 The regulation of the enzymatic activity and functional PSB 1115 of PTEN is complex and involves multiple cellular processes and interactions with other proteins. Hence,
    deficiency of any of these functions contributes to dis-ease.15–17 In fact, PTEN structure-function analyses reveal distinctive functional patterns that correlate with variants found in the catalytic active site. For example, there are variants (e.g., p.Gly129Glu) that specifically disrupt the lipid phosphatase activity while leaving the protein phosphatase activity intact and vice versa (p.Tyr138Leu, for example). Additionally, there are variants (e.g., p.Cys124Ser) that completely disrupt the phosphatase core motif, leaving a lipid- and protein-phosphatase-dead protein; this is a mechanism by which PTEN is inactivated in tumors.13,18–20 Furthermore, these variants result in specific alterations (i.e., expanding or contracting its depth) within the catalytic pocket, and they affect substrate preference.21
    1Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; 2Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA; 3Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleve- land, OH 44106, USA; 4Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA; 5Department of Genetics and Genome Sciences, Case West-
    ern Reserve University School of Medicine, Cleveland, OH 44106, USA
    *Correspondence: [email protected]
    In a recent pilot study, we sought to identify differences in ASD- versus cancer-associated germline PTEN missense variants in silico by investigating putative structural and conformational dynamics.22 Five of six ASD-associated variants showed localized destabilization, contributing to the partial opening of the active site, whereas all six cancer-associated variants showed long-range perturba-tions that decreased structural stability and increased dynamics across the domain interface, mediating a closed active site.22 Most notable was the identification of an inter-domain disruption with an increase in dynamics across the phosphatase-C2 domain interface in PTEN, and this disruption was observed in both the c.388C>G (p.Arg130Gly) (cancer only) and c.517C>T (p.Arg173Cys) (shared in individuals with both ASD and cancer) muta-tions, indicating both residue positions play a role in in-ter-residue signal propagation and are crucial to structural stability.22,23 These results provide evidence to support the recent identification of pivotal mutational-sites that might serve as key mediating bridges of allosteric commu-nication in PTEN.24 Allosteric propagation results in communication between distinct sites in the protein structure and takes place through dynamic shifts of conformational ensembles.25 The quantitation of key factors that govern structural communication is essential in order to assess signal propagation for predicting the effects of mutations.25 Thus, our pilot observations encouraged further investigation in order to profile conformational changes that mediate long-range effects and allosteric signal propagation and thus reveal separate molecular features contributing specifically to ASD or cancer. Despite the specific nature of PTEN’s functional dynamics, mutation-induced conformational changes that are associated with ASD or cancer and that govern potential allosteric signaling pathways and structural-communication propagation have yet to be investigated at an atomistic level. It is, therefore, essential to determine how ASD- and cancer-associated variants that disrupt PTEN’s long-range communication and inter-domain dy-namics give rise to a potential mutation-driven allosteric interface.