Structural mutation analysis of PTEN and its possible genotype-phenotype correlat

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DESCRIPTION (provided by applicant): Structural mutation analysis of PTEN and its possible genotype-phenotype correlations in Endometriosis and Cancer The phosphatase and tensin homolog deleted on chromosome ten (PTEN) gene encodes a tumor suppressor phosphatase frequently mutated in a variety of human cancers. It exerts its function by dephosphorylating phosphatidylinositol 3,4,5-triphosphate (PIP3), converting it to phosphatidylinositol 4,5-bisphosphate (PIP2). PIP3 activates a variety of downstream effectors that turn on the PI3K/Akt oncogenic pathway leading to unregulated cell proliferation and tumorigenesis. Loss of function and somatic missense mutations of PTEN have recently been found in patients with endometriosis, endometrial cancer and ovarian cancer although no structural information on these mutations is currently available. Through the cross-referencing of published literature, the phenotypes of distinct PTEN mutations affecting the signature motif of the catalytic phosphatase domain and C2 domain were identified. Among these mutations, moderate phenotypes were associated with endometriosis and endometrial hyperplasia and are distributed throughout both domains. Whereas the more severe phenotypes were associated with endometrial cancer and ovarian cancer and are clustered in the signature motif (H123CXXGXXR130) that forms the P loop at the bottom of the active site pocket. The signature motif contains residues that play a crucial role in loop conformation (H123 and G127) and are essential for catalysis (C124 and R130). One distinct residue within the active site R130, has mutations implicated in both moderate and severe phenotypes. In this proposed study, we will explore the structural effects that the identified PTEN mutations have on the relationship between genotype and phenotype, and investigate the specific molecular mechanisms involved. Molecular dynamics simulations wil be used to examine the clustered mutations to characterize their effects on P loop conformations and the functional distortions they may impose within the active site as well as mutations within the C2 domain that may affect PTEN's ability to interact with the membrane. We propose mutations within the active site disrupt the electrostatic interaction thus affecting P loop conformation. Loop flexibility imposed by these missense mutations may affect the binding of PTEN to its ligand and adversely affect the PI3K/Akt signaling pathway. Understanding the functional impact that these missense mutations have on the structure of PTEN is essential to elucidating the molecular mechanism of endometriosis, endometrial cancer and ovarian cancer in the development of novel therapeutics.