• Linkage between Dysregulation of Secretion and Autism Spectrum Disorders

    We have begun examining the role of the protein-lipid phosphatase PTEN in secretion. Mutations in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) have been shown to be important players in many cancer types. Over the last few years, it has been shown that PTEN plays an essential role in regulating signaling pathways involved in cell growth, migration and apoptosis, and mutations in the PTEN gene have been associated with macrocephaly and autism spectrum disorders (ASDs). PTEN is known to mediate its effects through at least two catalytic activities; its protein tyrosine phosphatase activity, and its lipid phosphatase activity, which catalyzes the removal of phosphates from the D3 position of phosphatidyl inositol-3, 4, 5-trisphosphate. These activities are supported by two distinct localizations of PTEN, seen within the same cell; a portion of PTEN is localized to the nucleus, where its signaling is independent of its lipid phosphatase action while the remainder is diffusely distributed in the cytoplasm. PTEN is the major negative regulator of the PI3K pathway, through dephosphorylation of PIP3. In its central role regulating levels of PIP3 and PIP2 in the membrane, it will also influence cellular processes in addition to proliferation. Calcium-triggered exocytosis is closely tied to PIP2 levels in the plasma membrane, and this is thought to be related to its role in promoting membrane fusion during the exocytic reaction. Consistent with this, we have found that over-expression of wild-type PTEN causes a down-regulation of secretion. We are in the process of examining the impact of ASD-linked mutations in PTEN on secretion in our system.