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Fig. 1 | Molecular and Cellular Therapies

Fig. 1

From: The PI3K signaling pathway as a pharmacological target in Autism related disorders and Schizophrenia

Fig. 1

PI3K signaling and common mutations related with ASD and schizophrenia. Class I PI3K is activated by growth factors through a tyrosin kinase receptor. The PI3K activation results in the conversion of PtdIns [4, 5]P2 (PIP2) to PtdIns [35]P3 (PIP3), a process that is reversed by the action of PTEN. PIP3 serves as docking for Akt and PDK1. Akt, indirectly, stimulates mTORC1 resulting in an augment of protein synthesis by phosphorylation of the ribosomal kinase p70S6K or 4E-BPs. Phosphorilation of the former releases its binding to eIF4E and enhances translation. The mTOR kinase is encoded by a single gene in mammals, but it is the active enzyme in two multi-protein complexes called mTORC1 and 2. mTORC1 is defined by the Raptor subunit (regulatory-associated protein of mTOR) while mTORC2 by the Rictor (rapamycin-insensitive companion of mTOR). mTORC2 is also activated by growth factors through a not well-defined PI3K-dependent mechanism. mTORC2 contributes to the full activation of Akt by phosphorylation on serine 473 (for a review see [156]). An important kinase downstream of PI3K is GSK3, which is inhibited by direct Akt phosphorylation. Among other functions GSK3 regulates TSC activity and indirectly protein translation. Several signaling pathways dramatically alter PI3K activity. Downstream mGLUR5, fmr1 regulates transcriptional levels of PIKE or the catalytic PI3K subunit p110β. Mutations in the phosphatase PTEN enhance mTOR dependent translation. Mutations on NF1 enhance Ras and p110 catalytic activity. Lack of MecP2 expression reduces BDNF levels that in turn contributes to a general deficit of PI3K signaling. Mutations in the PI3K catalytic subunit p110δ or Akt3 isoform are associated with schizophrenia. Elevated levels of CYT-1 expression, one of the isoforms of the ErbB4 receptor, raised expression of the p110δ subunit and are also connected with schizophrenia

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