Adaptor Proteins in the Akt Pathway

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Adaptor Proteins in the Akt Pathway

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Adaptor Proteins in the Akt Pathway Background

Signal transducing adaptor proteins are important proteins in the signal transduction pathway. The adaptor protein has various domains that bind to other proteins and can form various signal complexes. These proteins often lack the activity of enzymes themselves, but instead form a protein complex by specific protein-protein interactions to activate downstream signaling pathways. Common linker proteins are MyD88, Grb10, and SHC1.

The Grb10 superfamily of adaptor proteins consists so far of four members: Grb7, Grb10, Grb14, and Mig-10. Structural common features of this family are an N-terminal proline-rich putative SH3 domain binding region, pleckstrin homology (PH) domain, a BPS domain, and (exept for Mig-10) a C-terminal SH2 domain. Grb10 (mGrb10α) was originally identified as a binding partner of the epidermal growth factor receptor (EGFR) and of the Ret receptor tyrosine kinase.

Grb10 has been suggested as a downstream target in the phosphatidylinositol 3-kinase (PI3-K) signaling pathway. Although no direct effect of Grb10 on PI3-K or protein kinase B (PKB)/Akt has been observed, overexpression of a Grb10 isoform (hGrb10zeta) has been reported to negatively influence the insulin-stimulated activity of glycogen synthase in primary rat hepatocytes, which normally is regulated by PI-3K/Akt. So far, three human isoforms of Akt have been found, PKBα/Akt1, PKBα/Akt2, and PKBα/Akt3, which are expressed differentially at both the mRNA and protein levels. Akt family proteins consist of a central kinase domain with specificity for serine or threonine residues in substrate proteins. Activation of Akt is regulated primarily in a PI3-K-dependent manner and involves direct binding of PI3-K-generated phospholipids to the Akt PH domain and Akt translocation to the cell membrane, where the close proximity to other regulatory kinases leads to phosphorylation and activation of Akt. Activated Akt then de-taches from the plasma membrane and translocates to mitochondria and the nucleus, where it is thought to phosphorylate its substrates. Substrates of Akt containing the consensus site RXRXX(S/T) include Bad, caspase-9, and transcription factors of the forkhead family. These findings have provided important insights into the mechanism of Akt-mediated survival. In addition, a recent report links Akt-mediated P21Cip1/WAF1 phosphorylation in Her2/neuoverexpressing breast cancers to the deregulation of cell proliferation in cancer cells. A novel negative regulator at the plasma membrane, CTMP, has also recently been identified. Akt activity is induced by a variety of ligand-activated receptor tyrosine kinases including EGF-R, PDGF-R, and c-kit. The mechanism in c-kit-induced Akt activity involves association of the p85 subunit of PI3-K with c-kit and the subsequent activation of PI3-K, leading to activation of Akt. Tyrosine 719 in its phosphorylated state within the c-kit cytoplasmic tail is the critical residue in mediating the interaction with the C-terminal SH2 domain of p85. The crucial role of the PI3-K/Akt signaling pathway in c-kit-mediated signaling has become evident in knock-in mice expressing the c-kitY719F mutation encoding defects in spermatogenesis and oogenesis.


1. Liang Y.; et al. Role for the Adaptor Protein Grb10 in the Activation of Akt. Molecular and Cellular Biology, 2002, 979-991.

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