Ras gtp can bind and activate the catalytic subunit

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Unformatted text preview: can bind and activate the catalytic subunit of this enzyme that generates PI(3,4,5)P3 (phosphatidylinositol tri-phosphate) by phosphorylating PI(4,5)P2 in the 3-position. PI(3,4,5)P3 acts directly as a second messenger, binding several cytoskeleton kinase proteins and modulating their activity by conformational changes and/or membrane translocation. PI3K class I is consisted of a 110 kDa catalytic subunit and an 85 kDa regulatory subunit and are activated by RAS or by RTKs. The p110 catalytic subunit contains the RBD (RAS binding domain), to which RAS-GTP binds. The catalytic subunit also contains a p85 binding domain and the kinase domain. A major downstream target of PI3K is the serine/threonine kinase AKT (also called PKB). In mammals, three different isoforms of AKT (AKT1, 2, 3) have been described. This protein regulates extracellular growth signals using the lipid phosphatidylinositol phosphate (PIP3) as an intracellular second messenger. In the presence of growth factor signaling, the intracellular level of PIP3 rises, leading to phosphorylation of AKT, which is known to promote cell cycle progression and inhibit apoptosis. PTEN, is a negative regulator of the PI3K-AKT pathway (21). PTEN regulates PIP3 levels, and its inactivation results in accumulation of PIP3, AKT hyperphosphorylation, and enhanced cell survival and proliferation (22). The PI3K-AKT pathway is often hyperactive in melanoma. In addition, elevated phospho-AKT levels appear to correlate adversely with patient survival (21) (Figure 2). RAS-RAL signaling Another class of RAS effectors is the GEF family (RalGDS) that serve as activators of the RAL small monomeric GTPases. RAL seems to interact with Cdc42 and RACGAP. Rho, RAC, and Cdc42 constitute another family of monomeric G proteins that play an important role in cytoskeleton remodeling and activate kinases regulating the activity of various transcriptional factors. The signaling activity of RAS GTPases occurs not only through engagement of direct effectors, but also by the recruitment of 11 other GTPases, especially other members of the RAS subfamily (e.g. Rap) and...
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This document was uploaded on 03/06/2014.

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