RAS signaling and tumorigenesis (spike00028)
RAS signaling pathways originate from growth factor binding to its receptor (for example EGF binding to EGFR - shown the upper left of the map). This binding activates EGFR and primes the autophosphorylation of the cytoplasmic domain of EGFR, and the recruitment of adapter proteins, Grb2 and Sos. Sos is a primary Ras-GEF that will promote GTP loading of RAS and its activation. Activated RAS physically interact and activate RAF, and the signaling cascade continues by sequential phosphorylations (RAF-MEK-ERK). ERK then phosphorylate some transcription factors - (MYC, ETS1 etc. - in the middle-right side of the map). These TFs then acquire DNA binding competency to activate gene transcription to drive proliferation. RAS also activates the PI3K/AKT/mTOR pathway. AKT kinase is a central node in the PI3K signaling and its downstream targets for phosphorylation includes some regulators and effectors of the apoptosis machinery (the p53 inhibitor MDM2, BAD and CASP9, etc). These phosphorylations suppress apoptotic processes (due to lack of space the AKT-dependant activation of the anti-apoptotic NFkB TF is not shown). Rho GTPases are key regulators of actin reorganization, cell motility, cell-cell and cell-extracellular matrix (ECM) adhesion. Deregulation of RHO GTPases signaling (sometimes due to the aberrant expression of RAS and its many effectors (PI3K, RAF, RAL, PRKC, PLC) may promote invasion, migration, and metastasis of the tumor cells. Although the main role of RAS signaling is cells proliferation and anti-apoptotic processes, RAS may also activate cell death through the RASSF family of proteins (ATM-dependant phosphorylation of RASSF1 is needed in this pathway), or by p53 activation via RAF-p38-PRAK-p53 (not shown).
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