Ras signaling pathway

A wide variety of cell surface receptors activate Ras GTPase, including the tyrosine receptor linked to the epidermal growth factor receptor (EGFR) (Wells 1999). Upon receptor stimulation, son of sevenless (SOS) stimulates Ras to change from GDP to GTP resulting in Ras activation (Geyer and Wittinghofer 1997).

Ras GTPase

Ras GTPase shuttles between inactive GDP-bound and active GTP-bound conformation (Colicelli 2004). The best characterised isoforms of Ras GTPase are K-Ras, H-Ras and N-Ras, which are demonstrated to be mutated in 30% of human tumours (Repasky et al. 2004). Activated Ras phosphorylates and activates the Ser/Thr kinase Raf. The three isoforms of Raf are B-Raf, Raf-1 and A-Raf and these are activated by phosphorylation and protein-protein interactions (Wellbrock et al. 2004).

B-Raf Mutation & phosphorylation

The B-Raf gene is mutated in many cancers and is associated mainly with melanoma as well as with thyroid, colon and ovarian cancer (Garnett and Marais 2004). Raf phosphorylates MEK at two specific serine residues (Ser 217 and Ser 221) located at the MEK activation loop, leading to its activation. MEK is a dual specificity kinase and its only known substrate is extracellular signal-regulated kinase (ERK).

ERK1/2 activation

ERK1/2 is activated by MEK via the phosphorylation of threonine and tyrosine residues (Thr183 and Tyr 185) in the activation loop (Kolch 2005). ERK has been identified to regulate up to 70 substrates, including cytoskeleton protein, nuclear transcription factors, signalling proteins and receptors (Roux and Blenis 2004).

The MST2 pathway

The MST2 pathway is negatively regulated by the MAPK pathway. Raf-1 inhibits the pro-apoptotic response to RASSF1A and MST2 dependent apoptosis via the binding of MST2-Raf-1 complex which inhibits MST2 kinases activity (Matallanas et al. 2007, O’Neill et al. 2004). In addition, the constitutively active K-Ras activates MST2/LATS1 mediated cell death in colon cancer cells (Matallanas et al. 2011). Finally, LATS1 was identified to phosphorylate the Ser259 site of Raf-1 that inhibits its activation, and MST2 competes with MEK for binding to Raf-1 (Romano et al. 2014).

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