RAF/MAP kinase cascade PathwayStep5329 PathwayStep5330 PathwayStep5331 PathwayStep5332 RAS guanyl-nucleotide exchange mediated by SOS1 in complex with GRB2 and p-SHC1:Phosphorylated ERBB2 heterodimers SHC1 phosphorylation by ERBB2 heterodimers Recruitment of GRB2:SOS1 to p-SHC1 in complex with phosphorylated ERBB2 heterodimers SHC1 binds phosphorylated ERBB2 heterodimers SHC1 events in ERBB2 signaling All ERBB2 heterodimers, ERBB2:EGFR, ERBB2:ERBB3 and ERBB2:ERBB4, are able to activate RAF/MAP kinase cascade by recruiting SHC1 (Pinkas-Kramarski et al. 1996, Sepp-Lorenzino et al. 1996) to phosphorylated C-tail tyrosine residues in either EGFR (Y1148 and Y1173), ERBB2 (Y1196, Y1221, Y1222 and Y1248), ERBB3 (Y1328) or ERBB4 (Y1188 and Y1242 in JM-A CYT1 isoform, Y1178 and Y1232 in JM-B CYT1 isoform, Y1172 and Y1226 in JM-A CYT2 isoform). SHC1 recruitment is followed by phosphorylation (Segatto et al. 1993, Soler et al. 1994), and the phosphorylated SHC1 recruits GRB2:SOS1 complex (Xie et al. 1995), which leads to SOS1-mediated guanyl-nucleotide exchange on RAS (Xie et al. 1995) and downstream activation of RAF and MAP kinases. Authored: Orlic-Milacic, M, 2011-11-04 Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Reactome Database ID Release 431250196 Reactome, http://www.reactome.org ReactomeREACT_115993 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 PathwayStep3857