Meta-Biol

• Pathways

E2 treatment stimulates phosphorylation of MAPK3 and MAPK1 (also known as ERK1 and ERK2) downstream of GPER1 in a SRC- and G-protein beta gamma complex-dependent manner (Filardo et al, 2000; Quin et al, 2009). ERK phosphorylation through this pathway is mediated by SRC-dependent phosphorylation of the SHC adaptor protein, consistent with G beta gamma signaling in other pathways (Filardo et al, 2000; Quinn et al, 2009; Touhara et al, 1995; van Biesen et al, 1995; Luttrell et al, 1996; reviewed in Filardo and Thomas, 2012). Estrogen-dependent signaling through the G beta gamma -SRC -SHC module establishes crosstalk with integrin alpha5beta2 pathway and ultimately cross-talks with EGFR signaling, activating MAPK phosphorylation (reviewed in Filardo and Thomas, 2012; Prossnitz and Barton, 2014; Gaudet et al, 2015; Filardo et al, 2018). The mechanisms by which SRC and G beta gamma impinge on SHC phosphorylation are not fully elucidated, and direct phosphorylation of SHC by SRC has not been demonstrated in this pathway.