| (a) The autophosphorylated insulin receptor binds a scaffold protein, insulin receptor substrate (IRS)-1, which is phosphorylated by the receptor at several tyrosine residues that lie in YXXM motifs. These bind the SH2 domains of the p85 subunit of PI3K, stimulating the activity of the p110 catalytic subunit of PI3K, which phosphorylates the inositol head group of the phospholipid PI(4,5)P2 to yield PI(3,4,5)P3. The generation of PI(3,4,5)P3 creates binding sites at the plasma membrane for proteins with PH domains, notably the PKB/Akt serine/threonine protein kinase, leading to changes in cell growth and survival. (b) The activated EGF receptor forms multiple pYXN motifs, both within its own autophosphrylated carboxy-terminal tail and in the associated scaffold protein Shc, and these bind the SH2 domain of Grb2. This selective interaction is due to a bulky tryptophan residue in the specificity pocket of the Grb2 SH2 domain that forces the bound phosphopeptide into a beta turn, which is accommodated by an asparagine at the +2 position. The Grb2 SH2 domain is flanked by two SH3 domains, which associate with proline-rich motifs in Sos, a guanine nucleotide exchange factor that activates the Ras GTPase and its downstream targets such as the Erk MAP kinase pathway. |
