Figure 2

Tyr 845 is located in the catalytic domain of HER1 in a highly conserved subdomain that has functional homologs in other tyrosine kinases. Tyr 845 resides in the activation loop of the HER1 tyrosine kinase catalytic domain (upper panel), a region that shares a high degree of homology among all tyrosine kinases (lower panel). Upon ligand-binding to the EGF receptor (EGFR), the activation loop containing phosphorylated Tyr 845 is modeled (upper panel [63]) to flip into a configuration that promotes access to ATP and substrate, as is the case with phosphorylation of the analogous tyrosines within other tyrosine kinases. Mutation of sites in other tyrosine kinases that are analogous to Tyr 845 renders the molecules catalytically inactive and abrogates downstream biologic signaling. Similar effects of mutagenizing Tyr 845 have been observed [24*,32**]. A unique characteristic of Tyr 845 appears to be that its phosphorylation is mediated by c-Src, whereas homologs in other receptor tyrosine kinases are phosphorylated by the receptors themselves. The phosphorylation of Tyr 845 by c-Src is proposed to facilitate cross-talk between HER1 and signaling pathways activated by other cellular receptors, such as G-protein-coupled receptors and estrogen receptor.