Phospho-HER2/ErbB2 (Tyr1221/1222) Blocking Peptide

The ErbB2 (HER2) proto-oncogene encodes a 185 kDa transmembrane, receptor-like glycoprotein with intrinsic tyrosine kinase activity (1). While ErbB2 lacks an identified ligand, ErbB2 kinase activity can be activated in the absence of a ligand when overexpressed and through heteromeric associations with other ErbB family members (2). Amplification of the ErbB2 gene and overexpression of its product are detected in almost 40% of human breast cancers (3). Binding of the c-Cbl ubiquitin ligase to ErbB2 at Tyr1112 leads to ErbB2 poly-ubiquitination and enhances degradation of this kinase (4). ErbB2 is a key therapeutic target in the treatment of breast cancer and other carcinomas and targeting the regulation of ErbB2 degradation by the c-Cbl-regulated proteolytic pathway is one potential therapeutic strategy. Phosphorylation of the kinase domain residue Tyr877 of ErbB2 (homologous to Tyr416 of pp60c-Src) may be involved in regulating ErbB2 biological activity. The major autophosphorylation sites in ErbB2 are Tyr1248 and Tyr1221/1222; phosphorylation of these sites couples ErbB2 to the Ras-Raf-MAP kinase signal transduction pathway (1,5). 1.Muthuswamy, S.K. et al. (1999) Mol Cell Biol 19, 6845-57. 2.Qian, X. et al. (1994) Proc Natl Acad Sci USA 91, 1500-4. 3.Dittadi, R. and Gion, M. (2000) J Natl Cancer Inst 92, 1443-4. 4.Klapper, L.N. et al. (2000) Cancer Res 60, 3384-8. 5.Kwon, Y.K. et al. (1997) J Neurosci 17, 8293-9.