Role of ERBB2 in Signal Transduction and Oncology

Her2 or ERBB2 belongs to a class of proteins having high homology with epidermal growth factor receptor (EGFR or ERBB1). It encodes a protein with the molecular weight of 185 KDa. Unlike other members of EGFR family, no ligand for Her2 has been found and it usually associates with members of ERBB1 family to form functional heterodimers. It has been shown that it can form dimers with ERBB (EGFR), ERBB3 and ERBB4 as well as gp130 subunits of IL-6 receptor. In at least some cell types, the association between gp130 and HRBB2 is essential for HRBB2-ERBB3 phosphorylation and subsequent MAP kinase signaling. Although ERBB1 can form homodimers, the signaling for ERBB1 is usually transient and the receptor undergoes internalization after ligand binding and activation. EGFR-HER2 complex increases the signaling capacity of EGFR by increasing the ligand affinity as well as the recycling of the heterodimer. Of all the ERBB heterodimers, ERBB2-ERBB3 heterodimers perhaps elicit the strongest signal. Removing ERBB3 from the cell has a drastic effect on ERBB2 mediated signaling and downstream effectors. The clinical importance of HER2 cannot be overstated. In addition, monoclonal antibody (Herceptin) against this receptor has been shown to be an effective treatment of breast cancer patients who have a high level of HER2 over expression.

Contributor: Yen-Liang Chen, PhD

REFERENCES: Arteaga CL. Overview of epidermal growth factor receptor biology and its role as a therapeutic target in human neoplasia. Semin Oncol. 2002 Oct; 29(5 Suppl 14):3-9. Badache A, Hynes NE . Interleukin 6 inhibits proliferation and, in cooperation with an epidermal growth factor receptor autocrine loop, increases migration of T47D breast cancer cells. Cancer Res. 2001 Jan 1;61(1):383-91. Holbro T et al. The ErbB receptors and their role in cancer progression. Exp Cell Res. 2003 Mar 10;284(1):99-110. Holbro T et al. The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8933-8. Janda E et al. Oncogenic Ras/Her-2 mediate hyperproliferation of polarized epithelial cells in 3D cultures and rapid tumor growth via the PI3K pathway. Oncogene. 2002 Aug 1;21(33):5148-59. Johnston S et al. Integration of signal transduction inhibitors with endocrine therapy: an approach to overcoming hormone resistance in breast cancer. Clin Cancer Res. 2003 Jan; 9(1 pt 2):524S-32S. Lindberg LE et al. c-erbB2-induced disruption of matrix adhesion and morphogenesis reveals a novel role for protein kinase B as a negative regulator of alpha(2)beta(1) integrin function. Mol Biol Cell. 2002 Aug; 13(8):2894-908. Qiu Y et al. Requirement of ErbB2 for signalling by interleukin-6 in prostate carcinoma cells. Nature. 1998 May 7;393(6680):83-5. Vadlamudi RK et al. Heregulin and HER2 signaling selectively activates c-Src phosphorylation at tyrosine 215. FEBS Lett. 2003 May 22;543(1-3):76-80. Vijapurkar U et al. Roles of mitogen-activated protein kinase and phosphoinositide 3'-kinase in ErbB2/ErbB3 coreceptor-mediated heregulin signaling. Exp Cell Res. 2003 Apr 1;284(2):291-302.