Intracellular signaling pathways of ErbB2/HER-2 and family members

Abstract

ErbB (also termed HER) receptors are expressed in various tissues of epithelial, mesenchymal and neuronal origin, in which they are involved in the control of diverse biological processes such as proliferation, differentiation, migration and apoptosis. Furthermore, their deregulated expression has been implicated in many types of human cancers and is associated with poor clinical prognosis. Owing to the importance of ErbB proteins in both development and cellular transformation, a lot of attention has been drawn to the intracellular signals initiated by the engagement of this family of receptor tyrosine kinases. This review will focus on the membrane proximal events triggered by the ErbB receptor network and will address questions of how receptor heterodimerization may contribute to signal specification and diversification.

Towards Sustained Silencing of HER2/neu in Cancer By Epigenetic Editing

“…Upon ligand binding to the extracellular domain, the Her2/neu receptor heterodimerizes to other members of this family (1). Heterodimerized, activated receptors autophosphorylate specific tyrosine residues of their cytoplasmic tails, thereby triggering signaling pathways, which regulate cell proliferation (2).…”

Coexpression of the type 1 growth factor receptor family members HER‐1, HER‐2, and HER‐3 has a synergistic negative prognostic effect on breast carcinoma survival

“…2 Recently, there has been much interest in the prognostic and treatment implications of the expression by breast tumors of the HER-2 receptor, a member of the type 1 growth factor receptor (T1GFR) family. [3][4][5][6] The T1GFR family consists of 4 known transmembrane receptors: HER-1 (also known as epidermal growth factor receptor and c-erb B-1), HER-2 (c-erb B-2), HER-3 (c-erb B-3), and HER-4 (c-erb B-4). Signaling generated by members of the T1GFR family has evolved in a manner that is tightly controlled.…”

“…HER-2 and HER-3 are only active when they form a heterodimer because HER-2 is a ligandless receptor and HER-3 lacks tyrosine kinase activity. [3][4][5][6] The HER-2/HER-3 heterodimer has been described as the "pinnacle of ErbB receptor evolution" because it represents the development of a very powerful signaling module from a pair of singly inactive individual proteins. 3 At least 30 ligands have been identified that bind T1GFR family members.…”

“…8 Dimerization leads to autophosphorylation of tyrosine residues on the receptor's cytoplasmic domain and activation of signaling pathways involved in cell proliferation, survival, and transformation. [3][4][5][6] The intracellular signaling generated by HER-2-containing heterodimers is the most potent of the entire T1GFR family in terms of cell growth and transformation. 9 Despite HER-2 having no HER-activating ligand, its kinase not only potentiates signaling of HER-2-containing heterodimers, but also increases the binding affinity of ligands to HER-1 and HER-3.…”

“…9 Despite HER-2 having no HER-activating ligand, its kinase not only potentiates signaling of HER-2-containing heterodimers, but also increases the binding affinity of ligands to HER-1 and HER-3. [3][4][5][6] In a transgenic mouse breast carcinoma model, Siegel et al 10 demonstrated that coexpression of HER-2 and HER-3 transcripts leads to tumor progression and the development of distant metastases. Alimandi et al 11 showed evidence for cooperative signaling of HER-2 and HER-3 in neoplastic transformation of human breast carcinoma.…”