ERBB3

ERBB3 Full Name

erb-b2 receptor tyrosine kinase 3

ERBB3 Introduction

ERBB3 (erb-b2 receptor tyrosine kinase 3), commonly known as HER3, is a unique member of the epidermal growth factor receptor (EGFR/ERBB) family of transmembrane receptors. Unlike its relatives (EGFR, HER2, and HER4), ERBB3 is characterized as a "kinase-impaired" or "kinase-dead" receptor due to specific amino acid substitutions within its catalytic domain, rendering it nearly incapable of intrinsic autophosphorylation. Consequently, its physiological function is entirely dependent on ligand binding—primarily by Neuregulins (NRGs)—which induces heterodimerization with other kinase-active family members.

Figure 1. ErbB receptors and their ligands. (Source: Iwakura Y, et al. 2013)

ERBB3 is recognized as the preferred and most potent dimerization partner for HER2 (ERBB2). In this partnership, the active kinase of HER2 phosphorylates the cytoplasmic tail of ERBB3. Crucially, the phosphorylated ERBB3 tail functions as a powerful scaffolding protein, containing multiple docking sites specifically for the p85 regulatory subunit of phosphoinositide 3-kinase (PI3K). This unique structural feature makes the HER2-HER3 dimer the most robust activator of the downstream PI3K/AKT survival signaling pathway within the entire ERBB family.

While activating mutations in ERBB3 are relatively rare, the upregulation of HER3 protein and its robust signaling activity are centrally implicated in the pathogenesis of various carcinomas, including breast, lung, ovarian, and colorectal cancers. Its primary clinical significance lies in promoting tumor cell survival and mediating therapeutic resistance. In the context of HER2-amplified breast cancer or EGFR-mutant lung cancer, tumors often upregulate HER3 signaling as a compensatory mechanism to maintain PI3K/AKT pathway activation when the primary oncogenic driver (HER2 or EGFR) is pharmacologically inhibited. Because of this critical role in sustaining tumor survival under stress, ERBB3 has become a major target for the development of novel antibody-drug conjugates (ADCs) and bispecific antibodies in oncology.

Alternate Names for ERBB3

ERBB3; erb-b2 receptor tyrosine kinase 3; HER3; LCCS2; ErbB-3; c-erbB3; erbB3-S; MDA-BF-1; c-erbB-3; p180-ErbB3

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• 1. Iwakura Y, et al. ErbB1-4-dependent EGF/neuregulin signals and their cross talk in the central nervous system: pathological implications in schizophrenia and Parkinson's disease. Front Cell Neurosci. 2013 Feb 13;7:4.
  2. Gala K, et al. Molecular pathways: HER3 targeted therapy. Clin Cancer Res. 2014 Mar 15;20(6):1410-6.