ErbB/HER Signaling

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Search this pathway for protein information from PhosphoSitePlus^®, our expert-curated knowledge base of protein phosphorylation and other post-translational modifications.

Pathway Description:

The ErbB receptor tyrosine kinase family consists of four cell surface receptors: ErbB1/EGFR/HER1, ErbB2/HER2, ErbB3/HER3 and ErbB4/HER4. ErbB receptors are typical cell membrane receptor tyrosine kinases that are activated following ligand binding and receptor dimerization. Ligands can either display receptor specificity (i.e. EGF, TGF-α, AR and Epigen bind EGFR) or bind to one or more related receptors; neuregulins 1-4 bind ErbB3 and ErbB4 while HB-EGF, epiregulin and β-cellulin activate EGFR and ErbB4. ErbB2 lacks a known ligand, but recent structural studies depict a resemblance to a ligand-dependent form of EGFR from Drosophila melanogaster, suggesting ErbB2 is probably also regulated by ligand. ErbB3 has a kinase domain that lacks several key conserved amino acid residues but has recently been shown to possess catalytic activity through trans-autophosphorylation of receptor dimers.

Subsequent autophosphorylation of tyrosine residues leads to an interaction of the activated receptor with SH2 or PTB adaptor proteins to promote downstream signaling. The ErbB receptors are well known mediators of cell proliferation, migration, differentiation, apoptosis, and cell motility. ErbB family members are often over-expressed, amplified or mutated in many forms of cancer, making them important therapeutic targets. Amplification or overexpression of ErbB3 correlates with prostate, bladder, and breast malignancies. The ErbB2/3 dimer is the crucial mediator of ErbB2 signaling in tumors with ErbB2 amplification. While ErbB4 is thought to be antiproliferative in some cancers, recurring activating mutations of ErbB4 have been identified in melanomas. Coactivation of EGFR and other RTKs such as Met has been described in gliomas. In addition to cancer, ErbB4 polymorphisms have been associated with Schizophrenia. Besides functioning as receptors on the cell surface, ErbB family proteins are also present in the nucleus to act as transcriptional regulators. For example, membrane-bound ErbB2 interacts with importin β1 and Nup358 and migrates to the nucleus via endocytic vesicles. Inside the nucleus, ErbB2 modulates the transcription of multiple downstream genes including the cyclooxygenase enzyme (COX-2). In addition, NRG or TPA stimulation promotes ErbB4 cleavage by γ-secretase, releasing an 80 kDa intracellular domain that translocates to the nucleus to induce differentiation or apoptosis. Upon activation and cleavage, ErbB4 can also form a complex with TAB2 and N-CoR to repress gene expression. Activated receptors can be switched “off” through dephosphorylation, receptor ubiquitination, or removal of active receptors from the cell surface through endosomal sorting and lysosomal degradation.

Selected Reviews:

• Baselga J, Swain SM (2009) Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat. Rev. Cancer 9(7), 463–75.
• Citri A, Yarden Y (2006) EGF-ERBB signalling: towards the systems level. Nat. Rev. Mol. Cell Biol. 7(7), 505–16.
• Ferrer-Soler L, Vazquez-Martin A, Brunet J, Menendez JA, De Llorens R, Colomer R (2007) An update of the mechanisms of resistance to EGFR-tyrosine kinase inhibitors in breast cancer: Gefitinib (Iressa) -induced changes in the expression and nucleo-cytoplasmic trafficking of HER-ligands (Review). Int. J. Mol. Med. 20(1), 3–10.
• Hynes NE, Lane HA (2005) ERBB receptors and cancer: the complexity of targeted inhibitors. Nat. Rev. Cancer 5(5), 341–54.
• Moasser MM (2007) The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene 26(45), 6469–87.
• Yarden Y, Shilo BZ (2007) SnapShot: EGFR signaling pathway. Cell 131(5), 1018.

We would like to thank Dr. Jinyan Du, Dana-Farber Cancer Institute, Harvard Medical School, for contributing to this diagram.