ErbB/HER Signaling

• Description
• Reviews
• Pathway Key
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Pathway Description:

The ErbB receptor tyrosine kinase family consists of four cell surface receptors: ErbB1/EGFR/HER1, ErbB2/HER2, ErbB3/HER3 and ErbB4/HER4. ErbB2 is distinguished from the other receptors in lacking a known ligand, while ErbB3 lacks a functional kinase domain. All ErbB receptors are typical cell membrane receptor tyrosine kinases that are activated following ligand binding, and transmit growth factor activation signals to multiple downstream signaling pathways. Ligands can either display receptor specificity (i.e. EGF, TGF-α, AR and Epigen bind ErbB1) or bind to one or more related receptors; neuregulins 1-4 bind ErbB3 and ErbB4 while HB-EGF, epiregulin and β-cellulin activate ErbB1 and ErbB4. In general, ligand binding induces ErbB dimer formation and receptor activation. For example, EGF induces the formation of an ErbB1 asymmetric dimer where one ErbB1 kinase domain activates its partner via an allosteric mechanism. Subsequent autophosphorylation of tyrosine residues leads to an interaction of the activated receptor with SH2 or PTB adaptor proteins to promote the downstream signaling. Other receptors, including the insulin-like growth factor receptor, the interferon-α receptor, and the N-methyl-D-aspartate receptor interact with ErbB receptors to integrate signals across distinct pathways. Coactivation of EGFR and other RTKs such as MET has been described in gliomas. This reduces dependence on any single RTK and renders tumor cells refractory to RTK inhibitor monotherapy. The ErbB receptors are well known mediators of cell proliferation, migration, differentiation and apoptosis; interaction between activated receptors and proteins such as MUC1 and β-catenin affects cell adhesion and motility. ErbB1 and ErbB2 are often over-expressed, amplified or mutated in cancers, making them important therapeutic targets. Amplification or overexpression of ErbB3 correlates with prostate, bladder and breast malignancies, while ErbB4 polymorphisms have been associated with Schizophrenia. Interaction between ErbB1 and Stat3 transactivates inducible nitric oxide synthase (iNOS) expression within the nucleus. 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). Either 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. In addition, NRG1/ERBB4 signaling regulates transmission at brain glutamate and GABA synapses.

Selected Reviews:

• Citri A, Yarden Y (2006) EGF-ERBB signalling: towards the systems level. Nat. Rev. Mol. Cell Biol. 7(7), 505–16.
• 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.
• 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.

CST would like to thank Prof. Yosef Yarden, The Weizmann Institute of Science, Rehovot, Israel and Dr. Jinyan Du, DanaFarber Cancer Institute, Harvard Medical School, for contributing to the ErbB/HER Signaling diagram.