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Amin DN, Campbell MR, Moasser MM.. The role of HER3, the unpretentious member of the HER family, in cancer biology and cancer therapeutics. Semin Cell Dev Biol 21: 944-950

University of California, San Francisco, Medicine, San Francisco, CA 94143-1387, USA.
Seminars in Cell and Developmental Biology (Impact Factor: 5.97). 12/2010; 21(9):944-50. DOI: 10.1016/j.semcdb.2010.08.007
Source: PubMed

ABSTRACT Many types of human cancer are characterized by deregulation of the human epidermal growth factor receptor (HER) family of tyrosine kinase receptors. In some cancers, genomic events causing overactivity of individual HER family members are etiologically linked with the pathogenesis of these cancers, and constitute the driving signaling function underlying their tumorigenic behavior. HER3 stands out among this family as the only member lacking catalytic kinase function. Cancers with driving HER3 amplifications or mutations have not been found, and studies of its expression in tumors have been only weakly provocative. However, substantial evidence, predominantly from experimental models, now suggest that its non-catalytic functions are critically important in many cancers driven by its' HER family partners. Furthermore, new insights into the mechanism of activation in the HER family has provided clear evidence of functionality in the HER3 kinase domain. The convergence of structural, mechanistic, and experimental evidence highlighting HER3 functions that may be critical in tumorigenesis have now led to renewed efforts towards identification of cancers or subtypes of cancers wherein HER3 function may be important in tumor progression or drug resistance. It appears now that its failure to earn the traditional definition of an oncogene has allowed the tumor promoting functions of HER3 to elude the effects of cancer therapeutics. But experimental science has now unmasked the unpretentious role of HER3 in cancer biology, and the next generation of cancer therapies will undoubtedly perform much better because of it.

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    • "Although the precise role of ERBB4 in oncogenesis is not well established (Koutras et al., 2010), transforming somatic mutations in ERBB4 have been reported in melanoma (Prickett et al., 2009). Recently, ERBB3 has emerged as a potential cancer therapeutic target, given that it plays an important role in ERBB2 signaling and acquired resistance to existing therapeutics (Amin et al., 2010; Baselga and Swain, 2009). While ERBB3 amplification and/or overexpression is known in some cancers, only sporadic occurrence of ERBB3 somatic mutations has been reported (Ding et al., 2008; Greenman et al., 2007; Jeong et al., 2006; Kan et al., 2010; Stransky et al., 2011; TCGA, 2008, 2011). "
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    ABSTRACT: The human epidermal growth factor receptor (HER) family of tyrosine kinases is deregulated in multiple cancers either through amplification, overexpression, or mutation. ERBB3/HER3, the only member with an impaired kinase domain, although amplified or overexpressed in some cancers, has not been reported to carry oncogenic mutations. Here, we report the identification of ERBB3 somatic mutations in ∼11% of colon and gastric cancers. We found that the ERBB3 mutants transformed colonic and breast epithelial cells in a ligand-independent manner. However, the mutant ERBB3 oncogenic activity was dependent on kinase-active ERBB2. Furthermore, we found that anti-ERBB antibodies and small molecule inhibitors effectively blocked mutant ERBB3-mediated oncogenic signaling and disease progression in vivo.
    Cancer cell 05/2013; 23(5):603-17. DOI:10.1016/j.ccr.2013.04.012 · 23.89 Impact Factor
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    • "HER3 is different from EGFR, HER2 and HER4 in that it lacks intrinsic kinase activity and has not been reported to form homodimers on cell surface (Sierke et al., 1997; Berger et al., 2004). Since the catalytically inactive kinase domain of HER3 is not capable of activating the kinase domain of its partnering receptors, HER3 is suggested to have evolved as a dedicated and specialized activating receptor in the EGFR family (Jura et al., 2009a; Amin et al., 2010a). Despite the significant role that HER3 plays in cell signaling and cancer development, our understanding of the HER3 biology remains limited. "
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    ABSTRACT: Dimerization among the EGFR family of tyrosine kinase receptors leads to allosteric activation of the kinase domains of the partners. Unlike other members in the family, the kinase domain of HER3 lacks key amino acid residues for catalytic activity. As a result, HER3 is suggested to serve as an allosteric activator of other EGFR family members which include EGFR, HER2 and HER4. To study the role of intracellular domains in HER3 dimerization and activation of downstream signaling pathways, we constructed HER3/HER2 chimeric receptors by replacing the HER3 kinase domain (HER3-2-3) or both the kinase domain and the C-terminal tail (HER3-2-2) with the HER2 counterparts and expressed the chimeric receptors in Chinese hamster ovary (CHO) cells. While over expression of the intact human HER3 transformed CHO cells with oncogenic properties such as AKT/ERK activation and increased proliferation and migration, CHO cells expressing the HER3-2-3 chimeric receptor showed significantly reduced HER3/HER2 dimerization and decreased phosphorylation of both AKT and ERK1/2 in the presence of neuregulin-1 (NRG-1). In contrast, CHO cells expressing the HER3-2-2 chimeric receptor resulted in a total loss of downstream AKT activation in response to NRG-1, but maintained partial activation of ERK1/2. The results demonstrate that the intracellular domains play a crucial role in HER3's function as an allosteric activator and its role in downstream signaling.
    Protein & Cell 09/2012; 3(10):781-9. DOI:10.1007/s13238-012-2065-y · 2.85 Impact Factor
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    Quantum Electronics Conference, 1996. EQEC '96., 1996 European; 10/1996
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