| Structural highlights
Disease
[ERBB2_HUMAN] Defects in ERBB2 are a cause of hereditary diffuse gastric cancer (HDGC) [MIM:137215]. A cancer predisposition syndrome with increased susceptibility to diffuse gastric cancer. Diffuse gastric cancer is a malignant disease characterized by poorly differentiated infiltrating lesions resulting in thickening of the stomach. Malignant tumors start in the stomach, can spread to the esophagus or the small intestine, and can extend through the stomach wall to nearby lymph nodes and organs. It also can metastasize to other parts of the body. Defects in ERBB2 are involved in the development of glioma (GLM) [MIM:137800]. Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, and ependymomas. Defects in ERBB2 are a cause of susceptibility to ovarian cancer (OC) [MIM:167000]. Ovarian cancer common malignancy originating from ovarian tissue. Although many histologic types of ovarian neoplasms have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease. Defects in ERBB2 may be a cause of lung cancer (LNCR) [MIM:211980]. LNCR is a common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis. Defects in ERBB2 are a cause of gastric cancer (GASC) [MIM:613659]. A malignant disease which starts in the stomach, can spread to the esophagus or the small intestine, and can extend through the stomach wall to nearby lymph nodes and organs. It also can metastasize to other parts of the body. The term gastric cancer or gastric carcinoma refers to adenocarcinoma of the stomach that accounts for most of all gastric malignant tumors. Two main histologic types are recognized, diffuse type and intestinal type carcinomas. Diffuse tumors are poorly differentiated infiltrating lesions resulting in thickening of the stomach. In contrast, intestinal tumors are usually exophytic, often ulcerating, and associated with intestinal metaplasia of the stomach, most often observed in sporadic disease. Note=Chromosomal aberrations involving ERBB2 may be a cause gastric cancer. Deletions within 17q12 region producing fusion transcripts with CDK12, leading to CDK12-ERBB2 fusion leading to truncated CDK12 protein not in-frame with ERBB2.
Function
[ERBB2_HUMAN] Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding. Essential component of a neuregulin-receptor complex, although neuregulins do not interact with it alone. GP30 is a potential ligand for this receptor. Regulates outgrowth and stabilization of peripheral microtubules (MTs). Upon ERBB2 activation, the MEMO1-RHOA-DIAPH1 signaling pathway elicits the phosphorylation and thus the inhibition of GSK3B at cell membrane. This prevents the phosphorylation of APC and CLASP2, allowing its association with the cell membrane. In turn, membrane-bound APC allows the localization of MACF1 to the cell membrane, which is required for microtubule capture and stabilization.[1] [2] [3] [4] [5] [6] In the nucleus is involved in transcriptional regulation. Associates with the 5'-TCAAATTC-3' sequence in the PTGS2/COX-2 promoter and activates its transcription. Implicated in transcriptional activation of CDKN1A; the function involves STAT3 and SRC. Involved in the transcription of rRNA genes by RNA Pol I and enhances protein synthesis and cell growth.[7] [8] [9] [10] [11] [12]
Publication Abstract from PubMed
Receptor tyrosine kinases of the human epidermal growth factor receptor (HER or ErbB) family transduce biochemical signals across plasma membrane, playing a significant role in vital cellular processes and in various cancers. Inactive HER/ErbB receptors exist in equilibrium between the monomeric and unspecified pre-dimerized states. After ligand binding, the receptors are involved in strong lateral dimerization with proper assembly of their extracellular ligand-binding, single-span transmembrane, and cytoplasmic kinase domains. The dimeric conformation of the HER2 transmembrane domain that is believed to support the cytoplasmic kinase domain configuration corresponding to the receptor active state was previously described in lipid bicelles. Here we used high-resolution NMR spectroscopy in another membrane-mimicking micellar environment and identified an alternative HER2 transmembrane domain dimerization coupled with self-association of membrane-embedded cytoplasmic juxtamembrane region. Such a dimerization mode appears to be capable of effectively inhibiting the receptor kinase activity. This finding refines the molecular mechanism regarding the signal propagation steps from the extracellular to cytoplasmic domains of HER/ErbB receptors.
HER2 Transmembrane Domain Dimerization Coupled with Self-Association of Membrane-Embedded Cytoplasmic Juxtamembrane Regions.,Bragin PE, Mineev KS, Bocharova OV, Volynsky PE, Bocharov EV, Arseniev AS J Mol Biol. 2016 Jan 16;428(1):52-61. doi: 10.1016/j.jmb.2015.11.007. Epub 2015, Nov 14. PMID:26585403[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Olayioye MA, Beuvink I, Horsch K, Daly JM, Hynes NE. ErbB receptor-induced activation of stat transcription factors is mediated by Src tyrosine kinases. J Biol Chem. 1999 Jun 11;274(24):17209-18. PMID:10358079
- ↑ Wang SC, Lien HC, Xia W, Chen IF, Lo HW, Wang Z, Ali-Seyed M, Lee DF, Bartholomeusz G, Ou-Yang F, Giri DK, Hung MC. Binding at and transactivation of the COX-2 promoter by nuclear tyrosine kinase receptor ErbB-2. Cancer Cell. 2004 Sep;6(3):251-61. PMID:15380516 doi:10.1016/j.ccr.2004.07.012
- ↑ Anido J, Scaltriti M, Bech Serra JJ, Santiago Josefat B, Todo FR, Baselga J, Arribas J. Biosynthesis of tumorigenic HER2 C-terminal fragments by alternative initiation of translation. EMBO J. 2006 Jul 12;25(13):3234-44. Epub 2006 Jun 22. PMID:16794579 doi:10.1038/sj.emboj.7601191
- ↑ Hawthorne VS, Huang WC, Neal CL, Tseng LM, Hung MC, Yu D. ErbB2-mediated Src and signal transducer and activator of transcription 3 activation leads to transcriptional up-regulation of p21Cip1 and chemoresistance in breast cancer cells. Mol Cancer Res. 2009 Apr;7(4):592-600. doi: 10.1158/1541-7786.MCR-08-0316. PMID:19372587 doi:10.1158/1541-7786.MCR-08-0316
- ↑ Zaoui K, Benseddik K, Daou P, Salaun D, Badache A. ErbB2 receptor controls microtubule capture by recruiting ACF7 to the plasma membrane of migrating cells. Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18517-22. doi:, 10.1073/pnas.1000975107. Epub 2010 Oct 11. PMID:20937854 doi:10.1073/pnas.1000975107
- ↑ Li LY, Chen H, Hsieh YH, Wang YN, Chu HJ, Chen YH, Chen HY, Chien PJ, Ma HT, Tsai HC, Lai CC, Sher YP, Lien HC, Tsai CH, Hung MC. Nuclear ErbB2 enhances translation and cell growth by activating transcription of ribosomal RNA genes. Cancer Res. 2011 Jun 15;71(12):4269-79. doi: 10.1158/0008-5472.CAN-10-3504. Epub , 2011 May 9. PMID:21555369 doi:10.1158/0008-5472.CAN-10-3504
- ↑ Olayioye MA, Beuvink I, Horsch K, Daly JM, Hynes NE. ErbB receptor-induced activation of stat transcription factors is mediated by Src tyrosine kinases. J Biol Chem. 1999 Jun 11;274(24):17209-18. PMID:10358079
- ↑ Wang SC, Lien HC, Xia W, Chen IF, Lo HW, Wang Z, Ali-Seyed M, Lee DF, Bartholomeusz G, Ou-Yang F, Giri DK, Hung MC. Binding at and transactivation of the COX-2 promoter by nuclear tyrosine kinase receptor ErbB-2. Cancer Cell. 2004 Sep;6(3):251-61. PMID:15380516 doi:10.1016/j.ccr.2004.07.012
- ↑ Anido J, Scaltriti M, Bech Serra JJ, Santiago Josefat B, Todo FR, Baselga J, Arribas J. Biosynthesis of tumorigenic HER2 C-terminal fragments by alternative initiation of translation. EMBO J. 2006 Jul 12;25(13):3234-44. Epub 2006 Jun 22. PMID:16794579 doi:10.1038/sj.emboj.7601191
- ↑ Hawthorne VS, Huang WC, Neal CL, Tseng LM, Hung MC, Yu D. ErbB2-mediated Src and signal transducer and activator of transcription 3 activation leads to transcriptional up-regulation of p21Cip1 and chemoresistance in breast cancer cells. Mol Cancer Res. 2009 Apr;7(4):592-600. doi: 10.1158/1541-7786.MCR-08-0316. PMID:19372587 doi:10.1158/1541-7786.MCR-08-0316
- ↑ Zaoui K, Benseddik K, Daou P, Salaun D, Badache A. ErbB2 receptor controls microtubule capture by recruiting ACF7 to the plasma membrane of migrating cells. Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18517-22. doi:, 10.1073/pnas.1000975107. Epub 2010 Oct 11. PMID:20937854 doi:10.1073/pnas.1000975107
- ↑ Li LY, Chen H, Hsieh YH, Wang YN, Chu HJ, Chen YH, Chen HY, Chien PJ, Ma HT, Tsai HC, Lai CC, Sher YP, Lien HC, Tsai CH, Hung MC. Nuclear ErbB2 enhances translation and cell growth by activating transcription of ribosomal RNA genes. Cancer Res. 2011 Jun 15;71(12):4269-79. doi: 10.1158/0008-5472.CAN-10-3504. Epub , 2011 May 9. PMID:21555369 doi:10.1158/0008-5472.CAN-10-3504
- ↑ Bragin PE, Mineev KS, Bocharova OV, Volynsky PE, Bocharov EV, Arseniev AS. HER2 Transmembrane Domain Dimerization Coupled with Self-Association of Membrane-Embedded Cytoplasmic Juxtamembrane Regions. J Mol Biol. 2016 Jan 16;428(1):52-61. doi: 10.1016/j.jmb.2015.11.007. Epub 2015, Nov 14. PMID:26585403 doi:http://dx.doi.org/10.1016/j.jmb.2015.11.007
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