| Structural highlights
Function
[ERBB4_HUMAN] Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell proliferation, differentiation, migration and apoptosis. Required for normal cardiac muscle differentiation during embryonic development, and for postnatal cardiomyocyte proliferation. Required for normal development of the embryonic central nervous system, especially for normal neural crest cell migration and normal axon guidance. Required for mammary gland differentiation, induction of milk proteins and lactation. Acts as cell-surface receptor for the neuregulins NRG1, NRG2, NRG3 and NRG4 and the EGF family members BTC, EREG and HBEGF. Ligand binding triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Ligand specificity and signaling is modulated by alternative splicing, proteolytic processing, and by the formation of heterodimers with other ERBB family members, thereby creating multiple combinations of intracellular phosphotyrosines that trigger ligand- and context-specific cellular responses. Mediates phosphorylation of SHC1 and activation of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Isoform JM-A CYT-1 and isoform JM-B CYT-1 phosphorylate PIK3R1, leading to the activation of phosphatidylinositol 3-kinase and AKT1 and protect cells against apoptosis. Isoform JM-A CYT-1 and isoform JM-B CYT-1 mediate reorganization of the actin cytoskeleton and promote cell migration in response to NRG1. Isoform JM-A CYT-2 and isoform JM-B CYT-2 lack the phosphotyrosine that mediates interaction with PIK3R1, and hence do not phosphorylate PIK3R1, do not protect cells against apoptosis, and do not promote reorganization of the actin cytoskeleton and cell migration. Proteolytic processing of isoform JM-A CYT-1 and isoform JM-A CYT-2 gives rise to the corresponding soluble intracellular domains (4ICD) that translocate to the nucleus, promote nuclear import of STAT5A, activation of STAT5A, mammary epithelium differentiation, cell proliferation and activation of gene expression. The ERBB4 soluble intracellular domains (4ICD) colocalize with STAT5A at the CSN2 promoter to regulate transcription of milk proteins during lactation. The ERBB4 soluble intracellular domains can also translocate to mitochondria and promote apoptosis.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Analysis of the x-ray crystal structure of mono-substituted acetylenic thienopyrimidine 6 complexed with the ErbB family enzyme ErbB-4 revealed a covalent bond between the terminal carbon of the acetylene moiety and the sulfhydryl group of Cys-803 at the solvent interface. The identification of this covalent adduct suggested that acetylenic thienopyrimidine 6 and related analogs might also be capable of forming an analogous covalent adduct with EGFR, which has a conserved cysteine (797) near the ATP binding pocket. To test this hypothesis, we treated a truncated, catalytically competent form of EGFR (678-1020) with a structurally related propargylic amine (8). An investigation of the resulting complex by mass spectrometry revealed the formation of a covalent complex of thienopyrimidine 8 with Cys-797 of EGFR. This finding enabled us to readily assess the irreversibility of various inhibitors and also facilitated a structure-activity relationship understanding of the covalent modifying potential and biological activity of a series of acetylenic thienopyrimidine compounds with potent antitumor activity. Several ErbB family enzyme and cell potent 6-ethynyl thienopyrimidine kinase inhibitors were found to form covalent adducts with EGFR.
6-Ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiers of ErbB kinases.,Wood ER, Shewchuk LM, Ellis B, Brignola P, Brashear RL, Caferro TR, Dickerson SH, Dickson HD, Donaldson KH, Gaul M, Griffin RJ, Hassell AM, Keith B, Mullin R, Petrov KG, Reno MJ, Rusnak DW, Tadepalli SM, Ulrich JC, Wagner CD, Vanderwall DE, Waterson AG, Williams JD, White WL, Uehling DE Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):2773-8. Epub 2008 Feb 19. PMID:18287036[25]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Plowman GD, Culouscou JM, Whitney GS, Green JM, Carlton GW, Foy L, Neubauer MG, Shoyab M. Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1746-50. PMID:8383326
- ↑ Elenius K, Corfas G, Paul S, Choi CJ, Rio C, Plowman GD, Klagsbrun M. A novel juxtamembrane domain isoform of HER4/ErbB4. Isoform-specific tissue distribution and differential processing in response to phorbol ester. J Biol Chem. 1997 Oct 17;272(42):26761-8. PMID:9334263
- ↑ Cohen BD, Green JM, Foy L, Fell HP. HER4-mediated biological and biochemical properties in NIH 3T3 cells. Evidence for HER1-HER4 heterodimers. J Biol Chem. 1996 Mar 1;271(9):4813-8. PMID:8617750
- ↑ Elenius K, Paul S, Allison G, Sun J, Klagsbrun M. Activation of HER4 by heparin-binding EGF-like growth factor stimulates chemotaxis but not proliferation. EMBO J. 1997 Mar 17;16(6):1268-78. PMID:9135143 doi:10.1093/emboj/16.6.1268
- ↑ Carraway KL 3rd, Weber JL, Unger MJ, Ledesma J, Yu N, Gassmann M, Lai C. Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases. Nature. 1997 May 29;387(6632):512-6. PMID:9168115 doi:10.1038/387512a0
- ↑ 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
- ↑ Elenius K, Choi CJ, Paul S, Santiestevan E, Nishi E, Klagsbrun M. Characterization of a naturally occurring ErbB4 isoform that does not bind or activate phosphatidyl inositol 3-kinase. Oncogene. 1999 Apr 22;18(16):2607-15. PMID:10353604 doi:10.1038/sj.onc.1202612
- ↑ Harari D, Tzahar E, Romano J, Shelly M, Pierce JH, Andrews GC, Yarden Y. Neuregulin-4: a novel growth factor that acts through the ErbB-4 receptor tyrosine kinase. Oncogene. 1999 Apr 29;18(17):2681-9. PMID:10348342 doi:10.1038/sj.onc.1202631
- ↑ Kainulainen V, Sundvall M, Maatta JA, Santiestevan E, Klagsbrun M, Elenius K. A natural ErbB4 isoform that does not activate phosphoinositide 3-kinase mediates proliferation but not survival or chemotaxis. J Biol Chem. 2000 Mar 24;275(12):8641-9. PMID:10722704
- ↑ Sweeney C, Lai C, Riese DJ 2nd, Diamonti AJ, Cantley LC, Carraway KL 3rd. Ligand discrimination in signaling through an ErbB4 receptor homodimer. J Biol Chem. 2000 Jun 30;275(26):19803-7. PMID:10867024 doi:10.1074/jbc.C901015199
- ↑ Egeblad M, Mortensen OH, van Kempen LC, Jaattela M. BIBX1382BS, but not AG1478 or PD153035, inhibits the ErbB kinases at different concentrations in intact cells. Biochem Biophys Res Commun. 2001 Feb 16;281(1):25-31. PMID:11178955 doi:10.1006/bbrc.2001.4302
- ↑ Sartor CI, Zhou H, Kozlowska E, Guttridge K, Kawata E, Caskey L, Harrelson J, Hynes N, Ethier S, Calvo B, Earp HS 3rd. Her4 mediates ligand-dependent antiproliferative and differentiation responses in human breast cancer cells. Mol Cell Biol. 2001 Jul;21(13):4265-75. PMID:11390655 doi:10.1128/MCB.21.13.4265-4275.2001
- ↑ Komuro A, Nagai M, Navin NE, Sudol M. WW domain-containing protein YAP associates with ErbB-4 and acts as a co-transcriptional activator for the carboxyl-terminal fragment of ErbB-4 that translocates to the nucleus. J Biol Chem. 2003 Aug 29;278(35):33334-41. Epub 2003 Jun 13. PMID:12807903 doi:10.1074/jbc.M305597200
- ↑ Williams CC, Allison JG, Vidal GA, Burow ME, Beckman BS, Marrero L, Jones FE. The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone. J Cell Biol. 2004 Nov 8;167(3):469-78. PMID:15534001 doi:10.1083/jcb.200403155
- ↑ Vidal GA, Naresh A, Marrero L, Jones FE. Presenilin-dependent gamma-secretase processing regulates multiple ERBB4/HER4 activities. J Biol Chem. 2005 May 20;280(20):19777-83. Epub 2005 Mar 3. PMID:15746097 doi:10.1074/jbc.M412457200
- ↑ Naresh A, Long W, Vidal GA, Wimley WC, Marrero L, Sartor CI, Tovey S, Cooke TG, Bartlett JM, Jones FE. The ERBB4/HER4 intracellular domain 4ICD is a BH3-only protein promoting apoptosis of breast cancer cells. Cancer Res. 2006 Jun 15;66(12):6412-20. PMID:16778220 doi:10.1158/0008-5472.CAN-05-2368
- ↑ Maatta JA, Sundvall M, Junttila TT, Peri L, Laine VJ, Isola J, Egeblad M, Elenius K. Proteolytic cleavage and phosphorylation of a tumor-associated ErbB4 isoform promote ligand-independent survival and cancer cell growth. Mol Biol Cell. 2006 Jan;17(1):67-79. Epub 2005 Oct 26. PMID:16251361 doi:10.1091/mbc.E05-05-0402
- ↑ Muraoka-Cook RS, Sandahl M, Husted C, Hunter D, Miraglia L, Feng SM, Elenius K, Earp HS 3rd. The intracellular domain of ErbB4 induces differentiation of mammary epithelial cells. Mol Biol Cell. 2006 Sep;17(9):4118-29. Epub 2006 Jul 12. PMID:16837552 doi:10.1091/mbc.E06-02-0101
- ↑ Pitfield SE, Bryant I, Penington DJ, Park G, Riese DJ 2nd. Phosphorylation of ErbB4 on tyrosine 1056 is critical for ErbB4 coupling to inhibition of colony formation by human mammary cell lines. Oncol Res. 2006;16(4):179-93. PMID:17120616
- ↑ Strunk KE, Husted C, Miraglia LC, Sandahl M, Rearick WA, Hunter DM, Earp HS 3rd, Muraoka-Cook RS. HER4 D-box sequences regulate mitotic progression and degradation of the nuclear HER4 cleavage product s80HER4. Cancer Res. 2007 Jul 15;67(14):6582-90. PMID:17638867 doi:10.1158/0008-5472.CAN-06-4145
- ↑ Sundvall M, Peri L, Maatta JA, Tvorogov D, Paatero I, Savisalo M, Silvennoinen O, Yarden Y, Elenius K. Differential nuclear localization and kinase activity of alternative ErbB4 intracellular domains. Oncogene. 2007 Oct 18;26(48):6905-14. Epub 2007 May 7. PMID:17486069 doi:10.1038/sj.onc.1210501
- ↑ Tvorogov D, Sundvall M, Kurppa K, Hollmen M, Repo S, Johnson MS, Elenius K. Somatic mutations of ErbB4: selective loss-of-function phenotype affecting signal transduction pathways in cancer. J Biol Chem. 2009 Feb 27;284(9):5582-91. doi: 10.1074/jbc.M805438200. Epub 2008, Dec 19. PMID:19098003 doi:10.1074/jbc.M805438200
- ↑ Gilmore-Hebert M, Ramabhadran R, Stern DF. Interactions of ErbB4 and Kap1 connect the growth factor and DNA damage response pathways. Mol Cancer Res. 2010 Oct;8(10):1388-98. doi: 10.1158/1541-7786.MCR-10-0042. Epub , 2010 Sep 21. PMID:20858735 doi:10.1158/1541-7786.MCR-10-0042
- ↑ Veikkolainen V, Vaparanta K, Halkilahti K, Iljin K, Sundvall M, Elenius K. Function of ERBB4 is determined by alternative splicing. Cell Cycle. 2011 Aug 15;10(16):2647-57. Epub 2011 Aug 15. PMID:21811097
- ↑ Wood ER, Shewchuk LM, Ellis B, Brignola P, Brashear RL, Caferro TR, Dickerson SH, Dickson HD, Donaldson KH, Gaul M, Griffin RJ, Hassell AM, Keith B, Mullin R, Petrov KG, Reno MJ, Rusnak DW, Tadepalli SM, Ulrich JC, Wagner CD, Vanderwall DE, Waterson AG, Williams JD, White WL, Uehling DE. 6-Ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiers of ErbB kinases. Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):2773-8. Epub 2008 Feb 19. PMID:18287036
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