HER2/neu

HER2/neu
已知的結構
PDB	直系同源搜索: PDBe RCSB
PDBID列表
	1MFG、1MFL、1MW4、1N8Z、1QR1、1S78、2A91、2JWA、2KS1、2L4K、3BE1、3H3B、3N85、3PP0、3RCD、3MZW、3WLW、3WSQ、4GFU、4HRL、4HRM、4HRN、2N2A
識別號
别名	ERBB2；, CD340, HER-2, HER-2/neu, HER2, MLN 19, NEU, NGL, TKR1, erb-b2 receptor tyrosine kinase 2
外部ID	OMIM：164870 MGI：95410 HomoloGene：3273 GeneCards：ERBB2
EC number	2.7.10.1
相關疾病
	breast carcinoma、disease of cellular proliferation、非小細胞肺癌
為以下藥物的標靶
	阿法替尼、canertinib、達科米替尼、拉帕替尼、mubritinib、来那替尼、玛格妥昔单抗、達科米替尼、帕妥珠单抗、图卡替尼、bms-599626、bms-690514、cp-724714、cudc-101、poziotinib、sapitinib、varlitinib、tesevatinib
基因位置（人类）
染色体	17號染色體
终止	39,730,426 bp
基因位置（小鼠）
染色体	小鼠11号染色体
终止	98,328,542 bp
RNA表达模式
	; ;
	查阅更多表达数据
基因本體
分子功能	• ErbB-3 class receptor binding; • 轉移酶活性; • 核苷酸結合; • 蛋白激酶活性; • protein dimerization activity; • growth factor binding; • RNA polymerase I core binding; • 激酶活性; • protein C-terminus binding; • 血浆蛋白结合; • 相同蛋白质结合; • protein heterodimerization activity; • transmembrane receptor protein tyrosine kinase activity; • protein tyrosine kinase activity; • protein phosphatase binding; • ATP結合; • transmembrane signaling receptor activity; • phosphatidylinositol-4,5-bisphosphate 3-kinase activity; • 酪胺酸激酶受體;
細胞組分	• integral component of membrane; • 膜; • myelin sheath; • receptor complex; • 细胞膜; • basolateral plasma membrane; • apical plasma membrane; • 细胞质的核周区域; • endosome membrane; • cytoplasmic vesicle; • 细胞核; • 細胞質; • 细胞质基质; • integral component of plasma membrane; • basal plasma membrane;
生物學過程	• positive regulation of protein phosphorylation; • peripheral nervous system development; • regulation of transcription, DNA-templated; • negative regulation of immature T cell proliferation in thymus; • positive regulation of MAP kinase activity; • 磷酸化; • transmembrane receptor protein tyrosine kinase signaling pathway; • positive regulation of epithelial cell proliferation; • cellular response to growth factor stimulus; • 傷口癒合; • oligodendrocyte differentiation; • regulation of angiogenesis; • positive regulation of translation; • transcription, DNA-templated; • 神經系統的發育; • MAPK cascade; • protein phosphorylation; • 心脏发育; • cell surface receptor signaling pathway; • positive regulation of GTPase activity; • positive regulation of cell growth; • regulation of microtubule-based process; • neuromuscular junction development; • regulation of ERK1 and ERK2 cascade; • 髓鞘形成; • 自體磷酸化; • phosphatidylinositol 3-kinase signaling; • positive regulation of transcription by RNA polymerase I; • 細胞增殖; • positive regulation of transcription by RNA polymerase III; • motor neuron axon guidance; • enzyme linked receptor protein signaling pathway; • 訊息傳遞; • positive regulation of cell adhesion; • positive regulation of protein targeting to membrane; • ERBB2 signaling pathway; • phosphatidylinositol phosphate biosynthetic process; • positive regulation of gene expression; • peptidyl-tyrosine phosphorylation; • regulation of cell motility; • cellular response to epidermal growth factor stimulus; • regulation of transcription by RNA polymerase II; • negative regulation of ERBB signaling pathway; • positive regulation of protein kinase B signaling; • negative regulation of signal transduction; • 细胞分化; • negative regulation of apoptotic process; • positive regulation of ERK1 and ERK2 cascade; • intracellular signal transduction; • positive regulation of cell population proliferation; • neuron differentiation; • positive regulation of MAPK cascade;
	Sources:Amigo / QuickGO
直系同源
	2064
	13866
	ENSG00000141736
	ENSMUSG00000062312
	P04626
	P70424
	NM_001005862; NM_001289936; NM_001289937; NM_001289938; NM_004448
	NM_001003817; NM_010152
NP_001005862; NP_001276865; NP_001276866; NP_001276867; NP_004439;
	NP_001369711; NP_001369712; NP_001369713; NP_001369714; NP_001369715; NP_001369716; NP_001369717; NP_001369718; NP_001369719; NP_001369720; NP_001369721; NP_001369722; NP_001369723; NP_001369724; NP_001369725; NP_001369726; NP_001369727; NP_001369728; NP_001369729; NP_001369730; NP_001369731; NP_001369732; NP_001369733; NP_001369734; NP_001369735
	NP_001003817
	維基數據
檢視/編輯人類	檢視/編輯小鼠

人类表皮生长因子受体2（英語：human epidermal growth factor receptor 2，缩写为HER2，亦称为Neu、ErbB-2、CD340（分化群340）或p185）是一种由ERBB2基因编码的蛋白质。HER2是表皮生长因子受体（EGFR/ErbB）家族的成员。

功能

HER2是结合在细胞膜表面的受体酪氨酸激酶，参与导致细胞生长和分化的訊息傳遞途径，由原癌基因HER2/neu编码。一般认为HER2是一个孤受体，表皮生长因子家族的配体都不能激活它。但配体结合ErbB受体时可形成二聚体，且HER2可与ErbB家族的其他成员结合成异二聚体。^[7]HER2基因是原癌基因，位于人类17号染色体长臂（17q21-q22）。^[8]

與癌症的關係

HER-2基因是影響乳癌預後的一個重要因素，大約有25%-30%左右的乳癌患者，受到體內癌細胞HER-2基因過量表現的影響，他們的癌細胞不僅繁殖能力強，對部份化學治療藥物也容易有抗藥性，造成病患即使接受手術治療，癌細胞仍然有較高復發及轉移的機率，無法長期存活。

乳癌病患可分為Her-2/neu陽性或Her-2/neu陰性兩種截然不同的預後之乳癌。乳癌患者的腫瘤，若HER-2蛋白質出現過量表現，這類的腫瘤生長速度較快且生物行為較為惡性，使得手術後復發率高於其他類型的乳癌。^[9]

針对HER2的葯物

羅氏藥廠開發的賀癌平（Herceptin）即是以HER2為标靶的葯物，對晚期转移性的乳腺癌頗具效用。

重组型人源化单克隆抗体 Trastuzumab (Herceptin®), 是IgG1 monoclonal antibody，可透過結合到乳癌細胞膜上的HER2 receptor的Domain4去抑制下游的hetero- and homodimerization和信號傳遞。；
完全人源化单克隆抗体 Pertuzumab (Perjeta®)，和Trastuzumab藥理作用位點相似，但Pertuzumab 是結合在HER2的Domain2，去抑制下游路徑，而且因為Domain2是屬於extracellular receptor dimerization，因此可防止其他的HER family members和HER2進行dimerization，從而抑制了ligand-induced signaling，抑制了細胞生長而進行細胞凋亡，其中HER2/HER3被认为是下游通路激活的最强二聚体；
单抗结合型药物 Ado-Trastuzumab emtansine (Kadcyla®)，為新藥，是一種Antibody和Drug的conjugate（ADC）。Trastuzumab上述已介紹過他的作用位點，而新藥T-DM1則是將Trastuzumab和maytansine 1用thioether鍵結起來，DM1即derivative of maytansine 1，是一種合成Microtubule 過程中dimerization的抑制劑，將Trastuzumab和cytotoxic agent DM1結合，除了有Trastuzumab本身能夠與HER2 receptor Domain4結合，進而停止了癌細胞的生長，DM1透過receptor-mediated進入細胞內作用，並在lysosome內代謝，釋放出含DM1的代謝產物，此物質可結合在Microtubule上，導致有絲分裂終止和細胞死亡。^[10]
Neratinib，為口服製劑，irreversible inhibitor，抑制HER2 and EGFR protein tyrosine kinase(TK)。^[11]
酪氨酸激酶抑制剂 Lapatinib Ditosylate (Tykerb®)，口服製劑，和Neratinib相似，一樣是EGFR and HER2 tyrosine kinase的抑制劑。^[11]
mTOR 抑制剂 Everolimus (Afinitor®)

相互作用

参考文献

^ 與HER2/neu相關的疾病；在維基數據上查看/編輯參考.
^ 對人类表皮生长因子受体II起作用的藥物；在維基數據上查看/編輯參考.
^ ^3.0 ^3.1 ^3.2 GRCh38: Ensembl release 89: ENSG00000141736 - Ensembl, May 2017
^ ^4.0 ^4.1 ^4.2 GRCm38: Ensembl release 89: ENSMUSG00000062312 - Ensembl, May 2017
^ Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Olayioye MA. Update on HER-2 as a target for cancer therapy: intracellular signaling pathways of ErbB2/HER-2 and family members. Breast Cancer Res. 2001, 3 (6): 385–389. PMID 11737890. doi:10.1186/bcr327.
^ Coussens L. Tyrosine Kinase Receptor with Extensive Homology to EGF Receptor Shares Chromosomal Location with neu Oncogene. Science. 1985, 230: 1132–1139. doi:10.1126/science.2999974.
^ HER-2陽性早期乳癌治療的近況. 台灣癌症防治網. 2009年10月16日 [2009-10-06]. （原始内容存档于2011年5月25日）.
^ Sadeghi, S., Olevsky, O., & Hurvitz, S. A. (2014). Profiling and targeting HER2-positive breast cancer using trastuzumab emtansine. Pharmacogenomics and personalized medicine, 7, 329.
^ ^11.0 ^11.1 Goodman, L. S. (1996). Goodman and Gilman's the pharmacological basis of therapeutics (Vol. 1549). New York: McGraw-Hill.P.1208

深入阅读

Ross JS, Fletcher JA, Linette GP; et al. The Her-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy. Oncologist. 2003, 8 (4): 307–25. PMID 12897328. doi:10.1634/theoncologist.8-4-307.
Zhou BP, Hung MC. Dysregulation of cellular signaling by HER2/neu in breast cancer. Semin. Oncol. 2003, 30 (5 Suppl 16): 38–48. PMID 14613025. doi:10.1053/j.seminoncol.2003.08.006.
Ménard S, Casalini P, Campiglio M; et al. Role of HER2/neu in tumor progression and therapy. Cell. Mol. Life Sci. 2005, 61 (23): 2965–78. PMID 15583858. doi:10.1007/s00018-004-4277-7.
Becker JC, Muller-Tidow C, Serve H; et al. Role of receptor tyrosine kinases in gastric cancer: new targets for a selective therapy. World J. Gastroenterol. 2006, 12 (21): 3297–305. PMID 16733844.
Laudadio J, Quigley DI, Tubbs R, Wolff DJ. HER2 testing: a review of detection methodologies and their clinical performance. Expert Rev. Mol. Diagn. 2007, 7 (1): 53–64. PMID 17187484. doi:10.1586/14737159.7.1.53.
Bianchi F, Tagliabue E, Ménard S, Campiglio M. Fhit expression protects against HER2-driven breast tumor development: unraveling the molecular interconnections. Cell Cycle. 2007, 6 (6): 643–6. PMID 17374991. doi:10.4161/cc.6.6.4033.
Del Bimbo A., Meoni M., Pala P. Accurate evaluation of HER-2 amplification in FISH images. Imaging Systems and Techniques (IST), 2010 IEEE International Conference on. 2010: 407–10. ISBN 978-1-4244-6492-0. doi:10.1109/IST.2010.5548461.