HER2/neu

人類表皮生長因子受體2（英語：human epidermal growth factor receptor 2，縮寫為HER2，亦稱為Neu、ErbB-2、CD340（分化群340）或p185）是一種由ERBB2基因編碼的蛋白質。HER2是表皮生長因子受體（EGFR/ErbB）家族的成員。

HER2/neu
已知的結構 PDB 直系同源搜尋: 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
別名	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[1]
為以下藥物的標靶
阿法替尼、​canertinib、​達科米替尼、​拉帕替尼、​mubritinib、​來那替尼、​瑪格妥昔單抗、​達科米替尼、​帕妥珠單抗、​圖卡替尼、​bms-599626、​bms-690514、​cp-724714、​cudc-101、​poziotinib、​sapitinib、​varlitinib、​tesevatinib[2]
基因位置（人類） 染色體 17號染色體[3] 基因座 17q12 起始 39,687,914 bp[3] 終止 39,730,426 bp[3]
基因位置（小鼠） 染色體 小鼠11號染色體[4] 基因座 11 61.75 cM|11 D 起始 98,303,296 bp[4] 終止 98,328,542 bp[4]
RNA表現模式
查閱更多表現資料
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 • 血漿蛋白結合 • 相同蛋白質結合 • 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 • 細胞膜 • basolateral plasma membrane • apical plasma membrane • 細胞質的核周區域 • endosome membrane • cytoplasmic vesicle • 細胞核 • 細胞質 • 細胞質基質 • 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 • 心臟發育 • 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 • 細胞分化 • 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
物種	人類	小鼠
Entrez	2064	13866
Ensembl	ENSG00000141736	ENSMUSG00000062312
UniProt	P04626	P70424
mRNA​序列	​NM_001005862 ​NM_001289936 ​NM_001289937 ​NM_001289938 ​NM_004448	NM_001003817 ​NM_010152
蛋白序列	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
基因位置​（UCSC）	Chr 17: 39.69 – 39.73 Mb	Chr 11: 98.3 – 98.33 Mb
PubMed​查找	[5]	[6]
維基資料
檢視/編輯人類 檢視/編輯小鼠

功能

HER2是結合在細胞膜表面的受體酪胺酸激酶，參與導致細胞生長和分化的訊息傳遞途徑，由原癌基因HER2/neu編碼。一般認為HER2是一個孤受體，表皮生長因子家族的配體都不能活化它。但配體結合ErbB受體時可形成二聚體，且HER2可與ErbB家族的其他成員結合成異二聚體。^[7]HER2基因是原癌基因，位於人類17號染色體長臂（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]

表皮生長因子受體(EGFR)信號傳導級聯

針對HER2的葯物

羅氏藥廠開發的賀癌平（Herceptin）即是以HER2為標靶的葯物，對晚期轉移性的乳腺癌頗具效用。

1. 重組型人源化單株抗體 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。；
2. 完全人源化單株抗體 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被認為是下游通路活化的最強二聚體；
3. 單抗結合型藥物 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]
4. Neratinib，為口服製劑，irreversible inhibitor，抑制HER2 and EGFR protein tyrosine kinase(TK)。^[11]
5. 酪胺酸激酶抑制劑 Lapatinib Ditosylate (Tykerb®)，口服製劑，和Neratinib相似，一樣是EGFR and HER2 tyrosine kinase的抑制劑。^[11]
6. mTOR 抑制劑 Everolimus (Afinitor®)

相互作用

參考文獻

1. 與HER2/neu相關的疾病；在維基數據上查看/編輯參考.
2. 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. GRCh38: Ensembl release 89: ENSG00000141736 - Ensembl, May 2017
4. GRCm38: Ensembl release 89: ENSMUSG00000062312 - Ensembl, May 2017
5. Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
6. Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
7. 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.
8. 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.
9. 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]. （原始內容存檔於2011年5月25日）.
10. 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. Goodman, L. S. (1996). Goodman and Gilman's the pharmacological basis of therapeutics (Vol. 1549). New York: McGraw-Hill.P.1208

深入閱讀

• 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. 引文格式1維護：顯式使用等標籤 (link)
• 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. 引文格式1維護：顯式使用等標籤 (link)
• 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. 引文格式1維護：顯式使用等標籤 (link)
• 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.

外部連結

• ERBB2 expression across human cancerous and healthy tissues^{[永久失效連結]}
• AACR Cancer Concepts Factsheet on HER2
• Her2/neu Vaccine Protects Against Tumor Growth
• Chimeric molecules and Methods of Use
• Breast Friends for Life Network - A South African Breast Cancer Support Forum for HER2 Positive Women
• 醫學主題詞表（MeSH）：Receptor,+erbB-2