HER2/neu

HER2/neu
已知的结构
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
识别号
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
相关疾病
	breast carcinoma、disease of cellular proliferation、非小细胞肺癌
为以下药物的标靶
	阿法替尼、canertinib、达科米替尼、拉帕替尼、mubritinib、来那替尼、玛格妥昔单抗、达科米替尼、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号染色体
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
基因本体
分子功能	• ErbB-3 class receptor binding; • 转移酶活性; • 核苷酸结合; • 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结合; • transmembrane signaling receptor activity; • phosphatidylinositol-4,5-bisphosphate 3-kinase activity; • 酪氨酸激酶受体;
细胞组分	• 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; • 细胞质; • 细胞质基质; • integral component of plasma membrane; • basal plasma membrane;
生物学过程	• 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; • 伤口愈合; • oligodendrocyte differentiation; • regulation of angiogenesis; • positive regulation of translation; • transcription, DNA-templated; • 神经系统的发育; • 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; • 自体磷酸化; • phosphatidylinositol 3-kinase signaling; • positive regulation of transcription by RNA polymerase I; • 细胞增殖; • positive regulation of transcription by RNA polymerase III; • motor neuron axon guidance; • enzyme linked receptor protein signaling pathway; • 信号转导; • 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
	维基数据
查看/编辑人类	查看/编辑小鼠

人类表皮生长因子受体2（英语：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信号转导途径，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]

与癌症的关系

HER-2基因是影响乳癌预后的一个重要因素，大约有25%-30%左右的乳癌患者，受到体内癌细胞HER-2基因过量表现的影响，他们的癌细胞不仅繁殖能力强，对部分化学治疗药物也容易有抗药性，造成病患即使接受手术治疗，癌细胞仍然有较高复发及转移的几率，无法长期存活。

乳癌病患可分为Her-2/neu阳性或Her-2/neu阴性两种截然不同的预后之乳癌。乳癌患者的肿瘤，若HER-2蛋白质出现过量表现，这类的肿瘤生长速度较快且生物行为较为恶性，使得手术后复发率高于其他类型的乳癌。^[9]

表皮生长因子受体(EGFR)信号传导级联

针对HER2的药物

罗氏药厂开发的贺癌平（Herceptin）即是以HER2为标靶的药物，对晚期转移性的乳腺癌颇具效用。

重组型人源化单克隆抗体 Trastuzumab (Herceptin®), 是IgG1 monoclonal antibody，可透过结合到乳癌细胞膜上的HER2 receptor的Domain4去抑制下游的hetero- and homodimerization和信号传递。；
完全人源化单克隆抗体 Pertuzumab (Perjeta®)，和Trastuzumab药理作用位点相似，但Pertuzumab 是结合在HER2的Domain2，去抑制下游路径，而且因为Domain2是属于extracellular receptor dimerization，因此可防止其他的HER family members和HER2进行dimerization，从而抑制了ligand-induced signaling，抑制了细胞生长而进行细胞凋亡，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®)，为新药，是一种Antibody和Drug的conjugate（ADC）。Trastuzumab上述已介绍过他的作用位点，而新药T-DM1则是将Trastuzumab和maytansine 1用thioether键结起来，DM1即derivative of maytansine 1，是一种合成Microtubule 过程中dimerization的抑制剂，将Trastuzumab和cytotoxic agent DM1结合，除了有Trastuzumab本身能够与HER2 receptor Domain4结合，进而停止了癌细胞的生长，DM1透过receptor-mediated进入细胞内作用，并在lysosome内代谢，释放出含DM1的代谢产物，此物质可结合在Microtubule上，导致有丝分裂终止和细胞死亡。^[10]
Neratinib，为口服制剂，irreversible inhibitor，抑制HER2 and EGFR protein tyrosine kinase(TK)。^[11]
酪氨酸激酶抑制剂 Lapatinib Ditosylate (Tykerb®)，口服制剂，和Neratinib相似，一样是EGFR and HER2 tyrosine kinase的抑制剂。^[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. 台湾癌症防治网. 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.

外部链接

[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.

[refGRCh38Ensembl-3] 3.0 ^3.1 ^3.2 GRCh38: Ensembl release 89: ENSG00000141736 - Ensembl, May 2017

[refGRCm38Ensembl-4] 4.0 ^4.1 ^4.2 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.

[Olayioye_2001-7] 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.

[Coussens_1985-8] 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. 台湾癌症防治网. 2009年10月16日 [2009-10-06]. （原始内容存档于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.

[#1-11] 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

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