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[1]
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[2]
基因位置（人类）
染色体	17號染色體[3]
终止	39,730,426 bp[3]
基因位置（小鼠）
染色体	小鼠11号染色体[4]
终止	98,328,542 bp[4]
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

人类表皮生长因子受体2（英語：，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]

表皮生長因子受體(EGFR)信號傳導級聯

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®)

参考文献

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GRCh38: Ensembl release 89: ENSG00000141736 - Ensembl, May 2017
GRCm38: Ensembl release 89: ENSMUSG00000062312 - Ensembl, May 2017
. National Center for Biotechnology Information, U.S. National Library of Medicine.
. National Center for Biotechnology Information, U.S. National Library of Medicine.
Olayioye MA. . Breast Cancer Res. 2001, 3 (6): 385–389. PMID 11737890. doi:10.1186/bcr327.
Coussens L. . Science. 1985, 230: 1132–1139. doi:10.1126/science.2999974.
. 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.
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

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外部链接

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[1] .

[2] .

[refGRCh38Ensembl-3] GRCh38: Ensembl release 89: ENSG00000141736 - Ensembl, May 2017

[refGRCm38Ensembl-4] GRCm38: Ensembl release 89: ENSMUSG00000062312 - Ensembl, May 2017

[5] . National Center for Biotechnology Information, U.S. National Library of Medicine.

[6] . National Center for Biotechnology Information, U.S. National Library of Medicine.

[Olayioye_2001-7] Olayioye MA. . Breast Cancer Res. 2001, 3 (6): 385–389. PMID 11737890. doi:10.1186/bcr327.

[Coussens_1985-8] Coussens L. . Science. 1985, 230: 1132–1139. doi:10.1126/science.2999974.

[9] . 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）.

[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] Goodman, L. S. (1996). Goodman and Gilman's the pharmacological basis of therapeutics (Vol. 1549). New York: McGraw-Hill.P.1208