関: trastuzumab、乳癌

HER2/neu遺伝子はヒト上皮細胞増殖因子受容体遺伝子と類似の構造を有する癌遺伝子

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/04/03 06:17:28」(JST)

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HER2の細胞外ドメインとトラスツズマブの複合体の構造。

HER2の細胞外ドメインとペルツズマブの複合体の構造。トラスツズマブと異なり、第IIドメインに結合し、HER2の二量体化を防ぐ。

HER2（ハーツー）は、細胞表面に存在する約185 kDaの糖タンパクで、受容体型チロシンキナーゼである。上皮成長因子受容体 (EGFR、別名ERBB1) に類似した構造をもち、EGFR2、ERBB2、CD340、あるいはNEUとも呼ばれる。HER2タンパクをコードする遺伝子は HER2/neu、erbB-2 で17番染色体長腕に存在する。

HER2タンパクは正常細胞において細胞の増殖、分化などの調節に関与しているが、何らかの理由でHER2遺伝子の増幅や遺伝子変異が起こると、細胞の増殖・分化の制御ができなくなり、細胞は悪性化する。HER2遺伝子はがん遺伝子でもあり、多くの種類のがんで遺伝子増幅がみられる。

1 発見の歴史
2 機能
3 遺伝子
4 悪性腫瘍におけるHER2
5 HER検査の評価法
- 5.1 IHC法によるHER2検査の判定スコア(2007 ASCO/CAPガイドライン）
- 5.2 FISH法によるHER2検査の判定スコア(2007 ASCO/CAPガイドライン）
- 5.3 HER2蛋白および遺伝子の検査キット
6 HER2を標的にした治療
- 6.1 トラスツズマブ
- 6.2 ペルツズマブ
7 参考文献
8 外部リンク

発見の歴史

1985年、ヒトEGFRに類似した受容体型チロシンキナーゼがクローニングされ、ヒトEGFR関連物質2 human EGFR-related 2 の略よりHER2と名付けられた^[1]。このHER2をコードする遺伝子は、ラットの神経膠芽腫 neuroglioblastoma 細胞株から見つかったがん遺伝子 neu に一致しており、同一のものと考えられた^[1]。

また同時期、ヒト乳癌細胞や唾液腺腺癌で、トリ赤芽球症ウイルス avian erythroblastic leukemia virus のもつがん遺伝子 v-erbB に類似した遺伝子が増幅していることが発見された。ヒトEGFR遺伝子が v-erbBと相同性が高いことは知られていたが、この新たな遺伝子はEGFR遺伝子とは別個のものであり、ヒトEGFR遺伝子はc-erbB-1、この新たな遺伝子はc-erbB-2 と名付けられた。またこれは neu と同じものであることが確認された^[2]^[3]。1986年 c-erbB-2遺伝子産物がチロシンキナーゼ活性を持った185 kDaの糖タンパクであることが確認された^[4]。

機能

HER2は心臓や神経の発達や維持に関与し、その他の細胞でも細胞増殖、分化などの調節に関与している。HER2遺伝子を人為的に欠失させたマウスは、心臓や神経系の発達障害により胎生期に死亡する^[5]。また出生後に心筋のHER2遺伝子発現を人為的に低下させたマウスは拡張型心筋症を呈した^[6]^[7]。同様に腸管の神経のHER2遺伝子発現を人為的に低下させたマウスは、腸管の発育不良、腸管拡張をおこし、ヒトヒルシュスプルング病に類似した病態を呈した^[8]。

HER2タンパクは受容体型チロシンキナーゼである。同じEGFRファミリーに属するHER1, HER3, HER4 は細胞外領域にligandが結合することにより３次元構造が変化して他のHER family との二量体形成が可能となる。しかしHER2に結合する内因性リガンドは知られていない。ホモ二量体あるいは活性化したEGFR（HER1)やHER3、HER4と結合してヘテロ二量体を形成しシグナル伝達を行うと考えられている^[9]。このほかHER2 shedding (蛋白分解酵素によって細胞外ドメインECDが切断されること）によって残される細胞内領域と膜貫通領域からなる95kDの蛋白断片p95も増殖シグナル活性がある^[10]。HER2 shedding を引き起こす蛋白分解酵素は亜鉛含有メタロプロテアーゼと推定されている。

遺伝子

ヒトHER2をコードする遺伝子は、17番染色体長腕 (17q11.2-q12; 17q21.1) に存在する^[11]。

悪性腫瘍におけるHER2

HER2は正常細胞では、増殖、分化、移動、生存などの細胞機能調節に関与している。何らかの理由でHER2遺伝子に増幅や変異が起こると下流のシグナル伝達経路が活性化し、がん遺伝子として働く。唾液腺腺癌^[2]、胃癌、乳癌、卵巣癌^[12]等多くのがんでHER2の遺伝子増幅がみられる。

またHER2タンパクを過剰発現する乳癌・卵巣癌は予後不良である^[12]。ただし、これはHER2タンパクを標的とした治療を行う以前の話である。

HER検査の評価法

HER2検査には、HERタンパク質の過剰発現を調べる免疫組織化学（IHC)法と、HER2遺伝子の増幅を調べる蛍光in situ hybridization （FISH)法がある。検査対象は原発巣あるいは転移巣のホルマリン固定・パラフィン包埋組織標本である。固定は10％中性緩衝ホルマリンで6時間以上48時間までが推奨される。

IHC法によるHER2検査の判定スコア(2007 ASCO/CAPガイドライン）

スコア	所見
0	細胞膜染色なし、または10％未満の癌細胞の膜に染色
1+	10％以上の癌細胞の膜に不完全な染色
2+	10％以上の癌細胞の膜に弱～中等度の完全な染色または、10％以上30％以下の癌細胞の膜に強度の完全な染色
3+	30％を超える癌細胞の膜に強度の完全な染色

FISH法によるHER2検査の判定スコア(2007 ASCO/CAPガイドライン）

判定	FISHの結果
陰性	HER2/17cen(CEP17)比1.8未満
境界域	HER2/17cen(CEP17)比1.8～2.2
陽性	HER2/17cen(CEP17)比＞2.2

癌細胞の核を20個測定する。 ^[13]

HER2蛋白および遺伝子の検査キット

検査法	標的	検査対象	キット名	製造元／販売会社
免疫組織化学法	蛋白	癌組織	ダコHercep Test　ヒストファインHer2キット　ベンタナパスウェイHER2　協和ステインHER2/neu	ダコ・ジャパン　ニチレイ　ロッシュ・ダイアグノステイクス　協和メデイクス
FISH法	DNA	癌組織	パスビジョンHER-2 DNA プローベキット　ヒストラHER2 FISHキット	アボットジャパン　常光
CLEIA	蛋白	血液、乳頭分泌物、組織抽出液	ケミルミADVIA Centaur CP	シーメンス

CLEA: chemiluminescence enzyme immunoassay ^[14]

HER2を標的にした治療

HER2タンパクを標的とした分子標的治療薬に、トラスツズマブやペルツズマブがある。

トラスツズマブ

詳細はトラスツズマブを参照。

トラスツズマブ（ハーセプチン^®）はHER2タンパクに結合するモノクローナル抗体である。主にHER2タンパクを発現する乳癌に対する治療薬として用いられる^[15]。なお、治験段階における乳癌患者や医師らの苦悩の末に、ハーセプチン^®が乳癌治療薬としてFDAにより認可されるに至る、その険しい道のりを描いたノンフィクションに、映画『希望のちから』（原題：en:Living Proof (film)）がある。

ペルツズマブ

ペルツズマブは、トラスツズマブと同様HER2に結合する抗体であるが、トラスツズマブと異なるところに結合し、HER2の二量体化を防ぐ点が異なる。この薬剤は現在、臨床試験が進行中である。

参考文献

^ ^a ^b Coussens L, Yang-Feng TL, Liao YC, et al. "Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene." Science, Vol.230, No.4730, 1985, p.p. 1132-1139. PMID 2999974
^ ^a ^b Semba K, Kamata N, Toyoshima K, et al. "A v-erbB-related protooncogene, c-erbB-2, is distinct from the c-erbB-1/epidermal growth factor-receptor gene and is amplified in a human salivary gland adenocarcinoma." Proceedings of National Academy of Science of United States of America, Vol.82, No.19, 1985, p.p. 6497-6501. PMID 2995967
^ King CR, Kraus MH, Saronson SA. "Amplification of a novel v-erbB-related gene in a human mammary carcinoma." Science, Vol.229, No.4717, 1985, p.p. 974-976. PMID 2992089
^ Akiyama T, Sudo C, Ogawara H, et al. "The product of the human c-erbB-2 gene: a 185-kilodalton glycoprotein with tyrosine kinase activity." Science, Vol.232, No.4758, 1986, p.p. 1644-1646. PMID 3012781
^ Lee KF, Simon H, Chen H, et al. "Requirement for neuregulin receptor erbB2 in neural and cardiac development." Science, Vol.378, No.6555, 1995, p.p. 394-398. PMID 7477377
^ Crone SA, Zhao YY, Fan L, et al. "ErbB2 is essential in the prevention of dilated cardiomyopathy." Nature Medicine, Vol.8, No.5, 2002, p.p. 459-465. PMID 11984589
^ Ozcelik C, Erdmann B, Pilz B, et al. "Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy." Proceedings of National Academy of Science of United States of America, Vol.99, Bo.13, 2002, p.p. 8880-8885. PMID 12072561
^ Crone SA, Negro A, Trumpp A, et al. "Colonic epithelial expression of ErbB2 is required for postnatal maintenance of the enteric nervous system." Neuron, Vol.37, No.1, p.p. 29-40. PMID 12526770
^ Graus-Porta D, Beerli RR, Daly JM, Hynes NE. "ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling." EMBO Journal, Vol.16, No.7, 1997, p.p. 1647-1655. PMID 9130710
^ Tse C, Gauchez A, Jacot W, Lamy P. HER2 shedding and serum HER2 extracellular domain: Biology and clinical utility in breast cancer Cancer Treatment Reviews 2011
^ ERBB2 - Entrez Gene
^ ^a ^b Slamon DJ, Clark GM, Wong SG, et al. "Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene." Science, Vol.235, No.4785, 1987, p.p. 177-182. PMID 3798106
^ American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, McShane LM, Paik S, Pegram MD, Perez EA, Press MF, Rhodes A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M, Wheeler TM, Hayes DF; American Society of Clinical Oncology/College of American Pathologists. Arch Pathol Lab Med. 2007;131(1):18-43.
^ 熊木伸枝、梅村しのぶ「HER2の検索法と陽性の基準」　戸井雅和編「みんなに役立つ乳癌の基礎と臨床」p372
^ Slamon DJ, Leyland-Jones B, Shak S, et al. "Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2." NEJM., Vol.344, No.11, 2001, p.p. 783-792. PMID 11248153

外部リンク

Her2シグナルパスウェイ

wiki en

[Wiki en表示]

Receptor tyrosine-protein kinase erbB-2, also known as CD340 (cluster of differentiation 340), proto-oncogene Neu, Erbb2 (rodent), or ERBB2 (human) is a protein that in humans is encoded by the ERBB2 gene, which is also frequently called HER2 (from human epidermal growth factor receptor 2) or HER2/neu.

HER2 is a member of the human epidermal growth factor receptor (HER/EGFR/ERBB) family. Amplification or overexpression of this oncogene has been shown to play an important role in the development and progression of certain aggressive types of breast cancer. In recent years the protein has become an important biomarker and target of therapy for approx. 30% of breast cancer patients.^[1]

Name

HER2 is so named because it has a similar structure to human epidermal growth factor receptor, or HER1. Neu is so named because it was derived from a rodent glioblastoma cell line, a type of neural tumor. ErbB-2 was named for its similarity to ErbB (avian erythroblastosis oncogene B), the oncogene later found to code for EGFR. Gene cloning showed that HER2, Neu, and ErbB-2 are all encoded by the same orthologs.^[2]

Gene

ERBB2, a known proto-oncogene, is located at the long arm of human chromosome 17 (17q12).

Function

The ErbB family is composed of four plasma membrane-bound receptor tyrosine kinases, the other members being epidermal growth factor receptor, erbB-3 (neuregulin-binding; lacks kinase domain), and erbB-4.All four contain an extracellular ligand binding domain, a transmembrane domain, and an intracellular domain that can interact with a multitude of signaling molecules and exhibit both ligand-dependent and ligand-independent activity. HER2 can heterodimerise with any of the other three receptors and is considered to be the preferred dimerisation partner of the other ErbB receptors.^[3]

Dimerisation results in the autophosphorylation of tyrosine residues within the cytoplasmic domain of the receptors and initiates a variety of signaling pathways.

Signal transduction

Signaling pathways activated by HER2 include:^[4]

mitogen-activated protein kinase (MAPK)
phosphoinositide 3-kinase (PI3K/Akt)
phospholipase C γ
protein kinase C (PKC)
Signal transducer and activator of transcription (STAT)

In summary, signaling through the ErbB family of receptors promotes cell proliferation and opposes apoptosis, and therefore must be tightly regulated to prevent uncontrolled cell growth from occurring.

HER2 and cancer

Amplification or over-expression of the ERBB2 gene occurs in approximately 15-30% of breast cancers.^[1]^[5] It is strongly associated with increased disease recurrence and a poor prognosis.^[6] Over-expression is also known to occur in ovarian, stomach, and aggressive forms of uterine cancer, such as uterine serous endometrial carcinoma.^[7]

HER2 is co-localized, and, most of the time, co-amplified with the gene GRB7, which is a proto-oncogene associated with breast, testicular germ cell, gastric, and esophageal tumours.

HER2 proteins have been shown to form clusters in cell membranes that may play a role in tumorigenesis.^[8]^[9]

Furthermore, diverse structural alterations have been identified that cause ligand-independent firing of this receptor, doing so in the absence of receptor over-expression. HER2 is found in a variety of tumors and some of these tumors carry point mutations in the sequence specifying the transmembrane domain of HER2. Substitution of a valine for a glutamic acid in the transmembrane domain can result in the constitutive dimerization of this protein in the absence of a ligand.

Drugs targeting HER2

HER2 is the target of the monoclonal antibody trastuzumab (marketed as Herceptin). Trastuzumab is effective only in cancers where HER2 is over-expressed. An important downstream effect of trastuzumab binding to HER2 is an increase in p27, a protein that halts cell proliferation.^[10] Another monoclonal antibody, Pertuzumab, which inhibits dimerization of HER2 and HER3 receptors, was approved by the FDA for use in combination with trastuzumab in June 2012.

Additionally, NeuVax (Galena Biopharma) is a peptide-based immunotherapy that directs "killer" T cells to target and destroy cancer cells that express HER2. It has entered phase 3 clinical trials.

It has been found that patients with ER+ (Estrogen receptor positive)/HER2+ compared with ER-/HER2+ breast cancers may actually benefit more from drugs that inhibit the PI3K/AKT molecular pathway.^[11]

Over-expression of HER2 can also be suppressed by the amplification of other genes. Research is currently being conducted to discover which genes may have this desired effect.

The expression of HER2 is regulated by signaling through estrogen receptors. Normally, estradiol and tamoxifen acting through the estrogen receptor down-regulate the expression of HER2. However, when the ratio of the coactivator AIB-3 exceeds that of the corepressor PAX2, the expression of HER2 is upregulated in the presence of tamoxifen, leading to tamoxifen-resistant breast cancer.^[12]^[13]

Recent evidence has implicated HER2 signaling in resistance to the EGFR-targeted cancer drug cetuximab.^[14]

Her2 and Her3 distribution on a breast cell, (3D Dual Colour Super Resolution Microscopy SPDMphymod / LIMON,marked with Alexa 488 and 568)

HER2 testing

HER2 testing is performed in breast cancer patients to assess prognosis and to determine suitability for trastazumab therapy. It is important that trastazumab is restricted to HER2-positive individuals as it is expensive and has been associated with cardiac toxicity.^[15] For HER2-negative tumours, the risks of trastazumab clearly outweigh the benefits.

HER2 testing on tumor

Tests are usually performed on biopsy samples obtained by either fine-needle aspiration, core needle biopsy, vacuum-assisted breast biopsy, or surgical excision. Immunohistochemistry is used to measure the amount of HER2 protein present in the sample. Alternatively, fluorescence in situ hybridisation (FISH) can be used to measure the number of copies of the gene which are present.

HER2 testing on serum

The extracellular domain of HER2 can be shed from the surface of tumour cells and enter the circulation. Measurement of serum HER2 by enzyme-linked immunosorbent assay (ELISA) offers a far less invasive method of determining HER2 status than a biopsy and consequently has been extensively investigated. Results so far have suggested that changes in serum HER2 concentrations may be useful in predicting response to trastazumab therapy.^[16] However, its ability to determine eligibility for trastazumab therapy is less clear.^[17]

HER2 interactions

HER2/neu has been shown to interact with:

CTNNB1,^[18]^[19]^[20]
DLG4,^[21]
Erbin,^[22]^[23]^[24]
GRB2,^[25]^[26]^[27]
HSP90AA1,^[28]^[29]
IL6ST,^[30]
MUC1,^[31]^[32]
PICK1^[22] and
PIK3R2,^[33]
PLCG1,^[34]^[35] and
SHC1.^[25]^[27]^[36]

References

^ ^a ^b Mitri Z, Constantine T, O'Regan R (2012). "The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New Advances in Therapy". Chemother Res Pract 2012: 743193. doi:10.1155/2012/743193. PMC 3539433. PMID 23320171.
^ Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J et al. (December 1985). "Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene". Science 230 (4730): 1132–9. doi:10.1126/science.2999974. PMID 2999974. CS1 maint: Date and year (link)
^ Olayioye MA (2001). "Update on HER-2 as a target for cancer therapy: intracellular signaling pathways of ErbB2/HER-2 and family members". Breast Cancer Res. 3 (6): 385–9. doi:10.1186/bcr327. PMC 138705. PMID 11737890.
^ Roy V, Perez EA (November 2009). "Beyond trastuzumab: small molecule tyrosine kinase inhibitors in HER-2-positive breast cancer". Oncologist 14 (11): 1061–9. doi:10.1634/theoncologist.2009-0142. PMID 19887469. CS1 maint: Date and year (link)
^ Burstein HJ (October 2005). "The distinctive nature of HER2-positive breast cancers". N. Engl. J. Med. 353 (16): 1652–4. doi:10.1056/NEJMp058197. PMID 16236735. CS1 maint: Date and year (link)
^ Tan M, Yu D (2007). "Molecular mechanisms of erbB2-mediated breast cancer chemoresistance". Adv. Exp. Med. Biol. 608: 119–29. doi:10.1007/978-0-387-74039-3_9. PMID 17993237.
^ Santin AD, Bellone S, Roman JJ, McKenney JK, Pecorelli S (2008). "Trastuzumab treatment in patients with advanced or recurrent endometrial carcinoma overexpressing HER2/neu". Int J Gynaecol Obstet 102 (2): 128–31. doi:10.1016/j.ijgo.2008.04.008. PMID 18555254.
^ Nagy P, Jenei A, Kirsch AK, Szöllosi J, Damjanovich S, Jovin TM (June 1999). "Activation-dependent clustering of the erbB2 receptor tyrosine kinase detected by scanning near-field optical microscopy". J. Cell. Sci. 112 ( Pt 11) (11): 1733–41. PMID 10318765. Vancouver style error (help) CS1 maint: Date and year (link)
^ Kaufmann R, Müller P, Hildenbrand G, Hausmann M, Cremer C (April 2011). "Analysis of Her2/neu membrane protein clusters in different types of breast cancer cells using localization microscopy". J Microsc 242 (1): 46–54. doi:10.1111/j.1365-2818.2010.03436.x. PMID 21118230. Vancouver style error (help) CS1 maint: Date and year (link)
^ Le XF, Pruefer F, Bast RC (2005). "HER2-targeting antibodies modulate the cyclin-dependent kinase inhibitor p27Kip1 via multiple signaling pathways". Cell Cycle 4 (1): 87–95. doi:10.4161/cc.4.1.1360. PMID 15611642.
^ Loi S, Sotiriou C, Haibe-Kains B, Lallemand F, Conus NM, Piccart MJ et al. (2009). "Gene expression profiling identifies activated growth factor signaling in poor prognosis (Luminal-B) estrogen receptor positive breast cancer". BMC Med Genomics 2: 37. doi:10.1186/1755-8794-2-37. PMC 2706265. PMID 19552798. Lay summary – ScienceDaily.
^ "Study sheds new light on tamoxifen resistance". Cordis News. Cordis. 2008-11-13. Retrieved 2008-11-14.
^ Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson RI, Brown M et al. (November 2008). "Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen". Nature 456 (7222): 663–6. doi:10.1038/nature07483. PMC 2920208. PMID 19005469. CS1 maint: Date and year (link)
^ Yonesaka K, Zejnullahu K, Okamoto I, Satoh T, Cappuzzo F, Souglakos J et al. (September 2011). "Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab". Sci Transl Med 3 (99): 99ra86. doi:10.1126/scitranslmed.3002442. PMC 3268675. PMID 21900593. CS1 maint: Date and year (link)
^ Telli ML, Hunt SA, Carlson RW, Guardino AE (August 2007). "Trastuzumab-related cardiotoxicity: calling into question the concept of reversibility". J. Clin. Oncol. 25 (23): 3525–33. doi:10.1200/JCO.2007.11.0106. PMID 17687157. CS1 maint: Date and year (link)
^ Ali SM, Carney WP, Esteva FJ, Fornier M, Harris L, Köstler WJ et al. (September 2008). "Serum HER-2/neu and relative resistance to trastuzumab-based therapy in patients with metastatic breast cancer". Cancer 113 (6): 1294–301. doi:10.1002/cncr.23689. PMID 18661530. Vancouver style error (help) CS1 maint: Date and year (link)
^ Lennon S, Barton C, Banken L, Gianni L, Marty M, Baselga J et al. (April 2009). "Utility of serum HER2 extracellular domain assessment in clinical decision making: pooled analysis of four trials of trastuzumab in metastatic breast cancer". J. Clin. Oncol. 27 (10): 1685–93. doi:10.1200/JCO.2008.16.8351. PMID 19255335. CS1 maint: Date and year (link)
^ Schroeder JA, Adriance MC, McConnell EJ, Thompson MC, Pockaj B, Gendler SJ (2002). "ErbB-beta-catenin complexes are associated with human infiltrating ductal breast and murine mammary tumor virus (MMTV)-Wnt-1 and MMTV-c-Neu transgenic carcinomas". J. Biol. Chem. 277 (25): 22692–8. doi:10.1074/jbc.M201975200. PMID 11950845.
^ Bonvini P, An WG, Rosolen A, Nguyen P, Trepel J, Garcia de Herreros A et al. (2001). "Geldanamycin abrogates ErbB2 association with proteasome-resistant beta-catenin in melanoma cells, increases beta-catenin-E-cadherin association, and decreases beta-catenin-sensitive transcription". Cancer Res. 61 (4): 1671–7. PMID 11245482.
^ Kanai Y, Ochiai A, Shibata T, Oyama T, Ushijima S, Akimoto S et al. (1995). "c-erbB-2 gene product directly associates with beta-catenin and plakoglobin". Biochem. Biophys. Res. Commun. 208 (3): 1067–72. doi:10.1006/bbrc.1995.1443. PMID 7702605.
^ Huang YZ, Won S, Ali DW, Wang Q, Tanowitz M, Du QS et al. (2000). "Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses". Neuron 26 (2): 443–55. doi:10.1016/s0896-6273(00)81176-9. PMID 10839362.
^ ^a ^b Jaulin-Bastard F, Saito H, Le Bivic A, Ollendorff V, Marchetto S, Birnbaum D et al. (2001). "The ERBB2/HER2 receptor differentially interacts with ERBIN and PICK1 PSD-95/DLG/ZO-1 domain proteins". J. Biol. Chem. 276 (18): 15256–63. doi:10.1074/jbc.M010032200. PMID 11278603.
^ Bilder D, Birnbaum D, Borg JP, Bryant P, Huigbretse J, Jansen E et al. (2000). "Collective nomenclature for LAP proteins". Nat. Cell Biol. 2 (7): E114. doi:10.1038/35017119.
^ Huang YZ, Zang M, Xiong WC, Luo Z, Mei L (2003). "Erbin suppresses the MAP kinase pathway". J. Biol. Chem. 278 (2): 1108–14. doi:10.1074/jbc.M205413200. PMID 12379659.
^ ^a ^b Schulze WX, Deng L, Mann M (2005). "Phosphotyrosine interactome of the ErbB-receptor kinase family". Mol. Syst. Biol. 1: 2005.0008. doi:10.1038/msb4100012. PMC 1681463. PMID 16729043.
^ Bourguignon LY, Zhu H, Zhou B, Diedrich F, Singleton PA, Hung MC (2001). "Hyaluronan promotes CD44v3-Vav2 interaction with Grb2-p185(HER2) and induces Rac1 and Ras signaling during ovarian tumor cell migration and growth". J. Biol. Chem. 276 (52): 48679–92. doi:10.1074/jbc.M106759200. PMID 11606575.
^ ^a ^b Olayioye MA, Graus-Porta D, Beerli RR, Rohrer J, Gay B, Hynes NE (1998). "ErbB-1 and ErbB-2 acquire distinct signaling properties dependent upon their dimerization partner". Mol. Cell. Biol. 18 (9): 5042–51. PMC 109089. PMID 9710588.
^ Xu W, Mimnaugh E, Rosser MF, Nicchitta C, Marcu M, Yarden Y et al. (2001). "Sensitivity of mature Erbb2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90". J. Biol. Chem. 276 (5): 3702–8. doi:10.1074/jbc.M006864200. PMID 11071886.
^ Jeong JH, An JY, Kwon YT, Li LY, Lee YJ (2008). "Quercetin-induced ubiquitination and down-regulation of Her-2/neu". J. Cell. Biochem. 105 (2): 585–95. doi:10.1002/jcb.21859. PMC 2575035. PMID 18655187.
^ Grant SL, Hammacher A, Douglas AM, Goss GA, Mansfield RK, Heath JK et al. (2002). "An unexpected biochemical and functional interaction between gp130 and the EGF receptor family in breast cancer cells". Oncogene 21 (3): 460–74. doi:10.1038/sj.onc.1205100. PMID 11821958.
^ Li Y, Yu WH, Ren J, Chen W, Huang L, Kharbanda S et al. (2003). "Heregulin targets gamma-catenin to the nucleolus by a mechanism dependent on the DF3/MUC1 oncoprotein". Mol. Cancer Res. 1 (10): 765–75. PMID 12939402.
^ Schroeder JA, Thompson MC, Gardner MM, Gendler SJ (2001). "Transgenic MUC1 interacts with epidermal growth factor receptor and correlates with mitogen-activated protein kinase activation in the mouse mammary gland". J. Biol. Chem. 276 (16): 13057–64. doi:10.1074/jbc.M011248200. PMID 11278868.
^ Gout I, Dhand R, Panayotou G, Fry MJ, Hiles I, Otsu M et al. (1992). "Expression and characterization of the p85 subunit of the phosphatidylinositol 3-kinase complex and a related p85 beta protein by using the baculovirus expression system". Biochem. J. 288 ( Pt 2) (2): 395–405. PMC 1132024. PMID 1334406.
^ Peles E, Levy RB, Or E, Ullrich A, Yarden Y (1991). "Oncogenic forms of the neu/HER2 tyrosine kinase are permanently coupled to phospholipase C gamma". EMBO J. 10 (8): 2077–86. PMC 452891. PMID 1676673.
^ Arteaga CL, Johnson MD, Todderud G, Coffey RJ, Carpenter G, Page DL (1991). "Elevated content of the tyrosine kinase substrate phospholipase C-gamma 1 in primary human breast carcinomas". Proc. Natl. Acad. Sci. U.S.A. 88 (23): 10435–9. doi:10.1073/pnas.88.23.10435. PMC 52943. PMID 1683701.
^ Wong L, Deb TB, Thompson SA, Wells A, Johnson GR (1999). "A differential requirement for the COOH-terminal region of the epidermal growth factor (EGF) receptor in amphiregulin and EGF mitogenic signaling". J. Biol. Chem. 274 (13): 8900–9. doi:10.1074/jbc.274.13.8900. PMID 10085134.

External links

ERBB2 expression across human cancerous and healthy tissues
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
HerceptinR : Herceptin Resistance Database for Understanding Mechanism of Resistance in Breast Cancer Patients. Sci. Rep. 4:4483
Receptor, erbB-2 at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. 乳癌におけるHER2と治療の効果予測 her2 and predicting response to therapy in breast cancer
2. Adjuvant systemic therapy for HER2-positive breast cancer
3. 大腸癌の分子遺伝学 molecular genetics of colorectal cancer
4. 癌免疫療法の原則 principles of cancer immunotherapy
5. 限局性初期乳癌における予後予測因子 prognostic and predictive factors in early non metastatic breast cancer

English Journal

Aberrant keratin 7 and 20 expression in triple-negative carcinoma of the breast.

Kuroda H1, Imai Y2, Yamagishi H2, Ueda Y3, Kuroso K3, Oishi Y4, Ohashi H5, Yamashita A5, Yashiro Y5, Fukushima H5.
Annals of diagnostic pathology.Ann Diagn Pathol.2016 Feb;20:36-9. doi: 10.1016/j.anndiagpath.2015.10.007. Epub 2015 Oct 31.
Early studies characterizing the keratin (K) profile of various epithelial tissues indicated that breast carcinoma is K7 positive and K20 negative, but not all breast carcinomas show this profile. Triple-negative carcinoma (TNC) has been characterized by negativity for estrogen receptor (ER), proges
PMID 26670478

Heterogeneous Her2/Neu expression in gastric and gastroesophageal cancer-reply.

Ge X1, Wang H1, Xu C1, Liu Y1, Ji Y1, Tan Y1, Hou Y2, Qin J3.
Human pathology.Hum Pathol.2016 Feb;48:174-5. doi: 10.1016/j.humpath.2015.08.024. Epub 2015 Oct 29.
PMID 26697996

Heterogeneous Her2/Neu expression in gastric and gastroesophageal cancer.

Grillo F1, Fassan M2, Fiocca R3, Mastracci L3.
Human pathology.Hum Pathol.2016 Feb;48:173-4. doi: 10.1016/j.humpath.2015.08.023. Epub 2015 Oct 29.
PMID 26688559

Japanese Journal

PS-220-8 免疫組織化学染色法(IHC)にてHER2 score 2と判定された乳癌におけるHER2/neu遺伝子増幅に関する研究(PS-220 乳腺病理診断,ポスターセッション,第114回日本外科学会定期学術集会)

河野麻優子,徳永えり子,山下奈真,田中仁寛,田尻裕匡,堤智崇,由茅隆文,笠木勇太,財津瑛子,津田康雄,日高元,上尾裕紀,大津甫,河野浩幸,安藤幸滋,日吉幸晴,伊藤修平,佐伯浩司,沖英次,森田勝,前原喜彦
日本外科学会雑誌 115(臨時増刊号_2), 1015, 2014-03-05
NAID 110009871664

急速に進行増大したepidermal growth factor receptor陽性乳腺扁平上皮癌の1例

安座間隆,平尾隆文,松田泰樹,小林哲郎
日本外科系連合学会誌 38(4), 785-789, 2013-08-30
… は56歳，女性．右乳房腫瘤と乳房痛を主訴として来院した．右乳房に６cm大の腫瘤を触知し，切開生検にて乳腺原発扁平上皮癌と診断され，乳房切除術が施行された．病理組織学的所見はER陰性，PgR陰性およびHER2陰性であった．Epidermal growth factor receptor（EGFR）は陽性であった．術後早期に胸壁再発がみられたため，胸壁への放射線照射および，全身化学療法としてcapecitabine/cisplatin療法とdocetaxel療法を施行したがいずれも …
NAID 10031201413

イレウスを契機に診断された乳癌小腸転移の1例

高橋保正,関川浩司,後藤学,成田和広,太田竜,池田博斉
日本臨床外科学会雑誌 = The journal of the Japan Surgical Association 74(7), 1787-1792, 2013-07-25
… 腸壁の全周性肥厚を認め切除した．摘出標本の病理所見では乳癌由来と考えられる核異型の強い腫瘍細胞が漿膜下組織を中心に増殖し粘膜面にまで達していた．免疫組織学的にはER陽性，PgR陰性，Her2/neu蛋白は陽性であり初回の切除標本の組織所見と一致したため，乳癌の小腸転移によるイレウスと最終診断した．術後経過は良好で術後17日目に軽快退院したが術後83日目に癌性悪液質にて死亡した …
NAID 10031203013

Related Pictures

to block egfr and her2 neu signals include HER2 - HER2/neu Cancer: do's&dont's: Oncogen Her2-Neu Trastuzumab Fab-HER2 complex 1N8Z.png HER2+ breast cancer | The Musings of a Signalling Pathways of HER2/neu

★リンクテーブル★

「n」

V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2
	; PDB rendering based on 1n8z.
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	1MFG, 1MFL, 1MW4, 1N8Z, 1OVC, 1QR1, 1S78, 2A91, 2JWA, 2KS1, 2L4K, 3BE1, 3H3B, 3MZW, 3N85, 3PP0, 3RCD, 4GFU, 4HRL, 4HRM, 4HRN
Identifiers
Symbols	ERBB2 ; CD340; HER-2; HER-2/neu; HER2; MLN 19; NEU; NGL; TKR1
External IDs	OMIM: 164870 MGI: 95410 HomoloGene: 3273 ChEMBL: 1824 GeneCards: ERBB2 Gene
EC number	2.7.10.1
Gene ontology
Molecular function	• RNA polymerase I core binding; • protein tyrosine kinase activity; • transmembrane receptor protein tyrosine kinase activity; • receptor signaling protein tyrosine kinase activity; • transmembrane signaling receptor activity; • epidermal growth factor-activated receptor activity; • protein binding; • ATP binding; • protein C-terminus binding; • growth factor binding; • protein phosphatase binding; • identical protein binding; • ErbB-3 class receptor binding; • protein heterodimerization activity; • protein dimerization activity;
Cellular component	• nucleus; • cytoplasm; • plasma membrane; • endosome membrane; • integral component of membrane; • basolateral plasma membrane; • apical plasma membrane; • cytoplasmic vesicle; • receptor complex; • perinuclear region of cytoplasm;
Biological process	• positive regulation of protein phosphorylation; • transcription, DNA-templated; • protein phosphorylation; • signal transduction; • cell surface receptor signaling pathway; • enzyme linked receptor protein signaling pathway; • transmembrane receptor protein tyrosine kinase signaling pathway; • epidermal growth factor receptor signaling pathway; • nervous system development; • axon guidance; • peripheral nervous system development; • heart development; • neuromuscular junction development; • motor neuron axon guidance; • cell proliferation; • fibroblast growth factor receptor signaling pathway; • phosphatidylinositol 3-kinase signaling; • peptidyl-tyrosine phosphorylation; • signal transduction by phosphorylation; • positive regulation of cell growth; • mammary gland development; • positive regulation of Rho GTPase activity; • regulation of microtubule-based process; • negative regulation of immature T cell proliferation in thymus; • Fc-epsilon receptor signaling pathway; • wound healing; • myelination; • positive regulation of MAP kinase activity; • innate immune response; • positive regulation of translation; • regulation of angiogenesis; • positive regulation of cell adhesion; • positive regulation of transcription from RNA polymerase I promoter; • positive regulation of transcription from RNA polymerase III promoter; • protein autophosphorylation; • neurotrophin TRK receptor signaling pathway; • phosphatidylinositol-mediated signaling; • positive regulation of epithelial cell proliferation; • regulation of ERK1 and ERK2 cascade;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	This box: view; talk; edit;

　　[★]

n.

例数

関: number of experiment、sample size

pの前の[n]はmと記載する。synptom→symptom

「HER2」

　　[★] ヒト上皮細胞成長因子受容体2, human epidermal growth factor receptor 2

[Coussens1985-1] Coussens L, Yang-Feng TL, Liao YC, et al. "Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene." Science, Vol.230, No.4730, 1985, p.p. 1132-1139. PMID 2999974

[Semba1985-2] Semba K, Kamata N, Toyoshima K, et al. "A v-erbB-related protooncogene, c-erbB-2, is distinct from the c-erbB-1/epidermal growth factor-receptor gene and is amplified in a human salivary gland adenocarcinoma." Proceedings of National Academy of Science of United States of America, Vol.82, No.19, 1985, p.p. 6497-6501. PMID 2995967

[3] King CR, Kraus MH, Saronson SA. "Amplification of a novel v-erbB-related gene in a human mammary carcinoma." Science, Vol.229, No.4717, 1985, p.p. 974-976. PMID 2992089

[4] Akiyama T, Sudo C, Ogawara H, et al. "The product of the human c-erbB-2 gene: a 185-kilodalton glycoprotein with tyrosine kinase activity." Science, Vol.232, No.4758, 1986, p.p. 1644-1646. PMID 3012781

[5] Lee KF, Simon H, Chen H, et al. "Requirement for neuregulin receptor erbB2 in neural and cardiac development." Science, Vol.378, No.6555, 1995, p.p. 394-398. PMID 7477377

[6] Crone SA, Zhao YY, Fan L, et al. "ErbB2 is essential in the prevention of dilated cardiomyopathy." Nature Medicine, Vol.8, No.5, 2002, p.p. 459-465. PMID 11984589

[7] Ozcelik C, Erdmann B, Pilz B, et al. "Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy." Proceedings of National Academy of Science of United States of America, Vol.99, Bo.13, 2002, p.p. 8880-8885. PMID 12072561

[8] Crone SA, Negro A, Trumpp A, et al. "Colonic epithelial expression of ErbB2 is required for postnatal maintenance of the enteric nervous system." Neuron, Vol.37, No.1, p.p. 29-40. PMID 12526770

[9] Graus-Porta D, Beerli RR, Daly JM, Hynes NE. "ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling." EMBO Journal, Vol.16, No.7, 1997, p.p. 1647-1655. PMID 9130710

[10] Tse C, Gauchez A, Jacot W, Lamy P. HER2 shedding and serum HER2 extracellular domain: Biology and clinical utility in breast cancer Cancer Treatment Reviews 2011

[11] ERBB2 - Entrez Gene

[Slamon1987-12] Slamon DJ, Clark GM, Wong SG, et al. "Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene." Science, Vol.235, No.4785, 1987, p.p. 177-182. PMID 3798106

[13] American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, McShane LM, Paik S, Pegram MD, Perez EA, Press MF, Rhodes A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M, Wheeler TM, Hayes DF; American Society of Clinical Oncology/College of American Pathologists. Arch Pathol Lab Med. 2007;131(1):18-43.

[14] 熊木伸枝、梅村しのぶ「HER2の検索法と陽性の基準」　戸井雅和編「みんなに役立つ乳癌の基礎と臨床」p372

[15] Slamon DJ, Leyland-Jones B, Shak S, et al. "Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2." NEJM., Vol.344, No.11, 2001, p.p. 783-792. PMID 11248153

[pmid23320171-1] Mitri Z, Constantine T, O'Regan R (2012). "The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New Advances in Therapy". Chemother Res Pract 2012: 743193. doi:10.1155/2012/743193. PMC 3539433. PMID 23320171.

[Coussens_1985-2] Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J et al. (December 1985). "Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene". Science 230 (4730): 1132–9. doi:10.1126/science.2999974. PMID 2999974. CS1 maint: Date and year (link)

[Olayioye_2001-3] Olayioye MA (2001). "Update on HER-2 as a target for cancer therapy: intracellular signaling pathways of ErbB2/HER-2 and family members". Breast Cancer Res. 3 (6): 385–9. doi:10.1186/bcr327. PMC 138705. PMID 11737890.

[pmid19887469-4] Roy V, Perez EA (November 2009). "Beyond trastuzumab: small molecule tyrosine kinase inhibitors in HER-2-positive breast cancer". Oncologist 14 (11): 1061–9. doi:10.1634/theoncologist.2009-0142. PMID 19887469. CS1 maint: Date and year (link)

[pmid16236735-5] Burstein HJ (October 2005). "The distinctive nature of HER2-positive breast cancers". N. Engl. J. Med. 353 (16): 1652–4. doi:10.1056/NEJMp058197. PMID 16236735. CS1 maint: Date and year (link)

[pmid17993237-6] Tan M, Yu D (2007). "Molecular mechanisms of erbB2-mediated breast cancer chemoresistance". Adv. Exp. Med. Biol. 608: 119–29. doi:10.1007/978-0-387-74039-3_9. PMID 17993237.

[7] Santin AD, Bellone S, Roman JJ, McKenney JK, Pecorelli S (2008). "Trastuzumab treatment in patients with advanced or recurrent endometrial carcinoma overexpressing HER2/neu". Int J Gynaecol Obstet 102 (2): 128–31. doi:10.1016/j.ijgo.2008.04.008. PMID 18555254.

[pmid10318765-8] Nagy P, Jenei A, Kirsch AK, Szöllosi J, Damjanovich S, Jovin TM (June 1999). "Activation-dependent clustering of the erbB2 receptor tyrosine kinase detected by scanning near-field optical microscopy". J. Cell. Sci. 112 ( Pt 11) (11): 1733–41. PMID 10318765. Vancouver style error (help) CS1 maint: Date and year (link)

[pmid21118230-9] Kaufmann R, Müller P, Hildenbrand G, Hausmann M, Cremer C (April 2011). "Analysis of Her2/neu membrane protein clusters in different types of breast cancer cells using localization microscopy". J Microsc 242 (1): 46–54. doi:10.1111/j.1365-2818.2010.03436.x. PMID 21118230. Vancouver style error (help) CS1 maint: Date and year (link)

[Le_2005-10] Le XF, Pruefer F, Bast RC (2005). "HER2-targeting antibodies modulate the cyclin-dependent kinase inhibitor p27Kip1 via multiple signaling pathways". Cell Cycle 4 (1): 87–95. doi:10.4161/cc.4.1.1360. PMID 15611642.

[pmid19552798-11] Loi S, Sotiriou C, Haibe-Kains B, Lallemand F, Conus NM, Piccart MJ et al. (2009). "Gene expression profiling identifies activated growth factor signaling in poor prognosis (Luminal-B) estrogen receptor positive breast cancer". BMC Med Genomics 2: 37. doi:10.1186/1755-8794-2-37. PMC 2706265. PMID 19552798. Lay summary – ScienceDaily.

[urlCORDIS_:_News-12] "Study sheds new light on tamoxifen resistance". Cordis News. Cordis. 2008-11-13. Retrieved 2008-11-14.

[Hurtado1_2008-13] Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson RI, Brown M et al. (November 2008). "Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen". Nature 456 (7222): 663–6. doi:10.1038/nature07483. PMC 2920208. PMID 19005469. CS1 maint: Date and year (link)

[YonesakaZejnullahu2011-14] Yonesaka K, Zejnullahu K, Okamoto I, Satoh T, Cappuzzo F, Souglakos J et al. (September 2011). "Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab". Sci Transl Med 3 (99): 99ra86. doi:10.1126/scitranslmed.3002442. PMC 3268675. PMID 21900593. CS1 maint: Date and year (link)

[pmid17687157-15] Telli ML, Hunt SA, Carlson RW, Guardino AE (August 2007). "Trastuzumab-related cardiotoxicity: calling into question the concept of reversibility". J. Clin. Oncol. 25 (23): 3525–33. doi:10.1200/JCO.2007.11.0106. PMID 17687157. CS1 maint: Date and year (link)

[pmid18661530-16] Ali SM, Carney WP, Esteva FJ, Fornier M, Harris L, Köstler WJ et al. (September 2008). "Serum HER-2/neu and relative resistance to trastuzumab-based therapy in patients with metastatic breast cancer". Cancer 113 (6): 1294–301. doi:10.1002/cncr.23689. PMID 18661530. Vancouver style error (help) CS1 maint: Date and year (link)

[pmid19255335-17] Lennon S, Barton C, Banken L, Gianni L, Marty M, Baselga J et al. (April 2009). "Utility of serum HER2 extracellular domain assessment in clinical decision making: pooled analysis of four trials of trastuzumab in metastatic breast cancer". J. Clin. Oncol. 27 (10): 1685–93. doi:10.1200/JCO.2008.16.8351. PMID 19255335. CS1 maint: Date and year (link)

[pmid11950845-18] Schroeder JA, Adriance MC, McConnell EJ, Thompson MC, Pockaj B, Gendler SJ (2002). "ErbB-beta-catenin complexes are associated with human infiltrating ductal breast and murine mammary tumor virus (MMTV)-Wnt-1 and MMTV-c-Neu transgenic carcinomas". J. Biol. Chem. 277 (25): 22692–8. doi:10.1074/jbc.M201975200. PMID 11950845.

[pmid11245482-19] Bonvini P, An WG, Rosolen A, Nguyen P, Trepel J, Garcia de Herreros A et al. (2001). "Geldanamycin abrogates ErbB2 association with proteasome-resistant beta-catenin in melanoma cells, increases beta-catenin-E-cadherin association, and decreases beta-catenin-sensitive transcription". Cancer Res. 61 (4): 1671–7. PMID 11245482.

[pmid7702605-20] Kanai Y, Ochiai A, Shibata T, Oyama T, Ushijima S, Akimoto S et al. (1995). "c-erbB-2 gene product directly associates with beta-catenin and plakoglobin". Biochem. Biophys. Res. Commun. 208 (3): 1067–72. doi:10.1006/bbrc.1995.1443. PMID 7702605.

[pmid10839362-21] Huang YZ, Won S, Ali DW, Wang Q, Tanowitz M, Du QS et al. (2000). "Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses". Neuron 26 (2): 443–55. doi:10.1016/s0896-6273(00)81176-9. PMID 10839362.

[pmid11278603-22] Jaulin-Bastard F, Saito H, Le Bivic A, Ollendorff V, Marchetto S, Birnbaum D et al. (2001). "The ERBB2/HER2 receptor differentially interacts with ERBIN and PICK1 PSD-95/DLG/ZO-1 domain proteins". J. Biol. Chem. 276 (18): 15256–63. doi:10.1074/jbc.M010032200. PMID 11278603.

[pmid10878805-23] Bilder D, Birnbaum D, Borg JP, Bryant P, Huigbretse J, Jansen E et al. (2000). "Collective nomenclature for LAP proteins". Nat. Cell Biol. 2 (7): E114. doi:10.1038/35017119.

[pmid12379659-24] Huang YZ, Zang M, Xiong WC, Luo Z, Mei L (2003). "Erbin suppresses the MAP kinase pathway". J. Biol. Chem. 278 (2): 1108–14. doi:10.1074/jbc.M205413200. PMID 12379659.

[pmid16729043-25] Schulze WX, Deng L, Mann M (2005). "Phosphotyrosine interactome of the ErbB-receptor kinase family". Mol. Syst. Biol. 1: 2005.0008. doi:10.1038/msb4100012. PMC 1681463. PMID 16729043.

[pmid11606575-26] Bourguignon LY, Zhu H, Zhou B, Diedrich F, Singleton PA, Hung MC (2001). "Hyaluronan promotes CD44v3-Vav2 interaction with Grb2-p185(HER2) and induces Rac1 and Ras signaling during ovarian tumor cell migration and growth". J. Biol. Chem. 276 (52): 48679–92. doi:10.1074/jbc.M106759200. PMID 11606575.

[pmid9710588-27] Olayioye MA, Graus-Porta D, Beerli RR, Rohrer J, Gay B, Hynes NE (1998). "ErbB-1 and ErbB-2 acquire distinct signaling properties dependent upon their dimerization partner". Mol. Cell. Biol. 18 (9): 5042–51. PMC 109089. PMID 9710588.

[pmid11071886-28] Xu W, Mimnaugh E, Rosser MF, Nicchitta C, Marcu M, Yarden Y et al. (2001). "Sensitivity of mature Erbb2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90". J. Biol. Chem. 276 (5): 3702–8. doi:10.1074/jbc.M006864200. PMID 11071886.

[pmid18655187-29] Jeong JH, An JY, Kwon YT, Li LY, Lee YJ (2008). "Quercetin-induced ubiquitination and down-regulation of Her-2/neu". J. Cell. Biochem. 105 (2): 585–95. doi:10.1002/jcb.21859. PMC 2575035. PMID 18655187.

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HER2/neu