表皮生長因子受體 (EGFR) 訊號傳導

• 表皮生長因子受體 (EGFR) 與配體<
• 發育與疾病中的表皮生長因子受體 (EGFR)
• 背景

  表皮生長因子受體 (EGFR) 是最早被發現的受體酪氨酸激酶家族 (RTK) 的典型成員。它被細胞外環境中的各種配體激活，並傳遞細胞反應，介導各種細胞活動，包括細胞增殖、細胞存活、生長和發育。表皮生长因子受体在许多器官中表达，异常表达与各种癌症有关。本綜述重點介紹表皮生長因子受體通路的各種信號元件及其信號轉導通路。

  表皮生長因子受體 (EGFR) 與配體

  ErbB家族由四種受體組成，包括EGFR (ErbB-1/HER1)、ErbB-2 (Neu，HER2)、ErbB-3 (HER3)和ErbB-4 (HER4)。這種受體酪氨酸激酶家族（RTK）的蛋白質具有細胞外配體結合域、疏水跨膜域和細胞質酪氨酸激酶域（表 1）。ErbB 受體由 EGF-家族的生長因子活化，其特徵在於有三個二硫鍵賦予結合特異性。其他結構基元包括類免疫球蛋白結構域、肝素結合位點和糖基化位點^1,2。

表一 表皮生長因子受體和配體

Receptor<	配體
EGF, Transforming growth factor-α (TGF-α), ；Amphiregulin (AR), Betacellulin (BTC),  肝素結合表皮生長因子 (BTC)/(HB-EGF)及 Epiregulin (EPR)<
ErbB2	無
ErbB3	無
ErbB4	Betacellulin (BTC), 肝素結合EGF樣生長因子 (HB-EGF),  Epiregulin (EPR), Tomoregulin, Epiregulina href="/TW/zh/product/sigma/srp3055">NRG-1、NRG2、NRG3 和 NRG4

受體活化

受體活化是由細胞膜上的一連串事件所觸發。

• 配體結合： 每個配體結合到同源 ErbB 受體的細胞外域
• 受體二聚化： 配體結合誘導形成受體同源或異源二聚體³。
• 激酶域的活化： 羧基末端尾部內的關鍵酪氨酸殘基的自動磷酸化會活化 受體，並作為具有 Src 同源體 2 (SH2) 和磷酸酪氨酸結合域 (PTB) 的蛋白質的對接位點，以觸發細胞信號傳導^3,4。

圖 1. 表皮生長因子受體信號

Ras/Raf 訊息傳遞串聯

受體： Dimerization of any two ErbB receptors

Key Functions： 細胞存活和細胞 增殖⁵

受體活化後，Grb2和Sos形成的複合物會直接或通過與適應蛋白Shc結合，與受體上特定的酪氨酸殘基結合^6,7。這會導致 Sos 的構象改變，進而招募和活化 Ras-GDP。Ras-GDP 啟動 Raf-1，Raf-1 進一步啟動細胞外調節激酶 1 和 2 (ERK1 和 ERK2)，這些激酶是透過有細胞分裂原活化蛋白激酶 (MAPK) 介導^8,9。活化的激酶最終移動到細胞核中，使特定的轉錄因子（如 Elk1 和 C-myc）磷酸化，從而誘導細胞增殖。

磷脂酰肌醇 3- 激酶/Akt 訊號連鎖反應

受體： ErbB2 與 ErbB4 或 ErbB3 的二聚化

Key Functions： 細胞生長、抗凋亡、細胞侵襲和 遷移¹⁰

磷脂酰肌醇由 p85 和 p110 子單元組成，它們與 ErbB 受體對接以產生次要信使磷脂酰肌醇 3,4,5 三磷酸鹽，進一步活化絲氨酸/蘇氨酸激酶 AKT。活化後，AKT 磷酸化 mTOR，隨後磷酸化 S6K，S6K 介導蛋白質的合成¹⁰。

Signal Transducers and Activators of Transcription (STAT) Pathway

受體： ErbB

Key Functions： 腫瘤進程、腫瘤生成和 血管生成¹¹

磷脂酶 Cγ 訊號傳導

受體： ErbB1

主要功能： 調節離子通道、細胞遷移、鈣介導的 信號傳導¹³

磷脂酶 Cγ與 ErbB1 相互作用，水解磷脂酰肌醇 4,5- 二磷酸 (PIP2) 以產生肌醇 1,3,5- 三磷酸 (IP3) 和 1,2- 二酰甘油 (DAG)。IP3 會增加細胞內的鈣含量，而 DAG 則會介導蛋白激酶 C (PKC)¹³ 的活化。14 。

Nck/PAK 訊息傳遞連鎖反應

受體： ErbB1

主要功能： 細胞存活和細胞 遷移¹⁵

Nck是一種含有SH2結構域的適應蛋白，它能與EGF受體結合並引發下游信號傳導。Nck 透過 SH3 結構域活化 PAK1 (p21/CDC42/Rac1-Activated Kinase-1)。活化的 PAK1 會反過來活化分別由 MEKK1（MAP/ERK Kinase Kinase-1）和 MKK4/7（MAP Kinase Kinase-4/7）介導的 JNKs（c-Jun Kinases）。JNK 會轉移至細胞核，並磷酸化 c-Fos 和 c-Jun¹⁶等轉錄因子。

Cbl 介導的內吞

受體： ErbB1

Key Functions： 內吞

配體結合後，Cbl是一種底物，可透過SH2結構域或GRB2適應蛋白與EGF受體結合，並引發溶酶體降解 受體¹⁷。

EGFR轉移到細胞核中

EGF 受體具有逃避溶酶體降解並轉移到細胞核中介導生物功能的能力。在細胞核中，這些受體促進細胞存活基因如 Cyclin D1 基因的轉錄，同時也是 STAT 和 E2F1 轉錄因子¹⁸的輔助因子。 表皮生長因子受體的核定位與疾病的嚴重性有關，它賦予抗癌 mAbs 生長抑制效果的抵抗力¹⁹。

我們最受歡迎的高品質 EGF 蛋白供您研究使用

。

Product No.	SRP3196	SRP3329	SRP3027	E9644	E5036	E4127	E5160	E1257	SRP6253
Species	小鼠	Mouse<	人類	人類	小鼠	小鼠<	小鼠	人類
Expressed in/ extracted from	E.大腸桿菌	E.大腸桿菌	E.大腸桿菌	大腸桿菌	上頜下腺	E.大腸桿菌	上頜下腺	HEK293
經內毒素測試<	✔	✔	✔	✔	✔	✔	✔	✔	✔	✔	✔
無載體	✘	✔	✔	✘	✔	✘	✘	✘	✘	✘	✘
純度	≥98%	≥98%	≥98%	≥97%	≥97%		≥90%		≥97%
ED50/EC50	≤0.1 ng/mL	≤0.1 ng/mL	≤0.1 ng/mL	≤0.08-0.8 ng/mL	0.08-0.8 ng/mL	0.1-10 ng/mL	0.05-1 ng/mL	0.02-2.0 ng/mL	0.1-10 ng/mL

發育與疾病中的EGFRs

EGF受體 及其配體對各種器官的發育非常重要；EGFR基因敲除模型顯示胚胎致死和有缺陷的組織/器官。^20-25 EGFR在許多疾病中被異常激活或表達。20-25 EGFR在許多疾病中被異常活化或表達，特別是它們在癌症進程中的角色已被深入研究（表2）。

表二 人類疾病中表皮生長因子受體的基因改變

遺傳改變<	大腸癌的西妥昔單抗耐藥27
非小細胞肺癌
非小細胞甲狀腺癌29
肺腺癌
發炎性皮膚和腸道疾病36
Overexpression of ErbB2	Gastric and breast cancer31,32
表皮生长因子受体信号传导失调	EGFR 的過度表達	生成新的少突胶质细胞對早產兒白質損傷的潛在治療35

結論

EGFR信號在發育過程中具有多種功能，並調節各種生理功能。EGF 受體的異常表達與各種疾病的關係越來越密切。更多的研究尚待清楚揭示 EGFR 信號傳導在各種器官發育中的作用，包括腦部、心臟、皮膚、腎臟、乳腺和肺部。為了對抗抗藥性癌症病症，找出具有高效能、持續藥物活性及較少交叉反應的新型藥物，持續引起許多研究的興趣。

1. Arteaga C, Engelman J. 2014. ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics. Cancer Cell. 25(3):282-303. https://doi.org/10.1016/j.ccr.2014.02.025

2. Kovacs E, Zorn JA, Huang Y, Barros T, Kuriyan J. 2015. A Structural Perspective on the Regulation of the Epidermal Growth Factor Receptor. Annu. Rev. Biochem.. 84(1):739-764. https://doi.org/10.1146/annurev-biochem-060614-034402

3. Capuani F, Conte A, Argenzio E, Marchetti L, Priami C, Polo S, Di Fiore PP, Sigismund S, Ciliberto A. 2015. Quantitative analysis reveals how EGFR activation and downregulation are coupled in normal but not in cancer cells. Nat Commun. 6(1): https://doi.org/10.1038/ncomms8999

4. Zhang X, Gureasko J, Shen K, Cole PA, Kuriyan J. 2006. An Allosteric Mechanism for Activation of the Kinase Domain of Epidermal Growth Factor Receptor. Cell. 125(6):1137-1149. https://doi.org/10.1016/j.cell.2006.05.013

5. Gaestel M. 2006. MAPKAP kinases ? MKs ? two's company, three's a crowd. Nat Rev Mol Cell Biol. 7(2):120-130. https://doi.org/10.1038/nrm1834

6. Lowenstein E, Daly R, Batzer A, Li W, Margolis B, Lammers R, Ullrich A, Skolnik E, Bar-Sagi D, Schlessinger J. 1992. The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell. 70(3):431-442. https://doi.org/10.1016/0092-8674(92)90167-b

7. Batzer AG, Rotin D, Ureña JM, Skolnik EY, Schlessinger J. 1994. Hierarchy of binding sites for Grb2 and Shc on the epidermal growth factor receptor.. Mol. Cell. Biol.. 14(8):5192-5201. https://doi.org/10.1128/mcb.14.8.5192

8. B H, S I R, J D. 1994. Interaction of Ras and Raf in intact mammalian cells upon extracellular stimulation. J Biol Chem. 269(6):3913-6.

9. Liebmann C. 2001. Regulation of MAP kinase activity by peptide receptor signalling pathway: Paradigms of multiplicity. Cellular Signalling. 13(11):777-785. https://doi.org/10.1016/s0898-6568(01)00192-9

10. Vivanco I, Sawyers CL. 2002. The phosphatidylinositol 3-Kinase?AKT pathway in human cancer. Nat Rev Cancer. 2(7):489-501. https://doi.org/10.1038/nrc839

11. Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J, Zhang S, Wang T, Sinibaldi D, Coppola D, et al. 2002. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene. 21(13):2000-2008. https://doi.org/10.1038/sj.onc.1205260

12. Bromberg J. 2002. Stat proteins and oncogenesis. J. Clin. Invest.. 109(9):1139-1142. https://doi.org/10.1172/jci0215617

13. Patterson RL, van Rossum DB, Nikolaidis N, Gill DL, Snyder SH. 2005. Phospholipase C-?: diverse roles in receptor-mediated calcium signaling. Trends in Biochemical Sciences. 30(12):688-697. https://doi.org/10.1016/j.tibs.2005.10.005

14. Scho?nwasser DC, Marais RM, Marshall CJ, Parker PJ. 1998. Activation of the Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Pathway by Conventional, Novel, and Atypical Protein Kinase C Isotypes. Mol. Cell. Biol.. 18(2):790-798. https://doi.org/10.1128/mcb.18.2.790

15. Ye DZ, Field J. 2012. PAK signaling in cancer. Cellular Logistics. 2(2):105-116. https://doi.org/10.4161/cl.21882

16. Tomar A, Schlaepfer DD. 2010. A PAK-Activated Linker for EGFR and FAK. Developmental Cell. 18(2):170-172. https://doi.org/10.1016/j.devcel.2010.01.013

17. Yu P, Fan Y, Qu X, Zhang J, Song N, Liu J, Liu Y. 2016. Cbl-b regulates the sensitivity of cetuximab through ubiquitin-proteasome system in human gastric cancer cells. J Buon. 21(4):867-873.

18. Lo H, Hsu S, Ali-Seyed M, Gunduz M, Xia W, Wei Y, Bartholomeusz G, Shih J, Hung M. 2005. Nuclear interaction of EGFR and STAT3 in the activation of the iNOS/NO pathway. Cancer Cell. 7(6):575-589. https://doi.org/10.1016/j.ccr.2005.05.007

19. Lo H, Xia W, Wei Y, MA, Huang S, Hung M. 2005. Novel prognostic value of nuclear epidermal growth factor receptor in breast cancer. Cancer Res. 65(1):338-48.

20. Miettinen PJ, Berger JE, Meneses J, Phung Y, Pedersen RA, Werb Z, Derynck R. 1995. Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor. Nature. 376(6538):337-341. https://doi.org/10.1038/376337a0

21. Sibilia M, Wagner E. 1995. Strain-dependent epithelial defects in mice lacking the EGF receptor. Science. 269(5221):234-238. https://doi.org/10.1126/science.7618085

22. Park S, Miller R, Krane I, Vartanian T. 2001. The erbB2 gene is required for the development of terminally differentiated spinal cord oligodendrocytes. 154(6):1245-1258. https://doi.org/10.1083/jcb.200104025

23. Leu M. 2003. Erbb2 regulates neuromuscular synapse formation and is essential for muscle spindle development. 130(11):2291-2301. https://doi.org/10.1242/dev.00447

24. S L E, K S O, N G, L L, G F, M B, L H L, M W M. 1997. ErbB3 is required for normal cerebellar and cardiac development: a comparison with ErbB2-and heregulin-deficient mice. Development. 124(24):4999-5011.

25. Golub MS, Germann SL, Lloyd K. 2004. Behavioral characteristics of a nervous system-specific erbB4 knock-out mouse. Behavioural Brain Research. 153(1):159-170. https://doi.org/10.1016/j.bbr.2003.11.010

26. Maheswaran S, Sequist LV, Nagrath S, Ulkus L, Brannigan B, Collura CV, Inserra E, Diederichs S, Iafrate AJ, Bell DW, et al. 2008. Detection of Mutations inEGFRin Circulating Lung-Cancer Cells. N Engl J Med. 359(4):366-377. https://doi.org/10.1056/nejmoa0800668

27. Montagut C, Dalmases A, Bellosillo B, Crespo M, Pairet S, Iglesias M, Salido M, Gallen M, Marsters S, Tsai SP, et al. 2012. Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer. Nat Med. 18(2):221-223. https://doi.org/10.1038/nm.2609

28. Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, Majem M, Lopez-Vivanco G, Isla D, Provencio M, et al. 2009. Screening for Epidermal Growth Factor Receptor Mutations in Lung Cancer. N Engl J Med. 361(10):958-967. https://doi.org/10.1056/nejmoa0904554

29. Liu Z, Hou P, Ji M, Guan H, Studeman K, Jensen K, Vasko V, El-Naggar AK, Xing M. 2008. Highly Prevalent Genetic Alterations in Receptor Tyrosine Kinases and Phosphatidylinositol 3-Kinase/Akt and Mitogen-Activated Protein Kinase Pathways in Anaplastic and Follicular Thyroid Cancers. The Journal of Clinical Endocrinology & Metabolism. 93(8):3106-3116. https://doi.org/10.1210/jc.2008-0273

30. Gao SP, Mark KG, Leslie K, Pao W, Motoi N, Gerald WL, Travis WD, Bornmann W, Veach D, Clarkson B, et al. 2007. Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J. Clin. Invest.. 117(12):3846-3856. https://doi.org/10.1172/jci31871

31. Fukushige S, Murotsu T, Matsubara K. 1986. Chromosomal assignment of human genes for gastrin, thyrotropin (TSH)-? subunit and C-erbB-2 by chromosome sorting combined with velocity sedimentation and southern hybridization. Biochemical and Biophysical Research Communications. 134(2):477-483. https://doi.org/10.1016/s0006-291x(86)80445-4

32. Slamon D, Godolphin W, Jones L, Holt J, Wong S, Keith D, Levin W, Stuart S, Udove J, Ullrich A, et al. 1989. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 244(4905):707-712. https://doi.org/10.1126/science.2470152

33. Qiu Y, Ravi L, Kung H. 1998. Requirement of ErbB2 for signalling by interleukin-6 in prostate carcinoma cells. Nature. 393(6680):83-85. https://doi.org/10.1038/30012

34. Harskamp LR, Gansevoort RT, van Goor H, Meijer E. 2016. The epidermal growth factor receptor pathway in chronic kidney diseases. Nat Rev Nephrol. 12(8):496-506. https://doi.org/10.1038/nrneph.2016.91

35. Scafidi J, Hammond TR, Scafidi S, Ritter J, Jablonska B, Roncal M, Szigeti-Buck K, Coman D, Huang Y, McCarter RJ, et al. 2014. Intranasal epidermal growth factor treatment rescues neonatal brain injury. Nature. 506(7487):230-234. https://doi.org/10.1038/nature12880

36. Campbell P, Morton PE, Takeichi T, Salam A, Roberts N, Proudfoot LE, Mellerio JE, Aminu K, Wellington C, Patil SN, et al. 2014. Epithelial Inflammation Resulting from an Inherited Loss-of-Function Mutation in EGFR. Journal of Investigative Dermatology. 134(10):2570-2578. https://doi.org/10.1038/jid.2014.164