乳癌激酶促進癌細胞生長及移動之機制研究

The Mechanisms of Breast Tumor Kinase in Promoting Tumor Cell Growth and Migration

沈哲宏(Che-Hung Shen)

指導教授 ： 陳瑞華

國立臺灣大學/醫學院/分子醫學研究所/博士(2008年)

https://doi.org/10.6342/NTU.2008.00067

摘要

乳癌激酶是一種非受體型酪胺酸激酶與Src有高度相似性，其蛋白質結構由典型的SH3區塊、SH2區塊以及酪胺酸激酶區所組成。乳癌激酶已於乳癌、黑色素細胞瘤以及大腸癌等癌症中被報導具有高度表現性，也被認為在細胞癌化機轉(oncogenesis)中扮演重要角色。但是目前對於乳癌激酶的活性調控及其所參與的信息傳導路徑，乃至於生物功能的了解均十分有限。因此，探查乳癌激酶所作用的受質與其所參與的信息傳導途徑，能進一步揭開乳癌激酶的生物功能及致癌機轉。在此，我們找到了一新的乳癌激酶受質－p190RhoGAP-A (p190)。乳癌激酶透過磷酸化p190促使p190與p120RasGAP (p120)結合，此蛋白質複合體具有能抑制Rho及活化Ras的能力。乳癌激酶也藉由磷酸化p190抑制Rho及活化Ras，並且刺激細胞移動、促進細胞的侵入行為以及導致細胞增生。此外我們也發現若利用干擾蛋白破壞p190與p120之間的結合，將弱化乳癌激酶調控Rho及Ras的能力，也減弱其對細胞行為及生長的影響，並進一步降低乳癌激酶的致癌性(tumorigenicity)。因此p190在乳癌激酶所作用的信息傳導路徑及於生物功能上扮演重要功能。

關鍵字

乳癌激酶細胞增生 ； 細胞移動

並列摘要

Breast tumor kinase (Brk), a Src-like nonreceptor tyrosine kinase, is overexpressed in breast cancer and several other cancer types. Our previous study indicates that Brk promotes cell migration and tumor invasion by phosphorylating the focal adhesion protein paxillin. Here, we report the identification of p190RhoGAP-A (p190) as a Brk substrate. Brk phosphorylates p190 at the Y1105 residue both in vitro and in vivo, thereby promoting the association of p190 with p120RasGAP (p120). As a consequence, Brk stimulates p190 and attenuates p120 functions, leading to RhoA inactivation and Ras activation, respectively. In carcinoma cells expressing high levels of Brk, endogenous Brk functions as a key contributor to EGF-induced p190 tyrosine phosphorylation. We present evidence showing that p190 phosphorylation plays essential roles in both migratory and proliferative effects of Brk. Furthermore, disruption of p190 phosphorylation-induced p190/p120 complex in breast cancer cells abolishes not only the abilities of Brk to regulate RhoA and Ras, but also the stimulatory effects of Brk on proliferation, migration, invasion, transformation and tumorigenicity. Together, our findings reveal a previously unknown function of Brk in regulating both RhoA and Ras by phosphorylating p190, and provide evidence for the crucial roles of this Brk-elicited signaling pathway in promoting breast malignancy.

並列關鍵字

Brk ； Cell proliferation ； Cell migration

參考文獻

Aaronson, S. A. (1991). "Growth factors and cancer." Science 254(5035): 1146-53.

Abraham, M. T., M. A. Kuriakose, et al. (2001). "Motility-related proteins as markers for head and neck squamous cell cancer." Laryngoscope 111(7): 1285-9.

Adam, L., R. K. Vadlamudi, et al. (2001). "Tiam1 overexpression potentiates heregulin-induced lymphoid enhancer factor-1/beta -catenin nuclear signaling in breast cancer cells by modulating the intercellular stability." J Biol Chem 276(30): 28443-50.

Adjei, A. A. (2001). "Blocking oncogenic Ras signaling for cancer therapy." J Natl Cancer Inst 93(14): 1062-74.

Albanese, C., J. Johnson, et al. (1995). "Transforming p21ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions." J Biol Chem 270(40): 23589-97.