The coupling of alpha(6)beta(4) integrin to Ras-MAP kinase pathways mediated by Shc controls keratinocyte proliferation
The coupling of alpha(6)beta(4) integrin to Ras-MAP kinase pathways mediated by Shc controls keratinocyte proliferation
复制标题
DOI：
10.1093/emboj/16.9.2365
复制
发表时间：
1997-05-01
期刊：
影响因子：
11.4
通讯作者：
Giancotti, FG
中科院分区：
文献类型：
--
作者：
Mainiero, F;Murgia, C;Giancotti, FG
将整合素与核事件联系起来的信号通路还不完全清楚，我们已经研究了细胞内的信号转导，α(6)β(4)整合素是一种在基底角质形成细胞和其他细胞中表达的层粘连蛋白受体，在原代人类角质形成细胞中，α(6)β(4)的连接导致SHE的酪氨酸磷酸化，Grb2的募集，RAS的激活和MAP激酶Erk和JNK的刺激。相反，结扎层粘连蛋白和胶原结合的整合素α(3)β(1)和α(2)β(1)不会引起这些事件，而α(6)β(4)对Erk的刺激可被显性负性Shc、Pas和RhoA抑制，JNK的激活可被显性负性Pas和Rad以及磷脂酰肌醇3-激酶抑制剂wortmannin抑制。α(6)β(4)介导的黏附诱导了Fos血清反应元件的转录，并促进了对有丝分裂原反应的周期进程，相反，α(3)β(1)和α(2)β(1)依赖的黏附不能诱导这些事件。这些结果表明，α(6)β(4)整合素偶联调控SHE介导的细胞周期进程，调节基底层角质形成细胞以及可能与基底膜接触的其他细胞的增殖。
The signaling pathways linking integrins to nuclear events are incompletely understood, We have examined intracellular signaling by the alpha(6) beta(4) integrin, a laminin receptor expressed in basal keratinocytes and other cells, Ligation of alpha(6) beta(4) in primary human keratinocytes caused tyrosine phosphorylation of She, recruitment of Grb2, activation of Ras and stimulation of the MAP kinases Erk and Jnk. In contrast, ligation of the laminin- and collagen-binding integrins alpha(3) beta(1) and alpha(2) beta(1) did not cause these events, While the stimulation of Erk by alpha(6) beta(4) was suppressed by dominant-negative Shc, Pas and RhoA, the activation of Jnk was inhibited by dominant-negative Pas and Rad and by the phosphoinositide 3-kinase inhibitor Wortmannin. Adhesion mediated by alpha(6) beta(4) induced transcription from the Fos serum response element and promoted a:ll cycle progression in response to mitogens, In contrast, alpha(3) beta(1)- and alpha(2) beta(1)-dependent adhesion did not induce these events, These findings suggest that the coupling of alpha(6) beta(4) integrin to the control of cell cycle progression mediated by She regulates the proliferation of basal keratinocytes and possibly other cells which are in contact with the basement membrane in vivo.