Recruitment of phosphoinositide 3-kinase defines a positive contribution of tyrosine kinase signaling to E-cadherin function

被引:42
作者
Pang, JH
Kraemer, A
Stehbens, SJ
Frame, MC
Yap, AS [1 ]
机构
[1] Univ Queensland, Inst Mol Biosci, Div Mol Cell Biol, Brisbane, Qld 4072, Australia
[2] Univ Queensland, Sch Biomed Sci, Brisbane, Qld 4072, Australia
[3] Canc Res UK Beatson Labs, Beatson Inst Canc Res, Glasgow G61 1BD, Lanark, Scotland
关键词
D O I
10.1074/jbc.M412148200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Classical cadherin adhesion molecules can function as adhesion-activated cell-signaling receptors. One key target for cadherin signaling is the lipid kinase phosphoinositide (PI) 3-kinase, which is recruited to cell-cell contacts and activated by E-cadherin. In this study, we sought to identify upstream factors necessary for E-cadherin to activate PI 3-kinase signaling. We found that inhibition of tyrosine kinase signaling blocked recruitment of PI 3-kinase to E-cadherin contacts and abolished the ability of E-cadherin to activate PI 3-kinase signaling. Tyrosine kinase inhibitors further perturbed several parameters of cadherin function, including cell adhesion and the ability of cells to productively extend nascent cadherin-adhesive contacts. Notably, the functional effects of tyrosine kinase blockade were rescued by expression of a constitutively active form of PI 3-kinase that restores PI 3-kinase signaling. Finally, using dominant negative Src mutants and Src-null cells, we identified Src as one key upstream kinase in the E-cadherin/PI 3-kinase-signaling pathway. Taken together, our findings indicate that tyrosine kinase activity, notably Src signaling, can contribute positively to cadherin function by supporting E-cadherin signaling to PI 3-kinase.
引用
收藏
页码:3043 / 3050
页数:8
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