Phosphoinositide 3-kinase-dependent membrane recruitment of p62(dok) is essential for its negative effect on mitogen-activated protein (MAP) kinase activation.
Phosphoinositide 3-kinase-dependent membrane recruitment of p62(dok) is essential for its negative effect on mitogen-activated protein (MAP) kinase activation.
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DOI：
10.1084/jem.194.3.265
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发表时间：
2001-08-06
期刊：
影响因子：
--
通讯作者：
Van Aelst L
中科院分区：
文献类型：
--
作者：
Zhao M;Schmitz AA;Qin Y;Di Cristofano A;Pandolfi PP;Van Aelst L
生长因子如血小板衍生生长因子（PDGF）调节细胞增殖的主要途径是通过受体酪氨酸激酶/Ras/促分裂原活化蛋白激酶（MAPK）信号级联。该途径的输出受到正调节器和负调节器的严格调节。一个这样的调节器是p62 dok，一个新发现的适配器蛋白家族的原型。我们最近提供的证据，通过使用p62 dok缺陷细胞，p62 dok作为生长因子诱导的细胞增殖和Ras/MAPK通路的负调节剂。我们在这里表明，p62 dok重新引入p62 dok −/−细胞可以抑制这些细胞中观察到的细胞增殖增加和MAPK活性延长，并且p62 dok的质膜募集对其功能至关重要。我们还发现，PDGF触发的p62 dok质膜转位需要磷酸肌醇3-激酶（PI 3-kinase）的激活及其pleckstrin同源（PH）结构域与3′-磷酸化磷酸肌醇的结合。此外，我们证明p62 dok可以独立于其与RasGAP和Nck相关的能力对PDGFR/MAPK通路产生负面影响。我们的结论是，p62 dok作为PDGFR/Ras/MAPK信号通路的负调节剂的功能，通过一种机制，涉及PI 3激酶依赖性招聘p62 dok的质膜。
A major pathway by which growth factors, such as platelet-derived growth factor (PDGF), regulate cell proliferation is via the receptor tyrosine kinase/Ras/mitogen-activated protein kinase (MAPK) signaling cascade. The output of this pathway is subjected to tight regulation of both positive and negative regulators. One such regulator is p62dok, the prototype of a newly identified family of adaptor proteins. We recently provided evidence, through the use of p62dok-deficient cells, that p62dok acts as a negative regulator of growth factor–induced cell proliferation and the Ras/MAPK pathway. We show here that reintroduction of p62dok into p62dok−/− cells can suppress the increased cell proliferation and prolonged MAPK activity seen in these cells, and that plasma membrane recruitment of p62dok is essential for its function. We also show that the PDGF-triggered plasma membrane translocation of p62dok requires activation of phosphoinositide 3-kinase (PI3-kinase) and binding of its pleckstrin homology (PH) domain to 3′-phosphorylated phosphoinositides. Furthermore, we demonstrate that p62dok can exert its negative effect on the PDGFR/MAPK pathway independently of its ability to associate with RasGAP and Nck. We conclude that p62dok functions as a negative regulator of the PDGFR/Ras/MAPK signaling pathway through a mechanism involving PI3-kinase–dependent recruitment of p62dok to the plasma membrane.
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影响因子：
9.2
作者：
Jones, N;Dumont, DJ
通讯作者：
Dumont, DJ
影响因子：
64.5
作者：
KAPLAN, DR;MORRISON, DK;WILLIAMS, LT
通讯作者：
WILLIAMS, LT
DOI：
10.1073/pnas.040547997
发表时间：
2000-02-29
影响因子：
11.1
作者：
Kashige, N;Carpino, N;Kobayashi, R
通讯作者：
Kobayashi, R
影响因子：
11.4
作者：
Noguchi, T;Matozaki, T;Kasuga, M
通讯作者：
Kasuga, M
影响因子：
64.5
作者：
Carpino, N;Wisniewski, D;Clarkson, B
通讯作者：
Clarkson, B