Grb2 controls phosphorylation of FGFR2 by inhibiting receptor kinase and Shp2 phosphatase activity.
Grb2 controls phosphorylation of FGFR2 by inhibiting receptor kinase and Shp2 phosphatase activity.
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DOI：
10.1083/jcb.201204106
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发表时间：
2013-02-18
期刊：
影响因子：
--
通讯作者：
Ladbury JE
中科院分区：
文献类型：
--
作者：
Ahmed Z;Lin CC;Suen KM;Melo FA;Levitt JA;Suhling K;Ladbury JE
Grb2抑制FGFR2的激酶活性和Shp2的磷酸酶活性，维持受体磷酸化在非刺激状态下的稳态。组成受体酪氨酸激酶磷酸化需要激酶和磷酸酶活性的调节，以防止异常的信号转导。本文描述了一种动态机制，其中接头蛋白，生长因子受体结合蛋白2 (Grb2)，在没有细胞外刺激的情况下，通过调节受体激酶和含SH2结构域的蛋白酪氨酸磷酸酶2 （Shp2）磷酸酶活性来控制成纤维细胞生长因子受体2 （FGFR2）信号传导。FGFR2在其激酶活性、部分磷酸化、非信号状态和shp2去磷酸化状态之间循环。同时，Shp2在其fgfr2磷酸化和去磷酸化形式之间循环。Grb2与受体的结合抑制了FGFR2和Shp2的相互活性。FGFR2对Grb2的磷酸化解除了其与受体的结合，导致FGFR2激酶和Shp2磷酸酶活性上调。Shp2对Grb2的去磷酸化修复了FGFR2-Grb2复合物。这种酶活性的循环导致了一种稳态、信号不完备的状态。生长因子结合干扰了这种背景循环，促进了FGFR2磷酸化和激酶活性的增加，Grb2解离和下游信号传导。因此，Grb2对FGFR2和Shp2相互依赖的活性施加本构性控制。
Grb2 inhibits the kinase activity of FGFR2 and the phosphatase activity of Shp2 to maintain homeostasis of receptor phosphorylation in the nonstimulated state. Constitutive receptor tyrosine kinase phosphorylation requires regulation of kinase and phosphatase activity to prevent aberrant signal transduction. A dynamic mechanism is described here in which the adaptor protein, growth factor receptor–bound protein 2 (Grb2), controls fibroblast growth factor receptor 2 (FGFR2) signaling by regulating receptor kinase and SH2 domain–containing protein tyrosine phosphatase 2 (Shp2) phosphatase activity in the absence of extracellular stimulation. FGFR2 cycles between its kinase-active, partially phosphorylated, nonsignaling state and its Shp2-dephosphorylated state. Concurrently, Shp2 cycles between its FGFR2-phosphorylated and dephosphorylated forms. Both reciprocal activities of FGFR2 and Shp2 were inhibited by binding of Grb2 to the receptor. Phosphorylation of Grb2 by FGFR2 abrogated its binding to the receptor, resulting in up-regulation of both FGFR2’s kinase and Shp2’s phosphatase activity. Dephosphorylation of Grb2 by Shp2 rescued the FGFR2–Grb2 complex. This cycling of enzymatic activity results in a homeostatic, signaling-incompetent state. Growth factor binding perturbs this background cycling, promoting increased FGFR2 phosphorylation and kinase activity, Grb2 dissociation, and downstream signaling. Grb2 therefore exerts constitutive control over the mutually dependent activities of FGFR2 and Shp2.
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DOI：
10.1158/1541-7786.mcr-08-0021
发表时间：
2009-01
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Gartside MG;Chen H;Ibrahimi OA;Byron SA;Curtis AV;Wellens CL;Bengston A;Yudt LM;Eliseenkova AV;Ma J;Curtin JA;Hyder P;Harper UL;Riedesel E;Mann GJ;Trent JM;Bastian BC;Meltzer PS;Mohammadi M;Pollock PM
通讯作者：
Pollock PM
影响因子：
16
作者：
Kleiman LB;Maiwald T;Conzelmann H;Lauffenburger DA;Sorger PK
通讯作者：
Sorger PK
影响因子：
5.2
作者：
Johnson, D;Wall, SA;Wilkie, AOM
通讯作者：
Wilkie, AOM
影响因子：
4.8
作者：
Keilhack, H;David, FS;Neel, BG
通讯作者：
Neel, BG
影响因子：
5.7
作者：
Barford, D;Neel, BG
通讯作者：
Neel, BG