Stein E G, Gustafson T A, Hubbard S R
Skirball Institute of Biomolecular Medicine, Department of Pharmacology, New York University School of Medicine, NY, 10016, USA.
FEBS Lett. 2001 Mar 30;493(2-3):106-11. doi: 10.1016/s0014-5793(01)02282-7.
Grb7, Grb10 and Grb14 comprise a family of adaptor proteins that interact with numerous receptor tyrosine kinases upon receptor activation. Between the pleckstrin homology (PH) domain and the Src homology 2 (SH2) domain of these proteins is a region of approximately 50 residues known as the BPS (between PH and SH2) domain. Here we show, using purified recombinant proteins, that the BPS domain of Grb10 directly inhibits substrate phosphorylation by the activated tyrosine kinase domains of the insulin receptor and the insulin-like growth factor 1 (IGF1) receptor. Although inhibition by the BPS domain is dependent on tyrosine phosphorylation of the kinase activation loop, peptide competition experiments indicate that the BPS domain does not bind directly to phosphotyrosine. These studies provide a molecular mechanism by which Grb10 functions as a negative regulator of insulin- and/or IGF1-mediated signaling.
Grb7、Grb10和Grb14构成了一类衔接蛋白家族，它们在受体激活时与众多受体酪氨酸激酶相互作用。在这些蛋白的普列克底物蛋白同源（PH）结构域和Src同源2（SH2）结构域之间，有一个约50个残基的区域，称为BPS（PH与SH2之间）结构域。在此我们利用纯化的重组蛋白表明，Grb10的BPS结构域直接抑制胰岛素受体和胰岛素样生长因子1（IGF1）受体的活化酪氨酸激酶结构域对底物的磷酸化作用。尽管BPS结构域的抑制作用依赖于激酶激活环的酪氨酸磷酸化，但肽竞争实验表明BPS结构域并不直接结合磷酸酪氨酸。这些研究提供了一种分子机制，通过该机制Grb10作为胰岛素和/或IGF1介导信号的负调节因子发挥作用。
