Schroder Wayne A, Buck Marion, Cloonan Nicole, Hancock John F, Suhrbier Andreas, Sculley Tom, Bushell Gillian
The Queensland Institute of Medical Research, Brisbane, Australia.
Cell Signal. 2007 Jun;19(6):1279-89. doi: 10.1016/j.cellsig.2007.01.013. Epub 2007 Jan 20.
Human Sin1 (SAPK-interacting protein 1) is a member of a conserved family of orthologous proteins that have an essential role in signal transduction in yeast and Dictyostelium. This study demonstrates that most Sin1 orthologues contain both a Raf-like Ras-binding domain (RBD) and a pleckstrin homology (PH) domain. These domains are functional in the human Sin1 protein, with the PH domain involved in lipid and membrane binding by Sin1, and the RBD able to bind activated H-and K-Ras. Sin1 and Ras co-immunoprecipitated and co-localised, showing that these proteins associate with each other in vivo. Overexpression of Sin1 inhibited the activation of ERK, Akt and JNK signalling pathways by Ras. In contrast, siRNA knockdown of endogenous Sin1 protein expression in HEK293 cells enhanced the activation of ERK1/2 by Ras. These data suggest that Sin1 is a mammalian Ras-inhibitor.
人类Sin1（丝裂原活化蛋白激酶相互作用蛋白1）是一个保守的直系同源蛋白家族的成员，这些蛋白在酵母和盘基网柄菌的信号转导中起重要作用。本研究表明，大多数Sin1直系同源物都包含一个Raf样的Ras结合结构域（RBD）和一个普列克底物蛋白同源结构域（PH结构域）。这些结构域在人类Sin1蛋白中具有功能，其中PH结构域参与Sin1与脂质和膜的结合，而RBD能够结合活化的H-Ras和K-Ras。Sin1和Ras进行了共免疫沉淀和共定位，表明这些蛋白在体内相互关联。Sin1的过表达抑制了Ras对ERK、Akt和JNK信号通路的激活。相反，在HEK293细胞中通过小干扰RNA敲低内源性Sin1蛋白表达增强了Ras对ERK1/2的激活。这些数据表明Sin1是一种哺乳动物Ras抑制剂。
