Tyrosine-phosphorylated low density lipoprotein receptor-related protein 1 (LRP1) associates with the adaptor protein SHC in SRC-transformed cells
Tyrosine-phosphorylated low density lipoprotein receptor-related protein 1 (LRP1) associates with the adaptor protein SHC in SRC-transformed cells
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DOI：
10.1074/jbc.m011437200
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发表时间：
2001-06-01
影响因子：
4.8
通讯作者：
van der Geer, P
中科院分区：
文献类型：
--
作者：
Barnes, H;Larsen, B;van der Geer, P
v-Src在体外转化成纤维细胞，并通过关键细胞底物的酪氨酸磷酸化在动物中引起肿瘤形成。确切地说，v-Src如何与这些底物相互作用仍然是未知的。它的底物之一，衔接蛋白She，被认为在细胞转化过程中发挥了至关重要的作用，通过连接v-Src的has，我们使用She蛋白与突变的磷酸酪氨酸结合（PTB）或Src同源2结构域，以确定在v-Src表达细胞中的She的磷酸化依赖于功能性PTB结构域的存在。我们从Src转化细胞中纯化了100 kDa的She PTB结合蛋白，该蛋白被鉴定为低密度脂蛋白受体相关蛋白LRP 1的β链。LRP 1作为多种蛋白质的输入受体，参与β-淀粉样前体蛋白的清除。这项研究表明，LRP 1是酪氨酸磷酸化的v-Src转化细胞和酪氨酸磷酸化的LRP 1结合在体内和体外的She。She和LRP 1之间的结合可能提供了将She募集到质膜的机制，在那里它被v-Src磷酸化。这些观察结果进一步表明LRP 1可以作为信号受体发挥作用，并可能为研究其在胚胎发育和阿尔茨海默病发病过程中的可能作用提供新的途径。
v-Src transforms fibroblasts in vitro and causes tumor formation in the animal by tyrosine phosphorylation of critical cellular substrates. Exactly how v-Src interacts with these substrates remains unknown. One of its substrates, the adaptor protein She, is thought to play a crucial role during cellular transformation by v-Src by linking v-Src to has, We used She proteins with mutations in either the phosphotyrosine binding (PTB) or Src homology 2 domain to determine that phosphorylation of She in v-Src-expressing cells depends on the presence of a functional PTB domain. We purified a 100-kDa She PTB-binding protein from Src-transformed cells that was identified as the beta chain of the low density lipoprotein receptor-related protein LRP1. LRP1 acts as an import receptor for a variety of proteins and is involved in clearance of the beta -amyloid precursor protein. This study shows that LRP1 is tyrosine-phosphorylated in v-Src-transformed cells and that tyrosine-phosphorylated LRP1 binds in vivo and in vitro to She. The association between She and LRP1 may provide a mechanism for recruitment of She to the plasma membrane where it is phosphorylated by v-Src. It is at the membrane that She is thought to be involved in Ras activation, These observations further suggest that LRP1 could function as a signaling receptor and may provide new avenues to investigate its possible role during embryonal development and the onset of Alzheimer's disease.