Tyrosine-phosphorylated low density lipoprotein receptor-related protein 1(LRP1) associates with the adaptor protein SHC in SRC-transformed cells

v-Src transforms fibroblasts in vitro and causes tumor formation in the ani mal by tyrosine phosphorylation of critical cellular substrates. Exactly ho w v-Src interacts with these substrates remains unknown. One of its substra tes, the adaptor protein She, is thought to play a crucial role during cell ular 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 t he 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 tyrosin e-phosphorylated LRP1 binds in vivo and in vitro to She. The association be tween She and LRP1 may provide a mechanism for recruitment of She to the pl asma membrane where it is phosphorylated by v-Src. It is at the membrane th at She is thought to be involved in Ras activation, These observations furt her suggest that LRP1 could function as a signaling receptor and may provid e new avenues to investigate its possible role during embryonal development and the onset of Alzheimer's disease.