Members of the LDL receptor family play a major role in cargo transport by binding extracellular ligands and facilitating their delivery to lysosomes for degradation. In addition to their important cargo function, recent studies indicate that these two LDL receptors also modulate signaling pathways. While the details of this are not yet fully established, this is accomplished by cooperation with cell surface molecules that associate directly or indirectly with LDL receptor family members and cellular adaptor molecules that associate with their cytoplasmic tail. We recently obtained evidence that LRP may modulate the trafficking and therefore the signaling properties of certain receptor tyrosine kinases. Specifically, we found that activation of platelet derived growth factor (PDGF)beta receptor initiates a transient phosphorylation of the cytoplasmic domain of LRP. The phosphorylation occurs at the second NpXY motif within LRP's cytoplasmic domain, and provides a docking site for Shc, an adaptor protein that is thought to play a crucial role during cellular transformation by v-Src. This process requires c-Src family kinase and PI-3 kinase activity. In resting fibroblasts and smooth muscle cells, LRP co-localizes with PDGFbeta in caveolae, but following PDGF-stimulation, LRP and the PDGFbeta receptor are co-localized within endosomal compartments. The central hypothesis of this application is that LRP regulates signaling pathways mediated by the certain tyrosine-kinase receptors such as the PDGF receptor thereby modulating the function of this signaling pathway. The specific hypotheses to be tested are: 1) That LRP co-localizes with the PDGF receptor in caveolae and interacts via extracellular and/or cytoplasmic domain interactions; 2) that this association modulates the cellular trafficking of the PDGF receptor; and 3) that expression of the LRP gene modulates the response of the cells to PDGF. These hypotheses will be tested in the following specific aims: 1) Identify the molecular basis for the selective phosphorylation of LRP by the PDGF receptor; 2) Identify the cellular compartment where tyrosine-phosphorylation of LRP occurs, and determine if LRP modulates the trafficking of the PDGF receptor; and 3) Define the mechanism by which LRP modulates signaling pathways mediated by PDGF.
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