TGF Beta Receptor Dynamics

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): A central paradox in transforming growth factor beta (TGF-beta) biology is how the same growth factor can induce such divergent responses as growth stimulation (i.e., mesenchymal cells) and growth inhibition (i.e., epithelial cells)? Considering the pivotal role TGF-beta has in a number of normal and pathological conditions, addressing that issue is fundamental if we hope to develop specific intervention strategies. To that end, during the previous funding cycle we have determined that (i) TGF-beta receptors traffic to the basolateral domain of polarized epithelial cells, spatially separate from apically secreted ligand; (ii) the AP2 beta2 subunit directly binds the TGF-beta receptor complex; and (iii) the c-Abl nonreceptor tyrosine kinase functions as a crucial profibrogenic mediator of TGF-beta action. This latter point is extremely exciting as it has led to an investigator initiated Phase II clinical trial testing the efficacy of imatinib mesylate (Gleevec) vs. placebo in the treatment of idiopathic pulmonary fibrosis. In the competing renewal we wish to extend these findings and test the general hypothesis that the cellular response to TGF-beta is dependent upon an integrated action of the trafficking and signaling machinery. This hypothesis will be addressed through a variety of biochemical, biological, and morphologic approaches. First, we will define the route and characterize the receptor elements controlling polarized TGF-beta receptor trafficking; second, the role(s) of beta2 adaptin and the Rin1 adaptor in regulating TGF-beta receptor internalization, clathrin assembly/disassembly, and coupling to the signaling machinery will be determined; and third, the means by which the TGF-beta receptor complex activates the c-Abl kinase in a cell type-specific manner will be defined. Answers to these questions are critical if the processes mediating the various cellular phenotypes induced by TGF-beta are to be elucidated.
StatusNot started

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