Non-Smad Mechanisms of TGFBeta Signaling

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Development and tissue differentiation isdictated by secreted growth and differentiation factors. Among these, members of the TGF-beta superfamily are well known to play key roles. TGF-beta and related proteins also play key roles in normal lung development, while TGF-beta itself plays an important role in the response to injury. TGF-beta expression and signaling also contributes to pathobiology of some lung diseases and to carcinoma development and progression. Consequently the mechanisms of TGF-beta signaling have been of great interest in both normal development and in pathology. TGF-beta and related proteins signal through heteromeric, cell surface complexes of two types of transmembrane serine-threonine kinase receptors, which in turn activate, through phosphorylation, the Smads. Smad proteins act as intracellular effectors of TGF-beta signals that, following activation and heteromerization, translocate into the nucleus where they elaborate the ligand-induced transcription responses of many genes. The TGF-beta-induced Smad signaling pathway is now well accepted and its model of activation and mechanism of action are well developed. Increasing evidence, however, points out that the TGF-beta activation of the receptor complex also initiates other, non-Smad signaling pathways. Some of these observations are now being recognize, but very little is known about these non-Smad signaling mechanisms, how they link to receptors and what role they play inthe TGF-beta induced cellular response. Some of these parallel pathways may directlyregulate Smad signaling,while others may effect unrelated responses. This research proposal works from the hypothesis that these TGF-beta-induced non-Smad signaling pathways greatly contributeto the cellular response to TGF-beta and related factors. We propose to initiatea research program aimed at defining several TGF-beta-induced non-Smad signaling pathways, thereby specifically focusing on the activation of Erk MAP kinase, p38 MAP kinase, JNK and RhoA signaling in response to TGF-beta. The four Aims of this proposal will study how the activtion of these pathways is biochemically and mechanistically linked to the activation of the TGF-beta receptors and how they affect the cellular response to TGF-beta at the level of Smad activation and gene expression. Together, these studies should provide insight into the mechanisms of action of TGF-beta and related factors in normal development and inpathobiology.