Transforming growth factor-beta (TGF-beta) is prototypic of a large family of paracrine polypeptides that are present in organisms from insects to humans and involved in processes ranging from embryogenic pattern formation and morphogenesis to regulation of endocrine systems. Their mechanism of action is unknown. Our appreciation of the complexity of the TGF-beta system has escalated dramatically in the last five years. TGF-beta exists in multiple isoforms that regulate cell growth, differentiation, adhesion, migration and extracellular matrix deposition. TGF-beta is thought to play crucial roles in organismal development and tissue repair processes. Excess of TGF-beta activity can lead to fibrotic disorders and immunosuppression. Failure of TGF-beta to inhibit cell proliferation can promote or contribute to oncogenesis. The wealth of information that has accumulated during recent years on the structure, distribution and activity of the TGF-betas contrasts with the scanty understanding of its mechanism of action. The intracellular components known to play some role in mediating TGF-beta action are very few. The membrane receptors implicated in TGF-beta signal transduction have been identified only recently, and their mode of signaling is completely unknown. The long-term goal of this project is to elucidate the mechanisms that initiate and mediate TGF-beta signal transduction. To achieve this goal, I propose to molecularly clone TGF-beta receptor components I and II by taking advantage of their known properties and of a panel of cell mutants that have specific defects in these receptor components. The cloning of these cDNAs will allow a structural and functional analysis of the TGF-beta receptor and should lead to identification of the TGF-beta signaling mechanism. It should also assist in identifying analogous receptors for other members of the TGF-beta superfamily. To complement this approach, I also propose to clone cDNAs whose products suppress cellular responsiveness to TGF-beta. Such antagonists or negative regulators of TGF-beta action will be important as indicators of the nature of the signaling pathway. Finally, I propose to molecularly clone and functionally characterize betaglycan, and integral membrane proteoglycan whose core protein binds TGF-beta with high affinity and whose carbohydrate chains may bind to specific proteins in cell membranes and extracellular matrices. Betaglycan, which may function as a major pericellular reservoir and/or regulator of TGF-beta presentation to the signaling receptors, has been purified to homogeneity in our laboratory to characterize its function and as a step towards cloning its cDNA. Future progress towards the aims set forth in this proposal should clarify important gaps in our current understanding of fundamental mechanisms that control animal cell growth and phenotype.
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