The long term objective of this proposal is to understand how transforming growth factor beta (TGF-beta) receptor type II transduces growth-inhibitory signal into the cell. Recently, we have isolated a cDNA encoding the human type II TGF-beta receptor through expression cloning. This opens a great opportunity for studying TGF-beta signal transduction mechanism, the key to understanding how this multi-functional growth hormone controls and regulates many different aspects of cellular function. Preliminary results, indicate that the type II receptor belongs to a newly emerged group of receptor-- serine/threonine kinases. This finding is consistent with the notion that TGF-beta, as the most potent negative-growth hormone, works through different pathways from those used by many positive-growth hormones, namely the tyrosine-kinase pathways. Based on this finding, I propose two specific aims to further reveal and elucidate the precise molecular mechanism by which TGF-beta exerts its effect through the type II receptor kinase. The first specific aim is to determine the functional and structural relationship of the type II receptor kinase. Mechanisms involved in kinase activation and regulation of kinase activity will be probed through kinase autophosphorylation and receptor dimerization studies. The potential relationship between the type II and type I TGF-beta receptors will also be investigated. The second specific aim, the long term objective and interest of my laboratory, is to identify pathways downstream of the receptor involved in regulation of cellular growth and differentiation. A great deal of effort will be invested to first establish the role of the type II receptor in transducing negative-growth signals in several types of cells. Once this is done, emphasis will be put on identifying cellular components that serve as direct substrates for the receptor kinase and as initiators of downstream pathways. Particularly, the relationship between TGF-beta growth-inhibitory pathway and other cellular components that are known to be involved in cell growth regulation will be investigated. Since TGF-beta is involved in the control of many cellular functions, a better understanding of this important growth hormone signalling mechanism will contribute greatly to our knowledge how growth hormone receptors function generally. It has been suggested that cellular transformation and tumorigenesis in vivo are sequential multistep processes and loss of cellular responsiveness to negative growth signals may represent an early step of those processes. Therefore, results from the proposed experiments will not only reveal molecular mechanism regarding TGF-beta signal transduction pathway, but also provide insight into molecular events that lead to carcinogenesis in humans.
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