Analysis of the TGF-beta Receptor Signal Transduction Pathways and the TGE-betaReceptor Kinases

摘要

The principal goal of this project is to understand the transforming growthfactor-Beta (TGF Beta) receptor signal transduction pathways and the molecular mechanism underlying the regulation of the activity of the TOFQ receptor kinases. TGF Beta could suppress the growth of breast cancer cells both in vivo and in vitro (1, 2, 3), and this function requires the expression of functional TGF Beta receptors (2, 3) and downstream signaling molecules (4). The TGF Beta family of cytokines has a wide range of biological functions including tumor suppression, extracellular matrix production, embryonic development, and regulation of differentiation(5). These functions are mediated by three specific surface receptors, Types I, II and III, all of which have been cloned (6, 7, 8, 9). The types I and II receptors for TGF Beta, T BetaRI and T BetaRll, are members of the first known receptor serine/threonine kinase family, and share 40% homology between their kinase domains. T BetaRll contains an extracellular domain which binds TGF beta, a transmembrane domain and a cytoplasmic domain with serine/threonine kinase activity. T BetaRI also has an extracellular domain even though it does not bind TGF Beta when expressed without T BetaRII. The cytoplasmic portion of T BetaRI contains a kinase domain and a membrane proximal region which contains a Oly-Ser rich sequence (OS box) that has been proposed to be important for the activation of T BetaRI (10). Both receptors exist normally as homodimers on the cell surface (11, 12) and their kinase activities are essential for signal transduction (6, 8, 9, 13). Binding of TGF Beta1 to T BetaRII induces the formation of a heteromeric complex of T BetaRI and T BetaRll (6, 8, 9, 13), which results in transphosphorylation of T BetaRI by the constitutively active TJ3Rll.