Transforming growth factor-beta(TGF-beta) is a growth and differentiation factor that plays an important role in the interactions of the cell with the extracellular matrix and in the control of cell proliferation. TGF- beta also plays a key role in cell differentiation and tissue morphogenesis and, very importantly, in tumorigenesis and metastasis. Because of these many different activities, and especially its role as a potent growth inhibitor and regulator of cell-matrix interaction (unlike other growth factors), TGF-beta has received attention from both basic and clinical researchers, and is considered a potentially useful therapeutic target to manipulate repair processes and inhibit tumorigenesis. Two types of TGF-beta receptors, called type II and type I receptors, are the mediators of the TGF-beta induced signal transduction. The cloned type II receptor is a predicted serine- threonine kinase receptor, similarly to the receptor for activin, another member of the TGF-beta superfamily. It is now assumed that the receptors for all TGF-beta related factors are transmembrane serine-threonine kinase receptors. How the interaction of TGF-beta with its receptors leads to an inhibition of cell proliferation and the effects on the cell- matrix interaction, is largely unknown. Also, nothing is as yet known about the mechanism of action of any serine-threonine kinase receptors. This research proposal is aimed at gaining some insight into some important and specific questions on how the receptors for TGF-beta function. Two recent findings from our lab are at the basis of our research plan: 1) there are two signaling pathways for the different biological activities of TGF-beta; they are associated with the type II and type I receptor respectively; 2) we have recently isolated cDNAs for a type I receptor, named Tsk 7L, a predicted serine-threonine kinase receptor with structural similarity to the type II receptor. In addition, another research group has isolated a structurally related type I receptor, called ALK-5. The availability of cDNAs for the type II and type I TGF-beta receptors now allows us to pursue the following research aims that address specific functional questions.
In Aim 1, we will analyze the specific roles of the type II and type I receptors in the different biological activities of TGF-beta and in the few known aspects of the TGF-beta induced signal transduction.
Aim 2 will focus on a characterization of the nature of the kinase activity of the type II and type 1 receptors and the effect of TGF-beta binding on the receptor- associated kinase activity. Finally, in Aim 3, we will isolate cDNAs for proteins that associate with the cytoplasmic domain of the type II TGF- beta receptor and pursue their molecular characterization. We will then evaluate the effect of TGF-beta on these associations. These studies should provide us with a beginning insight on how TGF-beta exerts its various biological activities through its type II and type I receptors and how this new class of serine-threonine kinase receptors functions, and may provide us with means to control cell proliferation and cell- matrix interactions.
Showing the most recent 10 out of 43 publications
