Board Member Profile
Cell Biology Program
Memorial Sloan-Kettering Cancer Center
1275 York Avenue
New York, NY 10021
Former Member of Advisory Board (1999 - 2003)
Control of Cell Proliferation
Cell proliferation is controlled by a balance of positive and negative signals. Our goal is to elucidate how these signals are conveyed from the cell's environment and confront each other within the cell. Our work focuses on transforming growth factor-beta (TGF-beta), a classical antimitogen with potent antiproliferative activity in many cell types. Additionally, TGF-beta represents a large group of cytokines that control cell growth, differentiation, motility, organization, and death. Some of these factors participate in setting up the basic body plan during early embryogenesis in mammals, frogs, and flies, whereas others control the formation of cartilage, bone, and sexual organs; suppress epithelial cell growth; foster wound repair; or regulate important immune and endocrine functions. Alterations in the activity of TGF-beta and related factors are implicated in cancer and various other disorders in humans. Therefore, the study of TGF-beta signal transduction should show us ways to control these disorders while revealing the mode of action of this entire family of signaling molecules.
We have identified and cloned various membrane receptors for TGF-beta and related factors. Focusing on the specific receptor that mediates cell cycle arrest, we have elucidated the initial steps of this pathway. These steps involve an interplay between two related transmembrane protein kinases that has no precedent among previously identified growth factor receptors. In this scheme, one of the two TGF-beta receptor kinases, known as R-II, acts as a primary receptor that binds TGF-beta directly from the medium or from an auxiliary ligand-presenting protein known as betaglycan. Once bound to R-II, and only then, TGF-beta is recognized by the second transmembrane kinase, R-I. On recruitment into the receptor complex, R-I becomes phosphorylated and activated by R-II. R-II is a constitutively active kinase that, in effect, uses the ligand to recruit and phosphorylate R-I, which then propagates the signal to downstream substrates. Thus, brought together by the ligand and acting one on the other, these two kinases generate the first step of the TGF-beta signaling pathway.
We are examining the generality of this model through studies on receptors for the TGF-beta-related factors activins and bone morphogenic proteins. We identified several such receptors from human tissues and, in collaboration with other groups, in Drosophila and nematodes. This work has shown that the primary receptor for a given factor may recognize a small repertoire of related receptor substrates. Each of the different RII-RI combinations appears to mediate different sets of responses, thus providing an explanation for the multifunctional nature of TGF-beta and related factors. We are investigating whether the combinatorial nature of this receptor system can be manipulated to enhance or suppress selectively a given subset of responses to these factors. This possibility is of interest because the broad range of activities displayed by TGF-beta and related factors might otherwise preclude their potential therapeutic use. A grant from the National Institutes of Health provided partial support for this project.
Through intervening steps yet to be defined, the pathway initiated by the TGF-beta receptor complex leads to inhibition of cyclin-dependent kinases. These enzymes are required for cell transition through the G1 phase of the proliferative cycle, and their inhibition causes cell cycle arrest. We determined that this process involves p27, a small protein that binds to and blocks cyclin-dependent kinases in response to TGF-beta. We isolated and cloned the genes that express human p27 and the related p57. The p27 protein is also involved in mediating cell cycle arrest in response to cell-cell contact.
Furthermore, p27 and p57 are related to p21, the recently identified inhibitor of cyclin-dependent kinases that is induced by p53 in response to DNA damage. Thus TGF-beta, cell contact, and p53, which represent the three main classes of physiological growth inhibitory signals, act through a common strategy to inhibit cell cycle progression. We are studying the structure, regulation, mode of action, and possible mutation in human cancer of these cyclin-dependent kinase inhibitors. Based on this information, it may be possible to design novel strategies to control cell proliferation.
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