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Lawrence A. Quilliam, PhD
Professor of Biochemistry & Molecular Biology
This laboratory is interested in delineating signal transduction pathways induced by growth-stimulatory factors, and in determining the mechanisms by which these pathways are aberrantly activated during the course of malignant transformation. Many of the genes that become mutated in human cancers encode for mitogenic signaling proteins. It is anticipated that characterization of the enzymes and protein:protein interactions involved in mitogenic signaling will form the basis for the rational design of novel anti-cancer therapeutics.
Research is primarily focused on understanding the biological function of Ras family GTPases and the upstream guanine nucleotide exchange factors (GEFs) that regulate them. Ras proteins are a large family of cellular signaling molecules that mediate a variety of growth-promoting functions. The prototypic Ras proteins, H-, K-, and N-Ras, are mutationally activated in ~30% of human cancers and have been extensively studied. We are currently defining the roles of three Ras-related proteins, M-Ras, Rap1A and Rheb. We are examining the role of downstream effector pathways in mediating M-Ras-induced cell growth and transformation and have found that M-Ras might signal through Rap1.
Rap1 is a ubiquitously expressed protein that fulfills an essential role in eukaryotic cell function as proven by the embryonic lethality of Rap1-deficient flies. Rap1 has been identified as a key regulator of several adhesion-related events including phagocytosis, migration, and cell-cell contact. However, what triggers Rap1 activation and what downstream targets Rap1 employs to regulate cellular adhesion remain to be determined. We are using cell culture and a mouse genetic model to answer some of these questions in solid tissue and hematopoeitic cells.
Rheb has recently been implicated as the target of the TSC2 tumor suppressor. As such it may contribute to tumor formation or debilitating TSC-linked diseases such as lymphangioleiomyomatosis in patients that inherit or acquire TSC1 or TSC2 mutations. Since Rheb is upstream of mTOR (mammalian target of rapamycin) and is a farnesylated protein, the immuno-suppressant drug, rapamycin, or the farnesyltransferase inhibitors originally designed to block Ras-induced cancer might now be used to treat tumors involving the Akt/TSC2/Rheb/mTOR signal transduction pathway.
Ras family proteins are GTPases that switch between inactive GDP- and active GTP-bound states in response to extracellular stimuli. This activation event is mediated by guanine nucleotide exchange factors (GEFs) that swap GDP for GTP enabling a conformational change and activation of Ras family proteins. We have recently identified several novel GEFs that act on Rap1, M-Ras and another GTPase, Ral. One of these exchange factors has been implicated in estrogen-independent growth of breast cancer cells. Therefore, we are establishing how hormone and growth factor stimulation leads to the recruitment and activation of these novel GEFs and whether the activation of these proteins plays a role in cellular transformation. Finally we have found that the presence of Ras association (RA) domains in the regulatory regions of several GEFs enables them to initiate GTPase cascades and/or cross-talk between Ras family members. We are examining the implications of this cross talk on biological events.