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MERIT Award Recipient: G. Steven Martin, Ph.D.
Many human breast and colon cancers display elevated levels of the protein-tyrosine kinase Src. In normal cells this kinase functions to transmit signals from receptors for growth factors or extracellular matrix components. The Martin laboratory is using v-Src, a retrovirally-encoded and mutationally activated form of Src, as a model to study the process of malignant transformation. Expression of v-Src induces mitogenic transformation, that is the ability to proliferate under conditions that restrict the growth of normal cells. Expression of v-Src also induces morphological transformation, which involves a complex set of changes in cell motility, cytoskeletal regulation and extracellular matrix deposition. The Martin laboratory is studying the signaling pathways by which these changes in cellular phenotype are induced.
Work from the Martin laboratory has shown that transformation by Src involves the small GTPase Ras and the lipid kinase phosphatidylinositol-3-kinase (PI3K). These signaling molecules provide both mitogenic and survival signals; the survival signal is necessary because v-Src expression can also induce apoptosis (programmed cell death). The group is now using microarray techniques to investigate how activation of these pathways leads to changes in gene expression, and in particular how the changes in gene expression resulting from transient activation of cellular Src differ from those induced by expression of the constitutively active viral Src. Use of cells that are genetically deficient in the transcription factor Myc has shown that this protein is required for transformation by Src. One current line of research is the identification of Myc targets whose expression is necessary for Src transformation.
The Martin laboratory has also shown that transformation by v-Src involves activation of the small GTPases of the Rho family, in particular RhoA and Rac1. Expression of v-Src causes an increase in the level of RhoA[GTP], and the group is now investigating the mechanism by which this increase is induced. One function of RhoA is the induction of actin stress fibers, yet actin stress fibers are lost in v-Src-transformed cells, suggesting that RhoA signaling to the cytoskeleton may be inhibited downstream of RhoA itself. One goal of current research is to determine how v-Src suppresses RhoA signaling to the cytoskeleton.
The immediate aim of these studies is to define the mechanisms by which v-Src induces both mitogenic and morphological transformation. The answers to these questions should shed light on the role of Src activation in the growth and invasiveness of human cancer cells.
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