Faculty Research Page

G. Steven Martin

G. Steven Martin

Professor Emeritus of Cell and Developmental Biology*
*Affiliate, Division of Biochemistry and Molecular Biology

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Research Interests

We are interested in the signal transduction pathways that regulate cell growth and motility, and in the mechanisms that couple these pathways to the cell division cycle. In particular we are interested in the signaling pathways responsible for malignant transformation by viral and cellular oncoproteins, and how the pathways involved in malignant transformation are related to those that regulate the behavior of normal cells. Our work focuses on the oncoprotein Src, a non-receptor tyrosine-kinase, for two reasons. First, the Src oncoprotein is extremely potent, causing rapid transformation in cell culture, and thus transformation by activated Src has served for many years as an in vitro model of carcinogenesis. Second, the Src protein is overexpressed and activated in many human epithelial cancers, particularly breast and colon cancer, and Src inhibitors are currently being developed and tested as therapeutic agents. 

Current Projects

Src signaling and cell invasion. One of the most important characteristics of cancer cells is their ability to invade adjacent tissue. This is a prerequisite for metastasis, the migration of cancer cells to distant sites, which is a major cause of cancer death. Our work has identified a number of the Src effectors that are involved in the ability of Src to induce cellular invasion. In particular we have shown that the GTPase Rho and the regulatory enzyme aPKC (atypical protein kinase C) are both required for Src to promote cell invasion. We are currently attempting to identify the Rho and aPKC effectors involved in cell invasion, as well as the roles of other Src substrates in this process.

Association of Src with the cell membrane. It is known that in order for Src to induce cell transformation it must associate with the cell membrane through protein-lipid interactions. Our work has shown that the association of Src with the membrane is dynamic, and involves protein-protein interactions as well as protein-lipid interactions. We have discovered that after Src modifies its immediate effector proteins in the cell membrane, it associates with them through a specific segment, the SH2 domain, and this association now makes the Src protein less mobile in the membrane. We are currently examining the ways in which this dynamic association is regulated.

The role of the transcription factor Myc in transformation by Src. One of the major alterations found in cells transformed by Src is that they can proliferate in the absence of external growth factors. This growth autonomy is a characteristic of cancer cells. The oncoprotein and transcription factor Myc appears to be important in mediating the ability of Src to cause cells to undergo unregulated cell proliferation. Our work has shown that Src requires Myc in order to drive cell proliferation because without Myc Src cannot induce and activate regulators of the cell division cycle that are required for cellular DNA synthesis (S phase). This work may shed light on the question of why some tumors are dependent on Myc function while others are not, and we are currently pursuing this question.

Src in breast cancer. Under certain conditions normal mammary cells can morphologically differentiate into structures resembling the secretory units of normal breast tissue, and do not invade the surrounding matrix in which they are embedded. Breast cancer cells lose the ability to differentiate in this way, and become invasive. Our work has shown that the function of the Src protein is required both to block morphological differentiation at early stages of tumor progression, and to promote cellular invasion at later stages. Thus Src plays different roles at different stages of tumor progression. We are currently interested in identifying the signaling proteins and pathways that mediate these effects.

Assays for Src signaling. High-throughput assays to detect activated signaling are needed in the pharmaceutical industry to develop new therapeutics, and we have collaborated with investigators at Corning to develop a novel procedure for such drug screens. In addition we have collaborated with bioengineers to develop a very sensitive assay that can detect Src activity in very small numbers of cells; this will be very useful for detecting Src activity in developing metastases (micrometastases).

Selected Publications

Dual role of SnoN in mammalian tumorigenesis. [Q. Zhu,  A.R. Krakowski, E.E.Dunham, L. Wang, A. Bandyopdhyay, R. Berdeaux, G.S. Martin, L. Sun, and K. Luo (2007)  Mol. Cell. Biol. 27, 324-329]

Fly Src: the Yin and Yang of tumor invasion and tumor suppression. [G.S. Martin (2006) Cancer Cell 9, 4-6]

Transcription of the Schizosaccharomyces pombe gene cdc18+: roles of MCB elements and the DSC1 complex. [W.T. Jackson  and G.S. Martin (2006)  Gene 369, 100-108]

Activated Src abrogates the Myc requirement for the G0/G1 transition but not for the G1/S transition. [T. Prathapam, S. Tegen, T. Oskarsson, A. Trumpp and G.S. Martin (2006) Proc. Natl. Acad. Sci. USA 103, 2695-2700]

The road to Src. [G.S. Martin (2004) Oncogene 23, 7910-7917]

Active Rho is localized to podosomes induced by oncogenic Src and is required for their assembly and function. [R. Berdeaux, B. Diaz, L.C. Kim, A. Tu and G.S. Martin (2004) J. Cell Biol. 166, 317-323]

Cell signaling and cancer. [G.S. Martin (2003) Cancer Cell 4, 167-174]

A reporter system for reverse transfection cell arrays. [B.L. Webb, B. Daz, G.S. Martin, and F. Lai (2003) J. Biomolec. Screening 8, 620-623]

The transforming ability of Ski is dependent on its ability to repress the activity of Smad proteins [J. He, S. Tegen, A.R. Krawitz, G.S. Martin, and K. Luo (2003) J. Biol. Chem. 278, 30540-7]

Activation of oncogenic protein kinases [G.S. Martin (2003) In: Handbook of Cellular Signaling (R.Bradshaw and E. Dennis, eds.), Academic Press, pp. 441-449]

The hunting of the Src [G.S. Martin (2001) Nature Rev. Mol. Cell Biol. 2, 467-475]

Last Updated 2007-02-13