Description of Research Expertise

Research Interests
Connections between cell shape and cell division controls, and linked deregulation of these processes in cancer. Complex protein interactions in cell signaling.

Key words: HEF1, HEI-C, HEI10, two-hybrid, protein interactions

Description of Research
Our laboratory is interested in the dialog between cell shape controls and the cell cycle machinery in cancer. As theoretical background to this work, we consider that organismal development requires the synchronized interaction of cell differentiation, polarization, and division controls to enable the creation of highly organized structures from an isolated oocyte. At present, although the mechanisms by which these different processes are coordinated are not well understood, studies predominantly in lower eukaryotes have led to the identification of a number of proteins that act at cell-cell or cell-substrate interfaces in interphase, and at the mitotic machinery in M-phase. The complex functions of these proteins allow the direct specification of cleavage plane to be coordinated with the establishment or maintenance of a polarized cellular. A number of the proteins identified in these studies have homologs with presumably orthologous functions in higher eukaryotes. However, studies of mammalian signaling proteins typically have not focused on very early development, but rather emphasize the study of cell processes and protein function in 2-dimensional cell culture models, where the coordination of cell division polarity with cellular attachment status is less readily perceived and analyzed. Given that progression from differentiated cells, organized in 3 dimensions in tissues to an undifferentiated dysplastic cellular mass is absolutely characteristic of solid tumors, it is likely that proteins that control these changes will have important functions in cancer. We have focused our work on characterizing 3 proteins discovered by our laboratory that possess dual functions at points of cell-cell interaction and in control of the cell division cycle. Based on our studies, the HEF1, HEI-C, and HEI10 proteins have been characterized as links between the cell attachment and the mitotic machinery.

Rotation Projects for 2006-2007
General introduction to projects:
The three members of the Cas protein family (p130Cas, HEF1, and Efs/Sin) are scaffolding proteins at focal adhesions that are central mediators of integrin signaling. Prior work by our group and others in cell culture models has demonstrated that the Cas proteins positively regulate cell motility. Based on their known signaling properties, Cas proteins are well-situated to interact with a number of defined regulators of EMT. Intriguingly, upregulation of Cas proteins has been found to be associated with aggressive breast cancers of poor prognosis. In our own preliminary studies, we have found that Cas protein expression is significantly elevated in pre-malignant subpopulations of ovarian surface epithelial cells, in ovarian structures such as inclusion cysts that are associated with an early pre-malignant state, and in many ovarian tumors, suggesting a general relevance to cancer development of solid tumors. We have found that Cas proteins negatively regulate the protein expression and localization of the epithelial cell marker E-cadherin, and control the nuclear localization of the Snail repressor protein. We have also shown that increased levels of Cas proteins promote the activation of the GTPase Rac. Based on these and other observations, we propose that Cas proteins may have important roles in the EMT process in cancer.

Specific projects:

1. To determine the mechanisms by which the Cas proteins promote EMT. Based on our preliminary data, we hypothesize that the Cas proteins affect the ability of E-cadherin to form stable structures at adherens junctions. The goal of the project is to analyze the mechanism by which Cas proteins control E-cadherin protein expression and organization.
2. To test the idea that the upregulation of the Cas protein HEF1 is associated with EMT. This would involve contrasting the regulation of p130Cas and HEF1. Based on preliminary data, this will examine whether Cas proteins are essential intermediates in TGF-beta induction of EMT, and assessment of how signaling through TGF-beta controls the endogenous level of Cas proteins.
3. To determine whether a Cas-dependent signaling axis is specifically associated with a specific prognosis for cancer progression, and defines a subset of ovarian tumors.

Lab personnel:
Ilya G. Serebriiskii, Ph.D., Staff Scientist
Disha Dadke, Ph.D., Postdoctoral Fellow
Elena N. Pugacheva, Ph.D., Postdoctoral Associate
Mahendra K. Singh, Ph.D., Postdoctoral Fellow
Eugene Izumchenko, Graduate Student
Anna Potapova, M.S., Visiting Scientist
Natalya Skobeleva, Ph.D., Visiting Scientist