Richard K. Assoian
Professor, Dept of Pharmacology

Cell Biology and Physiology Program

Address

167 Johnson Pavillion
3610 Hamilton Walk
Philadelphia, PA 19104

Office tel.: 215 898-7157
Lab tel.: 215 898-7265
Fax: 215 573-5656
E-mail: rka@pharm.med.upenn.edu

Link(s)

Department of Pharmacology faculty page

Dr. Assoian's Lab Webpage

EDUCATION

Johns Hopkins: BA (Natural Sciences), 1975.

University of Chicago: PhD (Biochemistry), 1981.

Research Interests

• Integration of signal transduction and G1 phase cell cycle progression.

Key words: cyclins, ERK, PI3K, Rho GTPases, ECM, integrins, vascular remodeling.

Search PubMed for articles

Desrciption of Research

We are interested in the integration of signal transduction and G1 phase cell cycle progression. Within this broad field, we are currently working in the following areas:

1. Regulation of the cell cycle by integrin-mediated adhesion. Cell adhesion to the extracellular matrix (ECM) is required for cell proliferation because the binding of matrix protein (such as collagens, fibronectin, vitronectin, and laminin) to integrins (ECM receptors) is required for activation of the G1 phase cyclin-dependent kinases (cdks; the enzymes that mediate progression through the cell cycle). The genes encoding cyclin D1 and Skp2 (the E3 ubiquitin ligase that mediates proteosomal degradation of the cdk inhibitor, p27) appear to be the major targets of integrin signaling. We are currently investigating how integrin-dependent signaling regulates the expression of these genes. These studies involve an analysis of integrin-regulated kinases and Rho family GTPases.



2. Regulation of the cell cycle by substrate compliance and cellular tension. One of the main limitations of modern cell biology is the fact that cells are usually cultured on a plastic surface which is completely rigid rather than its native biological substratum which is flexible. The flexibility of an underlying substratum (its "compliance") has profound effects on cellular architecture, tension, and proliferation, raising the possibility that many of the signaling, differentiation, and proliferative responses identified in traditional culture may not be relevant in vivo. We have recently adopted a culture system in which cells are cultured on ECM proteins covalently bound to polyacrylamide gels. This system gives us complete control of substratum compliance and allows us to match the compliance of cultured cells to the compliance of their native tissues in vivo. We are using this system with fibroblasts and mammary epithelial cells before an after an epithelial-mesenchymal transition to characterize the effects of substrate compliance and cellular tension on cell cycle progression. We are characterizing compliance-dependent signaling pathways that regulate the G1 phase cyclin-cdks and determining how signaling to the cell cycle changes to accommodate the different compliance environments that cells see in vivo.



3. Regulation of the cell cycle during vascular remodeling. A major challenge in cell biology is to determine whether effects seen in culture occur in vivo. We are approaching this issue by examining ligands, receptors, and signaling pathways that regulate the proliferation of vascular smooth muscle cells in compliance-appropriate culture and in vivo, after fine-wire femoral artery vascular injury. Using wild-type mice and mice with knock-outs or knock-ins of cdk-regulatory genes, we identify mechanisms in vitro and then assess relevance for the onset of cell proliferation in vivo. This work also has strong biomedical relevance since smooth muscle cell proliferation and consequent vascular remodeling are important components of atherosclerosis and restenosis.

   Our current interests in this area are focused on:

   -a potent antimitogen called PGI2 and its receptor, IP
   -the signaling molecules FAK and Rac
   -hyaluronic acid (HA) a nonproteinaceous ECM component and its receptor CD44 (in collaboration with Ellen Puré's lab)
   

Recent Publications

Yung, Y., Walker, J.L., Roberts, J.M., and Assoian, R.K. (2007) A Skp2 autoinduction loop and restriction point control. J. Cell Biol., in press.

Klein, E.A., Yang, C., Kazanietz, M., and Assoian, R.K. (2007) NF-kB-independent signaling to the cyclin D1 gene by Rac. Cell Cycle. 6: 1115-1121.

Villanueva, J., Yung, Y., Walker, J.L., and Assoian, R.K. (2007) ERK activity and G1 phase progression: identifying dispensable versus essential activities and primary versus secondary targets. Mol. Biol. Cell, 18: 1457-63.

Kothapalli, D., Zhao, L., Hawthorne, Y., Cheng, E.A., Lee, E., Puré, E., and Assoian, R.K. (2007) Hyaluronan and CD44 antagonize mitogen-dependent cyclin D1 expression in mesenchymal cells.J. Cell. Biol.,176: 535-544

Kothapalli, D., Fuki, I., Ali, K., Stewart, S.A., Zhao, L., Yahil, R., Kwiatkowski, D., Hawthorne, E.A., FitzGerald, G.A., Phillips, M.C., Lund-Katz, S., Puré, E., Rader, D.J. and Assoian, R.K. (2004) Antimitogenic effects of HDL and apolipoprotein E mediated by cyclooxygenase-2–dependent IP activation. J. Clin. Invest, 609.

Lab

Rotation Projects

Rotation projects are developed in consultation with each student and geared towards their particular area(s) of interest. There are usually rotation projects available within each of the three areas outlined above. Lab members are always encouraged to suggest potential new projects falling within our research interests, broadly defined.

Lab personnel:

Devashish Kothapalli, PhD, Post-doctoral Research Associate
Liqun Yin, MD, Post-doctoral Research Associate
Yuval Yung, Postdoctoral Fellow
Paola Castagnino, PhD, Research Specialist
Eric Klein, Graduate Student
Latoya Campbell, Graduate Student
Beth Hawthorne, Research Specialist/Lab Manager
Tina Xu, Research Specialist
Jim Flowers, Graduate Student