faculty photo

Richard K. Assoian

Professor of Pharmacology
Department: Pharmacology
Graduate Group Affiliations

Contact information
Department of Pharmacology
421 Curie Blvd.
Rm 805(office)/833 (lab)
Philadelphia, PA 19104-6160
Office: (215) 898-7157
Fax: (215) 573-5656
Lab: (215) 898-7265
B.A. (Natural Science)
Johns Hopkins University, 1975.
Ph.D. (Biochemistry)
University of Chicago, 1981.
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Description of Research Expertise

Key words

Adhesion-dependent signal transduction, mechanotransduction, mechanochemical signaling, microenvironment, extracellular matrix, ECM, integrin, cadherin, actin, cytoskeleton, focal adhesions, matrix remodeling, cell cycle, proliferation, cyclin-dependent kinases, mouse modeling, cardiovascular biology.

Description of laboratory research:

We are cell/molecular biologists and bioengineers interested in the over-arching idea that cells can sense and respond to changes in the mechanical properties of their microenvironment and that they use this mechanical information, as well as more conventional chemical signals, to direct their behavior. Within this broad area, we try to understand how physiological and pathological changes in the stiffness of the extracellular matrix affect the composition of adhesion receptor signaling complexes, the actin cytoskeleton, intracellular forces, and proliferation. Our goal is to combine mechanistic analysis in cell culture, bioinformatics, and functional testing in mouse models of vascular aging, injury, and atherosclerosis.

We are currently working in the following general areas.

i) Mechanochemical signaling from the extracellular matrix to the cell cycle.
Most mammalian cells live in an elastic microenvironment; stiffening of the microenvironment occurs in several diseases and perturbs normal cellular function. The effects of matrix elasticity on cellular function are difficult to study when cells are cultured on traditional rigid plastic or glass substrata that are irrelevant to in vivo microenvironments. We are using bioengineered substrata (ECM-coated hydrogels), which can mimic the elasticity of tissues that cells inhabit in vivo, to determine how substratum stiffness affects signaling pathways regulating the cell cycle. With this approach, we study the effect of changes in matrix stiffness on the spatial distribution of intracellular forces, focal adhesion composition, and adhesion receptor (integrin and cadherin) expression/signaling. We also use micropatterned substrata to examine the effect of cell-cell adhesion on proliferation. Recent work with these approaches has led to the identification of stiffness-dependent signaling pathways, specific focal adhesion components controlling cyclin D1 expression, microRNAs controlling the cdk inhibitor, p27kip1, and novel mechanisms of crosstalk between cell-ECM and cell-cell adhesion.

ii) In vivo mechanobiology.
Ultimately, the importance of biomechanics to cellular function must be documented in vivo. We are approaching this issue by examining adhesion receptors and signaling pathways that regulate matrix remodeling, tissue stiffness, and vascular smooth muscle cell (VSMC) proliferation during the response to injury. We invoke the injury response by gently denuding the endothelium in the femoral artery of mice. By comparing the degree of VSMC proliferation in wild-type mice and mice with knock-outs/knock-ins of integrin regulated signaling and cell cycle genes, we can test, in vivo, the importance of the integrin- and stiffness-regulated signaling events we detect in primary VSMCs cultured on hydrogels. Similar studies are exploring the proliferative effects of N-cadherin and its potential interactions with integrins. This work has strong biomedical relevance since damage to the endothelial lining of blood vessels and smooth muscle cell proliferation play critical roles in cardiovascular disease.

iii) Cardiovascular protection through regulation of arterial stiffness
We are identifying novel regulators of ECM remodeling and arterial stiffness. One set of studies has focused on apolipoprotein E (apoE) and apoE-containing HDL. Although best known for their role in reverse cholesterol transport, we find that apoE and apoE-HDL suppress the expression of several ECM genes including those for collagen-I, collagen-VIII, fibronectin and lysyl oxidase. These effects protect against arterial stiffening, reduce monocyte adhesion to subendothelial ECM, and provide cholesterol-independent protection against atherosclerosis in mice. Our newest work has identified a global inducer of arterial stiffening with age, vascular injury and atherosclerosis. Overall, our work in this area is identifying new, biomechanically-inspired ways to protect against cardiovascular disease.

Current lab members:

Yong Ho Bae, PhD
Shu-Lin Liu, PhD
Keeley Mui, PhD
Ziba Razinia, PhD
Nancy Sehgel, PhD
Sue Lee, graduate student
Chris Yu, graduate student (with Rader lab)
Nate Bade, graduate student (with Stebe lab)
Beth Hawthorne, research specialist/lab manager
Tina Xu, research specialist

ITMAT Biomechanics Core:
Paola Castagnino, PhD (Technical Director)

Selected Publications

Mui, KM., Bae, YH, Gao, L., Liu, S-L. Xu, T., Radice, GL., Chen, CS, and Assoian, RK: N-cadherin induction by ECM stiffness and FAK overrides the spreading requirement for proliferation of vascular smooth muscle cells. Cell Reports 10: 1477-1486, 2015.

Bae YH, Mui KL, Hsu BY, Liu SL, Cretu A, Razinia Z, Xu T, Puré E, Assoian RK. : A FAK-Cas-Rac-Lamellipodin Signaling Module Transduces Extracellular Matrix Stiffness into Mechanosensitive Cell Cycling. Science Signaling 7: ra57, 2014.

Castagnino, P.*, Kothapalli, D.*, Hawthorne, E.A., Liu, S-L., Xu, T., Rao, S., Yung, Y., and Assoian, R.K. : miR-221/222 compensates for Skp2-mediated p27 degradation and is a primary target of cell cycle regulation by prostacyclin and cAMP. PLoS One, 8: e56140, 2013.

Kothapalli, D.*, Liu, S.L.*, Bae, Y.H., Monslow, J., Xu, T., Hawthorne, E.A., Castagnino, P., Byfield, F.J., Rao, S., Rader, D.J., Pure, E., Phillips, M.C., Lund-Katz, S., Janmey, P.A., Assoian, R.K.: Cardiovascular protection by apoE and apoE-HDL linked to suppression of ECM gene expression and arterial stiffening. Cell Reports 2: 1259-1271, 2012.

Klein, E.A., Yin, L., Kothapalli, D., Castagnino, P., Byfield, F.J., Xu, T., Levantal, I., Hawthorne, E., Janmey, P.A., and Assoian, R.K.: Cell cycle control by physiological matrix elasticity and in vivo tissue stiffening. Current Biology 19: 1511-8, 2009.

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Last updated: 08/28/2015
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