BMCB-Faculty Research, Joseph C. Loftus

Associate Professor of Biochemistry & Molecular Biology at Mayo Clinic Scottsdale,
and Adjunct Associate Professor, Department of Molecular & Cellular Biology
Ph.D., University of Wisconsin, Madison

Integrin adhesion and signaling in vascular cell biology.

Research Interests

The capacity of cells to recognize other cells and specific elements of their surrounding extracellular matrix plays a central role in the diverse range of cellular processes including cellular differentiation, cell migration, the immune response and the maintenance of tissue architecture. Unique among cell adhesion receptor families is the integrin receptor family whose members mediate both cell-cell and cell-matrix interactions. Research in the lab is focused on integrin receptor structure and function and the role of receptor mediated adhesion and signaling on the biology of vascular cells and in malignant glioma.

We are using both loss of function and signaling mutants to assess the role of integrin adhesion and signaling in the hypertrophic response of cardiac myocytes. Increased mechanical loading leads to hypertrophic growth of the terminally differentiated cardiac myocyte. While this process is initially compensatory, the signaling pathways that lead from compensated hypertrophy to decompensated heart failure are presently unknown. The capacity of integrins to function as stretch receptors and mechanotransducers makes them ideal candidates for translating abnormal strain into intracellular signals. We have been able to directly link integrin signaling to the hypertrophic response of cardiac myocytes in a cell culture model. Important pathways and critical effector molecules identified in these in vitro studies will be targeted in transgenic mice to obtain further insights into the role of integrins in cardiac function.

We have also begun studies investigating integrin signaling in the biology of malignant gliomas. The oncology of invasive gliomas is firmly rooted in the inverse relationship between migration and proliferation. Increased commitment to invasion is accompanied by decreased proliferative activity and increased resistance to cytotoxic agents. Integrin mediated adhesion is crucial to cellular migration and proliferation, not only through interactions with ECM proteins, but by mitigating the dynamic balance of various non-receptor tyrosine kinases that function as effectors of integrin mediated signaling. Specifically, we have focused on defining the role that the related focal adhesion kinases Pyk2 and FAK play as important signaling effectors regulating the temporal development of the invasive or proliferative behavior of gliomas. Insights into the molecular mechanisms that regulate glioma cell invasion are required to identify entry points for the development of novel anti-invasive therapies necessary to improve clinical outcome.

Select Publications

Any link on the below references will take you off of the BMCB site and to an abstract of that particular paper.

Lipinski, C.A., N.L. Tran, E. Menashi, C. Rohl, J. Kloss, R.C. Bay, M.E. Berens, and J.C. Loftus. 2005. The tyrosine kinase pyk2 promotes migration and invasion of glioma cells. Neoplasia 7: 435-445.

Hibner, M., J.F. Magrina, S. Lefler, J.L. Cornella, A. Pizarro, and J.C. Loftus. 2004. Effects of raloxifene hydrochloride on endometrial cancer cells in vitro. Gynecological Oncology 93: 642-646.

Lipinski, C.A., N.L. Tran, C. Bay, J. Kloss, W.S. McDonough, C. Beaudry, M.E. Berens, and J.C. Loftus. 2003. Differential role of proline-rich tyrosine kinase 2 and focal adhesion kinase in determining glioblastoma migration and proliferation. Molecular Cancer Research 1:323-332.

Valencik, M.L., R.S. Keller, J.C. Loftus, amd J.A. McDonald. 2002. A lethal perinatal cardiac phenotype resulting from altered integrin function in cardiomyocytes. Journal of Cardiac Failure 8: 262-272.

McMillan, R., L. Wang, J. Lopez-Dee, S. Jiu, and J.C. Loftus. 2002. Many alphaIIbbeta3 autoepitopes in chronic immune thrombocytopenic purpura are localized to alphaIIb between amino acids L1 and Q459. British Journal of Haematology 118: 1132-1136.

Tani, P.H., J.C. Loftus, and R.D. Bowditch. 2002. In vitro selection of fibronectin gain-of-function mutations. Biochemical Journal 365: 287-294.

Shai, S.Y., A.E. Harpf, C.J. Babbitt, M.C. Jordan, M.C. Fishbein, J. Chen, M. Omura, T.A. Leil, K.D. Becker, M. Jiang, D.J. Smith, S.R. Cherry, J.C. Loftus, and R.S. Ross. 2002. Cardiac myocyte-specific excision of the beta1 integrin gene results in myocardial fibrosis and cardiac failure. Circulation Research 90: 458-464.

Hauck, C.R., D.J. Sieg, D.A. Hsia, J.C. Loftus, W.A. Gaarde, B.P. Monia, and D.D. Schlaepfer. 2001. Inhibition of focal adhesion kinase expression or activity disrupts epidermal growth factor-stimulated signaling promoting the migration of invasive human carcinoma cells. Cancer Research 61: 7079-7090.

McMillan, R., J. Lopez-Dee, and J.C. Loftus. 2001. Autoantibodies to alpha(IIb)beta(3) in patients with chronic immune thrombocytopenic purpura bind primarily to epitopes on alpha(IIb). Blood 97: 2171-2172.

Keller, R.S., S.-Y. Shai, C.J. Babbitt, C.G. Pham, R.J. Solaro, M.L. Valencik, J.C. Loftus, and R.S. Ross. 2001. Disruption of integrin function in the murine myocardium leads to perinatal lethality, fibrosis, and abnormal cardiac performance. American Journal of Pathology 158: 1079-1090.

Pham, C.G., A.E. Harpf, R.S. Keller, H.T. Vu, S.-Y. Shai, J.C. Loftus, and R.S. Ross. 2000. Striated muscle-specific beta(ID)-integrin and FAK are involved in cardiac myocyte hypertropic response pathway. American Journal of Physiology. Heart and Circulatory Physiology 279: H2916-H2926.

Plow, E.F., T.A. Haas, L. Zhang, J.C. Loftus, and J.W. Smith. 2000. Ligand binding to integrins. Journal of Biological Chemistry 252: 21785-21788.

Tozer, E.C., E.K. Baker, M.H. Ginsberg, and J.C. Loftus. 1999. A mutation in the alpha subunit of the platelet integrin alpha-IIb beta-3 identifies a novel region important for ligand binding. Blood 93: 918-924.

Ross, R.R., V. Hoa, C. Fenczik, C.C. Glembotski, M.H. Ginsberg, and J.C. Loftus. 1998. Beta1 integrins participate in the hypertrophic response of rat ventricular myocytes. Circulation Research 82: 1160-1172.

Contact Information

Mailing:
Joseph C. Loftus, Associate Professor
Mayo Clinic Scottsdale
Biochemistry & Molecular Biology
13208 East Shea Boulevard
Scottsdale, AZ 85259

Web Site: Home Page

Telephone:
480-301-6274

Fax:
480-301-7017

Email:
loftus.joseph@mayo.edu

Please e-mail any comments to:
bmcb@email.arizona.edu