Laboratory of Suresh K. Alahari
PhD, Drexel University, 1994

This laboratory investigates the mechanism of action of Nischarin in tumor cell migration and invasion.
Dr. Alahari was recently approved for Tenure!

	Recent News: Dr. Suresh Alahari was interviewed by Louisiana Network about his research targeting new treatments for invasive breast cancer. Stories aired on LA Network affiliates, about 80 radio stations across Louisiana and Mississippi. read more... Watch the video news story on Dr. Alahari and his lab here!
From Left: Yanfang Wang, Tanja Milosavljevic,Prachi Jain, Deepak Chander Megan Fitzmaurice, Somesh Barawal, Amelia Walch, Dr. Alahari

Integrins are cell adhesion receptors that mediate cell to cell and cell to extracellular matrix interactions. Integrins have been implicated in several cellular processes including, the organization of the cytoskeleton, cell growth and survival, cell motility, control of gene expression and cell differentiation. Integrins can function as positive or negative regulators of tumor progression, affecting growth, cell migration, and invasion and metastasis. It seems likely that intracellular proteins that interact with integrins also play a role in tumorigenesis. We have identified a novel protein that we termed Nischarin, which is derived from Sanskrit that connotes slowness of motion. This molecule is ubiquitously expressed, is a cytosolic protein, and it interacts with the alpha5beta1 integrin in vivo. Fibroblasts over-expressing Nischarin constructs have “basket-like” networks of peripheral actin filaments rather than typical stress fibers. Our recent data indicate that Nischarin inhibits Rac induced cell migration and invasion in carcinoma cells. Furthermore, with the help of effector domain mutants of Rac1 we demonstrate that Nischarin selectively inhibits Rac driven signaling cascades that act through p21 activated kinase (PAK). These observations suggest Nischarin affects the process of cytoskeletal regulation mediated by Rac specifically by affecting PAK. Additional experiments have shown that Nischarin associates with PAK1 a well as PAK4. Nischarin binds strongly to active form of PAK, and further data revealed that Nischarin binds to open conformation of PAK. Al so Nischarin modulates the kinase activity of PAK1. Consistent with this, Nischarin siRNA stimulates cell migration and stimulates PAK activation.

Tumor cell migration and invasion are important factors in development of solid tumors and are essential for metastasis to various organs. Recently, it has been shown that PAK regulates motile and invasive phenotypes of breast cancer cells through reorganization of actin cytoskeleton. In addition PAK1 plays a role in breast morphogenesis and differentiation. It has been suggested there is a functional correlation between high grade breast tumors and enhanced PAK kinase activity, and thus PAK may have an important role in in vivo tumorigenesis. Since both PAK1 and PAK4 have been shown to strongly promote growth in soft agar, and since Nischarin binds to both of these kinases, it seems likely that Nischarin may affect anchorage independent growth as well as tumor growth in nude mice and thus Nischarin may be an important regulator of cancer progression.

A movie of nischarin is shown below. Immunofluorescence localization of nischarin in adherent cells viewed using confocal microscopy. It may take a few moments for the movie to load. You may need QuickTime Player to view the movie. If you do not have QuickTime Player, click here to download.

Thus we are investigating the role of Nischarin in breast tumor progression, and also we are in the process of identifying proteins that interact with Nischarin in breast cancer cells using proteomics as well as yeast two-hybrid approaches. A detailed understanding of the mechanistic basis of these events can significantly advance the development of new therapeutic approaches for cancer.

Publications

Suppression of tumorigenicity 14 (ST14) gene is a target for miR- 27b, and the inhibitory effect of ST14 on cell growth is independent of miR- 27b regulation (2009), Wang, Y., Rathinam. R., Walch, A., and Alahari, S.K. Journal of Biological Chemistry (In Press)

MicroRNA function in cancer; Oncogene or  a tumor suppressor? (2009) Shenouda, S.K. and Alahari, S.K. Cancer and Metastasis reviews (In Press).

Molecular mechanisms controlling E-cadherin expression in breast cancer (2009) Baranwal, S and Alahari, S.K. Biochemical and Biophysical Research Communications 384: 6-11

Ding Y, Milosavljevic T, Alahari SK. Nischarin inhibits LIM Kinase to regulate Cofilin phosphorylation and Cell Invasion. Mol Cell Biol. Mar 10 (2008)

Alahari, S.K., Reddig, P., Juliano, R.L. The integrin binding protein Nischarin regulates cell migration by inhibiting PAK. EMBO J, 23: 2777-2788 (2004)

Juliano, R.L., Reddig, P.J., Alahari, S.K., Edin, M.L., Howe, A.K., and Aplin, A.E., Integrin Regulation of Cell Signaling and Motility.Biochem., Society Transactions 32: 443-446 (2004)

Alahari, S.K. and H. Nasrallah : A Membrane proximal region of alpha-5 integrin is essential for its interaction with Nischarin. Biochemical Journal 15: 449-457 (2004)

Alahari, S.K.: Nischarin inhibits Rac induced migration and invasion of epithelial cells by affecting signaling cascades involving PAK. Exp. Cell Res. 288: 415-424 (2002)

Alahari, S.K., Reddig, P., Juliano, R.L. Biological aspects of signal transduction by cell adhesion receptors. Int. J. Cytology 220: 145-174 (2002)

Alahari, S.K.,: Mapping of the gene for Nischarin, a novel integrin binding protein, to chromosome 3 by fluorescence in situ hybridization). Intl. J. Human Genetics 1: 271-274 (2001)

Alahari, S.K., Lee, J.L., and Juliano, R.L.: NISCHARIN, a novel protein that interacts with integrin alpha-5 subunit, and inhibits cell migration. J. Cell Biology 151: 1141-1154 (2000)

Methods for study of integrin regulation of receptor tyrosine kinase and G protein coupled receptor signaling to MAP kinases. Methods In Enzymology 333:151-163 (2001)

Shock, D.D., Naik, U.P., Brittain, J.E., Alahari, S. K., Sondek, J., and Parise, L.V.: Calcium-dependent properties of CIB binding to the integrin alphaIIb cytoplasmic domain and translocation to the platelet cytoskeleton Biochemical Journal 342: 729-735 (1999)

DeLong, R.K., Hoon, Y., Alahari, S.K., Fisher, M., Short, S.M., Kole, R and Juliano, R. L.: Novel cationic amphiphiles as delivery reagents for antisense oligonucleotides. Nucleic Acids Research 27:3334-3341.(1999)

Hughes, J. A., Astriab,A., Yoo, H., Alahari, S.K., Liang, E., Sergueev, D., Shaw, B. and Juliano, R.L.: In Vitro Transport and delivery of oligonucleotides. Methods in Enzymology 313:343-359. (1999)

Juliano, R.L., Alahari, S.K., Yoo, H., Kole, R., and Cho, M. Antisense Pharmacodynamics: Critical issues in the transport & delivery of antisense oligonucleotides. Pharmaceutical Research 16: 494-502.(1999)

Alahari, S.K., Delong, R., Fisher, M.H., Dean, N. M. Viliet, P and Juliano, R.L. Novel chemically modified oligonucleotides provide potent inhibition of P-glycoprotein expression. J.Pharm.Exp. Therapeutics 286:419-428 (1998)

Howe.A., Aplin, A., Alahari, S.K., and Juliano, R.L.. Integrin signaling and cell growth Control.Current Opinion in Cell Biology 10: 220-231 (1998)

Aplin, A., Howe, A., Alahari, S. K., and Juliano, R.L. Signal transduction and signal modulation by cell adhesion receptors: the role of integrins, cadherins, IG-CAMS and selectins. Pharmacological Reviews 50: 197-263 (1998)

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