Wei Xiong, MD Research Fellow Sajjad Hossain, MA Research Assistant
Xiong, X., Cui, P., Warner, B., Hossain, S., Guo, X., An, X., Debnath, A.K., and L. Kotula 2008. Allosteric inhibition of c-Abl tyrosine kinase by phosphopeptides derived from Abi1/Hssh3bp1. BBA 1783, 737-747.
Macoska, J. A., Xu, J., Ziemnicka-Kotula, D., Schwab, T., Rubin, M., Kotula L. Loss of expression of human spectrin Src homology domain binding protein 1 is associated with 10p loss in human prostatic adenocarcinoma. Neoplasia 2001; 3: 99-104.
Xu, J., Ziemnicka-Kotula, D., Merz, G.S., Kotula L. Human spectrin SH3 domain binding protein 1 regulates macropinocytosis in NIH 3T3 cells. J. Cell Sci. 2000; 113:3805-3814.
Huang, J-H., Qi, Z., Wu, F., Kotula, L., Jiang, S., and Y-H. Chen 2008. Interaction of HIV-1 gp41 core with NPF motif in Epsin: implication in endocytosis of HIV. J Biol Chem. 2008 May 30;283(22):14994-5002
Ziemnicka D, Xu J, Gu H, Potempska A, Kim KS, Jenkins EC, Trenkner E, Kotula L. Identification of A Candidate Spectrin SH3 Binding Protein Suggests A General Mechanism of Association of Tyrosine Kinases with the Spectrin-Based Membrane Skeleton. J. Biol. Chem. 1998; 273: 13681-13692.
Red blood cells provide an excellent model system to study membrane biology and functional interactions of integral and membrane-associated proteins. These interactions usually occur in a specific order resulting in signal transduction processes or cellular signals that control basic functions of cells such as cell growth and death, cell division and differentiation. Cellular signals are precisely controlled and disturbances in the fidelity of these processes often result in a variety of serious human diseases such as cancer, heart disease and diabetes, and immunological disorders including immunodeficiencies leading to people being more prone to infections.
The research of the Laboratory of Cell Signaling, headed by Leszek Kotula, MD, evolves around the genetics and the function of a protein, ABI1/HSSH3BP1, that was originally identified through its interaction with human spectrin, the major red blood cell membrane protein. Recent findings indicate ABI1/HSSH3BPI plays a role in cell growth and in macropinocytosis or "cell drinking" - how cells take in fluids and molecules - and that this process may be abnormally regulated in cancer cells. The long-term goal of this research is to develop a detailed understanding of how abnormal cells grow, paving the way to a cure
One of the major functions of ABI1/HSSH3BP1 might be the regulation of cellular enzyme, a tyrosine kinase, called c-Abl. Mutations in c-Abl underlie chronic myleogenous leukemia, hence understanding Abl kinase regulation is of clinical significance. Moreover, the ABi1/Hssh3bp1 mutation in prostate cancer cell line, LNCaP (Macoska et al, 2001), leads to dysregulation of Abl kinase activity (Xiong et al, 2008). This points to the possibility of abnormal Abl kinase activity and Abi1/Hssh3bp1 involvement in prostate cancer tumorigenesis. Prostate cancer claims nearly 30,000 victims a years in the U.S., making it one of the leading causes of cancer-related deaths. Nearly a quarter-million new prostate cancer cases are diagnosed each year.
Laboratory of Cell Signaling has formed several collaborations both within and outside LFKRI. Outside collaborations include researchers from Memorial Sloan-Kettering Cancer Center in New York, Yale University (New Haven, CT); and the Lankenau Institute for Medical Research (Wynenewood, PA). Recently, the Laboratory has formed an international collaboration with researchers from Helmholtz Institute for Infectious Disease in Braunschweig, Germany.
