Basic Science Tower, Stony Brook University, Stony Brook, NY 11794-8651 / 631-444-3219
Medical Scientist (M.D./Ph.D.) Training Program
Saadat U. Aleem
B.S. University of California Berkeley, 2003

5th Year Graduate Student

Advisor: Todd Miller, PhD

Department: Physiology & Biophysics

Graduate Program: Molecular & Cellular Biology

Title:
Investigations into the C-Terminal Regulatory Mechanisms of Protein Tyrosine Kinase 6

Abstract:

          Breast Tumor Kinase (Brk) is a non-receptor tyrosine kinase that has been found to be up-regulated in metastatic breast tumors. In normal mammary tissue or benign lesions, expression of Brk has been found to be low or undetectable. Experimental evidence suggests that Brk contributes to the development of breast cancer. It has been demonstrated that expression of Brk in cultured epithelial mammary cells stimulates anchorage independent growth. Further, expression of Brk in fibroblasts has been shown to stimulate partial transformation.

          One of the goals of our lab has been to elucidate the regulatory mechanisms involved with Brk. Brk is distantly related to the Src family of tyrosine kinases. Brk possesses sequences that form a Src Homology 2 (SH2) domain. The corresponding domain in Src forms an intramolecular interaction with the phosphorylated form of Tyr-527 in its C-terminus. This interaction stabilizes an inactive conformation of the protein. Brk contains a homologous tyrosine residue (Tyr-447) in its C-terminus, which we believe may be contributing to a similar inhibitory mechanism of the kinase via an intramolecular interaction with its SH2 domain. Experimental studies performed by our lab have demonstrated that mutations of Tyr-447 increased enzyme activity and also SH2 domain accessibility, which supported an autoinhibitory mechanism at this site. Currently our lab is studying to characterize this regulatory mechanism of Brk, including searching for evidence of this intramolecular interaction by performing experiments utilizing hydrogen-deuterium exchange mass spectrometry and other analytical tools at our disposal. This interaction would shed light into one of the mechanisms by which Brk is regulated and would aid in solving how Brk is involved with breast malignancy.

Publications:
(pre-MSTP publications indicated with an *)

*Dong L., Aleem S., Fink C. A. (2010). Microwave-accelerated reductive amination between ketones and ammonium acetate. Tetrahedron Letters. 51(39):5210-5212

*Bagdanoff J.T., Donoviel M.S., Nouraldeen A., Carlsen M., Jessop T.C., Tarver J., Aleem S., Dong L., Zhang H., Boteju L., Hazelwood J., Yan J., Bednarz M., Layek S., Owusu I.B., Gopinathan S., Moran L., Lai Z., Kramer J., Kimball S.D., Yalamanchili P., Heydorn W.E., Frazier K.S., Brooks B., Brown P., Wilson A., Sonnenburg W.K., Main A., Carson K.G., Oravecz T., Augeri D.J. (2010). Inhibition of sphingosine 1-phosphate lyase for the treatment of rheumatoid arthritis: discovery of (E)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone oxime (LX2931) and (1R,2S,3R)-1-(2-(isoxazol-3-yl)-1H-imidazol-4-yl)butane-1,2,3,4-tetraol (LX2932).J Med Chem.
53(24):8650-62. Epub 2010 Nov 22.

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