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

7th Year MSTP
5th Year Molecular and Cell Biology Graduate Student

Advisor: Todd Miller, PhD

Department: Physiology & Biophysics, Stony Brook University

Graduate Program: Molecular & Cellular Biology

Title:
Specificity in Tyrosine Kinases and Phosphatases in Regulating Src & Brk

Abstract:

The non-receptor tyrosine kinases Src and Brk (PTK6) are frequently deregulated in human breast cancer, and have been implicated in tumor growth and metastasis. Both kinases are regulated by tyrosine phosphorylation at their C-termini, inducing intramolecular interactions with their own SH2 domains that inhibit kinase activity. The kinases and phosphatases responsible for this regulation, however, have not been fully elucidated. We report here that the poorly characterized kinase Srms, but not Csk, phosphorylates the C-terminus of Brk. We also demonstrate opposing effects of the protein tyrosine phosphatase, PTP1B, on Brk and Src. While PTP1B inhibited Brk by directly dephosphorylating Tyr342 in the activation loop, PTP1B potentiated Src activity by regulating interactions with CBP/PAG and Csk. Src associated with and phosphorylated the transmembrane protein PAG at Tyr317, resulting in Csk recruitment. A significant amount of PTP1B was detected in lipid rafts, where most PAG resides. We identified PAG as a substrate of PTP1B, and the dephosphorylation largely abolished Csk recruitment. Overall, these findings show that a single tyrosine phosphatase can exert opposing regulatory effects on two closely related tyrosine kinases by two distinguishable molecular mechanisms.


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

* Fan, G.,1 Aleem, S.,1 Miller, W. T., Tonks, N.; Specificity in Tyrosine Kinases and Phosphatases in Regulating Src & Brk (Submitted)

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-2yl)ethanone oxime (LX2931) and (1R,2S,3R)-1-(2-(isoxazol-3-yl)-1H-imidazol-4-yl)butane1,2,3,4-tetraol (LX2932).J Med Chem. 53(24):8650-62. Epub 2010 Nov 22.

1 – These authors contributed equally to this manuscript

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