Year Graduate Student
W. Todd Miller, Ph.D.
Department: Physiology & Biophysics
Graduate Program: Molecular & Cellular Biology
Title: Investigations into the C-Terminal Regulatory Mechanisms
of Protein Tyrosine Kinase 6
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.
(pre-MSTP publications indicated with an *)
L., Aleem S., Fink C. A. (2010). Microwave-accelerated
reductive amination between ketones and ammonium acetate. Tetrahedron
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.