W. Todd Miller
Professor

Ph.D. Rockefeller University, 1988

Basic Science Tower, T-5, Room 133
Stony Brook University
Stony Brook, NY, 11794-8661

Phone: (631) 444-3533
Fax: (631) 444-3432
Email:

Research

There are approximately 100 tyrosine kinases in the human genome, and they are important regulators of growth and differentiation in normal mammalian cells. Tyrosine kinases are normally under tight control and have low basal activity; they are activated transiently in response to specific stimuli. Inappropriate activation of tyrosine kinase signaling (by mutation, overexpression, or chromosomal rearrangement) often occurs in human cancers. For example, human chronic myelogenous leukemia (CML) is characterized by a chromosomal translocation that leads to deregulation of the Abl tyrosine kinase. In May 2001, the Food and Drug Administration approved the first small-molecule tyrosine kinase inhibitor, imatinib (Gleevec), which has proven to be an effective therapy for CML. The development of drugs such as Gleevec indicates that an understanding of oncogenic tyrosine kinases can lead to the design of new strategies for cancer treatment. The major research goals of our laboratory are: (1) to understand how tyrosine kinases recognize their target proteins in cells; (2) to determine the regulatory mechanisms that control tyrosine kinase activity; and (3) to develop strategies to block the action of oncogenic tyrosine kinases. Research in the Miller laboratory is supported by grants R01-CA58530 and R01-CA122091 from the National Institutes of Health.

Selected Publications

P. Patwardhan, Y. Shen, G. Goldberg, and W.T. Miller (2006). Individual Cas phosphorylation sites are dispensable for processive phosphorylation by Src and anchorage-independent cell growth. J. Biol. Chem 281, 20689-20697.
J. DaSilva, H.-J. Kim, L.Z. Xu, W.T. Miller, and D. Bar-Sagi (2006). Regulation of Sprouty stability by MNK1-dependent phosphorylation. Mol. Cell. Biol. 26, 1898-1907.
N. Yokoyama and W.T. Miller (2006). Purification and enzyme activity of ACK1. Methods Enz. 406, 250-260.
L. Liu, Y. Gao, W.T. Miller, V. Poli, and N.C. Reich (2006). Identification of STAT3 as a specific substrate of the breast tumor kinase (Brk). Oncogene 25, 4904-4912.
W. Li and W.T. Miller (2006). Role of the activation loop tyrosines in regulation of the insulin-like growth factor I receptor tyrosine kinase. J. Biol. Chem. 281, 23785-23791.
S.R. Hubbard and W.T. Miller (2007). Receptor tyrosine kinases: mechanisms of activation and signaling. Current Opin. Cell Biol. 19, 117-123.
P. Patwardhan and W.T. Miller (2007). Processive phosphorylation: mechanism and biological importance. Cell Signal. 19, 2218-2226.
B.P. Craddock, C. Cotter, and W.T. Miller (2007). Autoinhibition of the insulin-like growth factor I receptor by the juxtamembrane region. FEBS Lett. 581, 3235-3240.
S.S. Yadav and W.T. Miller (2007). Cooperative activation of Src-family kinases by SH3 and SH2 ligands. Cancer Letters 257, 116-123.
H. Chen, J. Ma, W. Li, A.V. Eliseenkova, C. Xu, T.A. Neubert, W.T. Miller, and M. Mohammadi (2007). A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases. Molecular Cell 27, 717-730.
N. King, M.J. Westbrook, S.L. Young, A. Kuo, M. Abedin, J. Chapman, S. Fairclough, U. Hellsten, Y. Isogai, I. Letunic, M. Marr, D. Pincus, N. Putnam, A. Rokas, K.J. Wright, R. Zuzow, W. Dirks, M. Good, D. Goodstein, D. Lemons, W. Li, J. Lyons, A. Morris, S. Nichols, D.J. Richter, A. Salamov, P. Bork, W.A. Lim, G. Manning, W. T. Miller, W. McGinnis, H. Shapiro, R. Tjian, I.V. Grigoriev, and D. Rokhsar (2008). The genome of the choanoflagellate Monosiga brevicollis and the origins of metazoan multicellularity. Nature 451, 783-788.
W. Li, S.L. Young, N. King, and W.T. Miller (2008). Signaling properties of a non-metazoan Src kinase and the evolutionary history of Src negative regulation. J. Biol. Chem. 283, 15491-15501.
G. Manning, S.L. Young, W.T. Miller, and Y. Zhai (2008). A protozoan tyrosine kinase signaling network more elaborate and diverse than seen in any metazoan. Proc. Natl. Acad. Sci. USA. 105, 9674-9679.
J. Wu, W. Li, B.P. Craddock, K.W. Foreman, M.J. Mulvihill, Q.Ji, W.T. Miller, and S.R. Hubbard (2008). Small-molecule inhibition and activation loop trans-autophosphorylation of the IGF1 receptor. EMBO Journal. 27, 1985-1994.
S.S. Yadav and W.T. Miller (2008). The evolutionarily conserved arrangement of domains in Src family kinases is important for substrate recognition. Biochemistry 47, 10871-10880.
B. Xiang, K. Chatti, H. Qiu, B. Lakshmi, A. Krasnitz, J. Hicks, W.T. Miller, and S.K. Muthuswamy (2008). Brk is coamplified with ErbB2 to promote proliferation in breast cancer. Proc. Natl. Acad. Sci. USA 105, 12463-12468.
E. Ozkirimli, S.S. Yadav, W.T. Miller, and C.B. Post (2008). An electrostatic network and long-range regulation of Src kinases. Protein Science 17, 1871-1880.
W. Li, S. Scarlata, and W.T. Miller (2009). Evidence for convergent evolution in the signaling properties of a choanoflagellate tyrosine kinase. Biochemistry 48, 5180-5186.
H. Chen, C. Xu, J. Ma, A.V. Eliseenkova, W. Li, P.M. Pollock, N. Pitteloud, W.T. Miller, T.A. Neubert, and M. Mohammadi (2008). A crystallographic snapshot of tyrosine trans-autophosphorylation in action. Proc. Natl. Acad. Sci. USA 105, 19660-19665.
P. Patwardhan, K. Shiba, C. Gordon, B.P. Craddock, M. Tamiko, and W.T. Miller (2009). Synthesis of functional signaling domains by combinatorial polymerization of phosphorylation motifs. ACS Chem. Biol 4, 751-758.
S.S. Yadav, B.J. Yeh, B.P. Craddock, W.A. Lim, and W.T. Miller (2009). Reengineering the signaling properties of a Src family kinase. Biochemistry 48, 10956-10962.
W.T. Miller (2009). Making sense of signal transduction. Science Signaling 2, 79.
V.P. Echagüe, A. Gucwa, B.P. Craddock, D.A. Brown, and W.T. Miller (2010). Cancer-associated mutations activate the nonreceptor tyrosine kinase Ack1. J. Biol. Chem. 285, 10605-10615.
V. P. Echagüe, A. Gucwa, D.A. Brown, and W.T. Miller (2010). Regulation of Ack1 localization and activity by the amino-terminal SAM domain. BMC Biochemistry 11, 42.
V. Prieto-Echagüe and W.T. Miller (2011). Regulation of Ack1-family nonreceptor tyrosine kinases. J. Signal Trans. 742372.
V. Prieto-Echagüe, P.M. Chan, B.P. Craddock, E. Manser, and W.T. Miller (2011). PTB domain-directed substrate targeting in a tyrosine kinase from the unicellular choanoflagellate Monosiga brevicollis. PLoS ONE 6, e19296