W. Todd Miller
|There are approximately 90 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 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; (3) to develop strategies to block the action of oncogenic tyrosine kinases; and (4) to examine the evolution of phosphotyrosine-based signaling.|
S.J. Collins, J. Gun, RC. Rizzo, and W. T. Miller (2023). Inhibition of mutationally activated HER2. Chem. Biol. Drug Des. doi: 10.1111/cbdd.14125.
Y. Kan, Y. Paung, M.A. Seeliger, and W.T. Miller (2023). Biochemical studies of systemic lupus erythematosus-associated mutations in nonreceptor tyrosine kinases Ack1 and Brk. Biochemistry 62: 1124-1137.
Y. Kan, Y. Paung, M.A. Seeliger, and W.T. Miller (2023). Domain architecture of the nonreceptor tyrosine kinase Ack1. Cells 12: 900, doi.org/10.3390/
S. Ahmed and W. T. Miller (2022). The noncatalytic regions of the tyrosine kinase Tnk1 are important for activity and substrate specificity. J Biol Chem. doi: 10.1016/j.jbc.2022.102664
D. Sridaran, S. Chouhan, K. Mahajan, A. Renganathan, C. Weimholt, S. Bhagwat, M. Reimers, E.H. Kim, M.K. Thakur, M.A. Saeed, R.K.Pachynski, M.A. Seeliger, W.T. Miller, F.Y. Feng, and N.P. Mahajan (2022). Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance. Nature Communications doi: 10.1038/s41467-022-34724-
Y. Kan and W. T. Miller (2022). Activity of the nonreceptor tyrosine kinase Ack1 is regulated by tyrosine phosphorylation of its Mig6 homology region. FEBS Lett. doi: 10.1002/1873-3468.14505.
P. Suresh, W.T. Miller, and E. London (2021). Phospholipid exchange shows insulin receptor activity is supported by both the propensity to form wide bilayers and ordered raft domains. J. Biol. Chem. 297, 101010.
L. Tapia, N. Solozabal, J. Sola, Y. Perez, W.T. Miiler, and I. Alfonso (2021). Modulation of Src kinase activity by selective substrate recognition with pseudopeptidic cages. Chemistry 27, 9542.
W.T. Miller (2020). Temperature sensitivities of metazoan and pre-metazoan Src kinases. Biochem. Biophys. Rep. 23, 100775.
C.J. McClendon and W.T. Miller (2020). Structure, function, and regulation of the SRMS tyrosine kinase. Int. J. Mol. Sci. 21, 4233
M.K. Josh, R.A. Burton, H. Wu, A.M. Lipchik, B.P. Craddock, H. Mo, L.L. Parker, W.T. Miller, and C.B. Post (2020). Substrate binding to Src: a new perspective on tyrosine kinase substrate recognition from NMR and molecular dynamics. Prot. Sci. 29, 350-359.
R.J. Delle Bovi, J. Kim, P. Suresh, E. London, and W. T. Miller (2019). Sterol structure dependence of insulin receptor and insulin-like growth factor 1 receptor activation. BBA Biomembranes 1861, 819-826.
S.M. Hanson, G. Georghiou, M.K. Thakur, W.T. Miller, J.S. Rest, J.D. Cheddar, and M.A. Seeliger (2019). What makes a kinase promiscuous for inhibitors? Cell Chem.Biol. 26, 390-399.
H. Krishnan, W.T. Miller, F.J. Blanco, and G.S. Goldberg (2019). Src and podoplanin forge a path to destruction. Drug Discovery Today 24, 241-249.
J. Guo, S. Collins, W.T. Miller, and R.C. Rizzo (2018). Identification of a water-coordinating HER2 inhibitor by virtual screening using similarity-based scoring. Biochemistry 57, 4934-4951.
H. Suga and W.T. Miller (2018). Src signaling in a low-complexity unicellular kinome. Sci. Rep. 8: 5362.