Roy J. Carver Chair and University Professor of Biochemistry, Biophysics and Molecular Biology
Finely tuned signal transduction cascades control all aspects of cell renewal and cell death in normal, healthy cells. Altered gene products introduce the possibility of imbalance within the tightly controlled signaling networks that regulate cell growth and proliferation. This is evident in the malignant form of the src tyrosine kinase, the viral oncogene v-src. For this protein it has been shown (both biochemically and structurally) that a single amino acid mutation disrupts the intramolecular interactions responsible for inactivating the enzyme, thus rendering the protein constitutively active(1). Aberrant signaling due to excess phosphorylation ensues, leading to dire consequences for the cell and, ultimately, for the organism. While the molecular details of the regulation of some families of kinases (i.e. Src) have now been clarified, it is not understood how the substrate binding and catalytic activity of other families of protein tyrosine kinases are controlled. We are particularly interested in a family of intracellular signaling molecules that is exclusively expressed in hematopoeitic cells, and we have focused our attention on the IL2-inducible tyrosine kinase (Itk), a member of the Tec family of tyrosine kinases that is restricted to the T-cell lineage.