Our laboratory is currently focusing on the elucidation of the mechanism by which tyrosine kinases mediate signals to the cytoskeleton during mouse development as well as in cancer using gene targeting technology and mouse genetics. We are also investigating the connection between tyrosine kinases and human malignancies at the interface of the cytoskeleton.

Like other abnormal genes that are linked to cancer, the oncogene v-src has multiple effects on mammalian cells, including, most dramatically, the induction of cellular transformation, which is believed to correspond to the change of normal cells into cancerous cells. v-src was identified as the first oncogene encoding a protein tyrosine kinase (PTK), an enzyme that transfers a phosphoryl group in an energy-dependent manner onto a tyrosine residue of a protein (a process known as tyrosine phosphorylation) to modify the function of the target. Most cancer cells have elevated levels of tyrosine kinase activity. Unlike its normal cellular counterpart (c-src) from which the oncogene is derived, the product of v-src lacks a key regulatory tyrosine residue, which when phosphorylated represses tyrosine kinase activity. Therefore, the v-Src protein lacks this regulatory mechanism and is always active. Members of another class of PTKs, Csk, and Ctk, phosphorylate in vitro the regulatory tyrosine conserved within the Src family. By phosphorylation at the key tyrosine residue, these PTKs regulate cellular Src, which otherwise is potentially oncogenic.

Knock-out (genetic inactivation) of the csk gene in the mouse results in embryonic lethality with lack of: i) cephalic neural tube closure, ii) inversion of the germ layers, and iii) connection of the allantois to the chorion; indicating that regulation of Src family PTKs by Csk is essential during mouse development. Further analysis of cells isolated from mutant embryos suggests that the phenotype of csk homozygous mutants may result from rearrangement of the cytoskeleton. Interestingly, one of the cytoskeletal proteins hyperphosphorylated in csk mutant cels is also known to be amplified in a population of breast cancers with poor prognosis. Thus, cytoskeletal proteins and PTKs may play a role in malignant progression of cancer cells.