Akira Imamoto, D.D.S., Ph.D.

Tyrosine Kinase-mediated Signaling to the Cytoskeleton in Mouse Development and in Cancer.

Research Summary

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 to cancer. 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 (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. 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 resulted 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 Src family PTKs by Csk is essential during mouse development. Further analysis of cells isolated from mutant embryos suggested that the phenotype of csk homozygous mutants may result from rearrangement of the cytoskeleton. Interestingly, one of the cytoskeletal proteins hyperphosphorylated in csk mutant cells is also known to be amplified in a population of breast cancers with poor prognosis. Thus, cytoskeletal proteins may play a role in malignant progression of cancer cells.

Selected Papers

Imamoto A and Soriano P. (1993). Disruption of the csk gene, encoding a negative regulator of Src family tyrosine kinases, leads to neural tube defects and embryonic lethality in mice. Cell, 73:1117-1124.

Imamoto A, Soriano P, and Stein PL. (1994). Genetics of signal transduction: tales from the mouse. Curr. Opin. Genet. Dev., 4:40-46.

Thomas S M, Soriano P, Imamoto A. (1995). Specific and redundant roles of Src and Fyn in organizing the cytoskeleton. Nature, 376:267-271.

Xian W, Kiguchi K, Imamoto A, Rupp T, Zilberstein A, and DiGiovanni J. (1995). Activation of the epidermal growth factor receptor by skin tumor promoters and in skin tumors from SENCAR mice. Cell Growth Differ., 6:1447-1455.

Zambrowicz BP, Imamoto A, Fiering S, Herzenberg LA, Kerr WG, and Soriano P. (1997). Widespread expression of b-galactosidase in the ROSA bgeo 26 gene trap strain is associated with the disruption of two of three overlapping transcripts. Proc. Natl. Acad. Sci. USA, in press.