Akira Imamoto, Ph.D.

Our laboratory has a long-standing interest in elucidating the role of tyrosine kinase signaling in development and in cancer.  We currently focus on neural crest development.

Neural crest cells are stem cell-like population derived from the dorsal ridge of the neural tube in vertebrates.  Upon induction, they migrate laterally and ventrally, and contribute to many different type of tissues such as the peripheral nervous system, craniofacial structures, the outflow tract of the heart, the thymus and the parathyroid.  Abnormal development of neural crest cells causes many congenital birth defects as well as some forms of cancer.  Several tyrosine kinases have been implicated in neural crest development.

Tyrosine kinases are enzymes that phosphorylate substrates at specific tyrosine residues to modulate their functions by, for example, changing their ability to interact with other proteins.  The adapter protein CrkL (Crk-Like) is one such molecule that interacts with tyrosine kinase substrates upon phosphorylation.  Although CrkL is widely expressed, it is concentrated in neural crest cells and their derivatives during development.  We have found that knockout (inactivation) of this gene in mice produces a phenotype that closely mimics the symptoms of DiGeorge/velocardiofacial syndrome (DGS/VCFS) in which defects of neural cells are implicated.  The human /CRKL /is mapped within the chromosome 22q11.21 region commonly deleted in this syndrome.  These results therefore suggest that defective CRKL-dependent pathways underlie the molecular etiology of DGS/VCFS.  We currently investigate the relationship of /CRKL/ with other genes important for neural crest development.  In addition, our results suggest that CrkL is required for cell survival and/or normal differentiation.  We are testing this hypothesis in order to understand the biology of neural crest cells.

Although CrkL may mediate signals from multiple tyrosine kinases, our recent results suggest that Src may lie upstream of CrkL.  Src is a prototype tyrosine kinase first discovered as the product of an oncogene (cancer-causing gene) found in Rous sarcoma virus.  Many Src substrates are found at a subcellular structure called focal adhesion.  While CrkL is found in the nucleus and cytosolic compartment in quiescent normal cells, a subset of CrkL constitutively localizes to focal adhesions in cells that express an activated mutant of Src or cells lacking Csk, a negative regulator of Src family kinases.  We are currently investigating the role of CrkL in focal adhesions.

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

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

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

Zambrowicz, B. P., Imamoto, A., Fiering, S., Herzenberg, L.A., Kerr, W. G., and Soriano, P. Widespread expression of beta-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, 94:3789-3794, 1997.

Tsuda, M., Matozaki, T., Fukunaga, K., Fujioka, Y., Imamoto, A., Noguchi, T., Takada, T., Yamao, T., Takeda, H., Ochi, F., Yamamoto, T. and Kasuga, M.  Integrin-mediated tyrosine phosphorylation of SHPS-1: the role of SHPS-1/SHP-2 complex in fibronectin-stimulated MAP kinase activation.  J. Biol. Chem., 273:13223-13229, 1998.

Dey, A., She, H., Kim, L., Boruch, a., Guris, D.L., Carlberg, K., Sebti, S.M., Woodley, D.T., Imamoto, A. and Li, W.  Colony-stimulating factor-1 receptor utilizes multiple signaling pathways to induce cyclin D2 expression.  Mol. Biol. Cell., 11:3835-3848, 2000.

Guris, D.L., Fantes, J., Tara, D., Druker, B.J. and Imamoto, A.  Mice lacking the homologue of the human 22q11.2 gene /CRKL/ phenocopy neurocristopathies of DiGeorge syndrome.  Nature Genetics, 27:293-298, 2001.

Hagel, M., George, E.L., Kim, A., Tamimi, R., Opitz, S.L., Turner, C.E., Imamoto, A. and Thomas, S.M. The adaptor protein paxillin is essential for normal development in the mouse and is a critical transducer of fibronectin signaling. Mol. Cell. Biol., 22:901-915, 2002. [PubMed] [FullText]

Li, L., Okura, M. and Imamoto, A. Focal adhesions require catalytic activity of Src family kinases to mediate integrin-matrix adhesion. Mol. Cell. Biol., 22:1203-1217 2002. [PubMed] [FullText]  Selected for the cover photo of the issue

Li, L., Guris, D.L., Okura, M. and Imamoto, A. Translocation of CrkL to focal adhesions mediates integrin-induced migration downstream of Src family kinases. Mol. Cell. Biol., 23:2883-2892, 2003. [PubMed] [FullText]  Selected for the cover photo of the issue (see Images from the Lab)

Duan, L.J., Imamoto, A. and Fong, G.H. Dual roles of the C-terminal Src kinase (Csk) during developmental vascularization. Blood, 103:1370-1372, 2004. [PubMed] [FullText]

Ballif, B.A., Arnaud, L., Arthur, W.T., Guris, D., Imamoto, A. and Cooper, J.A.  Activation of a Dab1/CrkL/C3G/Rap1 pathway in Reelin-stimulated neurons. Curr. Biol., 14:606-610, 2004. [PubMed] [FullText]

Guris, D.L., Duester, G. Papaioannou, V.E., and Imamoto, A.  Dose-dependent interaction of Tbx1 and Crkl and locally aberrant RA signaling in a model of del22q11 syndrome. Dev. Cell., 10:81-92, 2006. [PubMed] [FullText]  Back-to-back with the article by Moon et al. (below) in the same issue

Moon, A.M., Guris, D.L., Seo, J.-H., Li, L., Talbot, A., Hammond, J., and Imamoto, A.  Crkl deficiency disrupts Fgf8 signaling in a mouse model of 22q11 deletion syndrome. Dev. Cell., 10:71-80, 2006. [PubMed] [FullText]  Back-to-back with the article by Guris et al. (above) in the same issue