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Department of Biochemistry & Molecular Biology

Raymond Birge, Ph.D.




Ph.D., 1989, University of Connecticut



Current Research

Our long-range research goals are to understand the molecular mechanisms of cellular signaling and intracellular communication. Much of our research is focussed on the cellular actions of viral oncogenes and cellular proto-oncogenes, and how these gene products function and transduce intracellular signals. Signal Transduction by Crk Gene Products: The Crk protein (v-Crk) encoded by the CT10 avian sarcoma retrovirus has domains homologous to the NH2-terminal region of Src. These SH2 and SH3 (Src homology 2 and 3) domains are important components of many proteins involved in signal transduction. While Crk has no catalytic domain, over-expression in fibroblasts or epithelial cells induces tyrosine phosphorylation of specific focal adhesion proteins, and binding of Crk to cytoskeletal proteins influences both mitogenic and cell adhesion signaling pathways. Studies involving Crk have led to the discovery that SH2 domains bind short sequences of tyrosine phosphorylated proteins, while SH3 domains bind proline-rich motifs, with the general consensus of PXXP. Protein interacting domains, such as SH2 and SH3, serve as the building blocks for how diverse cellular regulatory circuits are regulated during signal transdunction. Both the v-Crk oncogene and the Crk II proto-oncogene participate in integrin and receptor tyrosine kinase signal transduction. The Crk N-terminal SH3 domain binds to guanine nucleotide exchange factors, including SOS and DOCK180/ELMO complex suggesting that Crk plays a role in coupling cytoskeletal signals with the Rho family of GTPases. Crk proteins are overexpresed in several human tumors and likely function in cell migration and tumor metastatic behavior. Curiously, we have also shown that Crk is involved in phagocytosis of apoptotic cells, and our laboratory is exploring how Crk is linked to phagocytic receptors that interact with apoptotic cells. Chronic Myelogenous Leukemia (CML) and Transactivation of Abl by Crk. Chronic Myelogenous Leukemia (CML), a lethal hematopoietic malignancy effecting tens of thousands of new patients per year, results from a chromosomal translocation fusing the Breakpoint cluster gene (Bcr) on chromosome 9 with the Abelson tyrosine kinase (Abl) on chromosome 22. The Bcr-Abl fusion protein demonstrates constitutive kinase activation, and like other kinases, functions by binding ATP and phosphorylating multiple effectors leading to increased proliferation and decreasing apoptosis. It has been shown that increased kinase activity of Bcr-Abl is the main factor contributing to Bcr-Abl activation. Imatinib mesylate or Gleevec (Novartis) is a 2-phenylaminopyrimidine tyrosine kinase inhibitor with specific activity towards Bcr-Abl. The pharmacological basis of Abl inhibition by Imitinib has been elucidated by crystallographic studies, and revealed that Imatinib binds to the ATP-binding site and stabilizes the inactive, non-ATP binding form of Abl, preventing tyrosine phopshorylation and the conversion of Abl to the active configuration. Despite the high rates of hematologic and cytogenetic responses to Imatinib, the emergence of drug resistance is a major limitation for long-term CML treatment. Our group has recently shown that Abl tyrosine kinase is regulated by Crk. In collaboration with Babis Kalodimos at Rutgers University, we are also exploring the solution structure of the Abl-Crk complex to better understand the mechanism of Abl trans-activation.



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