John H. Kehrl, M.D.
Chief, B-Cell Molecular Immunology Section
Description of Research Program
Extracellular signals modulate and regulate the function of cells that participate in immune responses. Some of these signals activate pathways that utilize heterotrimeric G proteins as transducing elements and mitogen activated protein kinases (MAP kinases) as downstream effectors. The critical importance of chemokines in the orchestration and coordination of immune cell trafficking is but one example of the importance of heterotrimeric G-protein-mediated signaling in immune function. Our goals are to understand how G-protein-coupled receptors (GPCR) transduce signals to downstream effectors such as the MAP kinases, to discern the mechanisms that control these responses, to understand how G-protein activation leads to transcriptional responses, and to determine the physiologic consequences of G-protein activation for lymphocyte function.
A major accomplishment of the B-Cell Molecular Immunology Section (BCMIS) was the identification of a family of proteins that regulate heterotrimeric G-protein signaling, which have been termed RGS proteins. RGS proteins are GTPase-activating proteins (GAPs) for Gα subunits of heterotrimeric G proteins. By shortening the duration that a Gα subunit is GTP bound, the RGS proteins curtail both Gα and Gβ µ signaling. RGS proteins may also affect heterotrimeric G-protein signaling via other mechanisms.
A clear role for RGS proteins as effector antagonists has been shown, and there is emerging evidence that RGS proteins may directly interact with some downstream effectors. Furthermore, a direct role for certain RGS proteins in the regulation of Gβ µ signaling is becoming clear. There are approximately 20 RGS family members and at least 5 members are abundantly present in lymphocytes. A significant role for RGS proteins in regulating the response of lymphocytes to chemokines has been shown.
In conjunction with Dr. H. Gu (Laboratory of Immunology, NIAID), mice in which the RGS1 gene has been disrupted have been created and the consequences of the loss of RGS1 for immune function are being evaluated. Many RGS proteins have been found to reside in the cytoplasm and to translocate to the membrane upon stimulation. The biochemical mechanisms that underlie this translocation are now partially understood.
Another major accomplishment of the BCMIS was the identification of Germinal Center Kinase (GCK), the prototype member of a family of serine/threonine protein kinases, which activates a MAP kinase cassette termed the stress activated protein kinase pathway (SAPK, also referred to as the Jun kinase pathway). GCK and GCK-related (GCKR) are both activated by tumor necrosis factor (TNF)-α and serve to link the TNF receptor to the SAPK pathway. There is also evidence that GCK family members mediate SAPK activation by other TNF receptor family members. GCKR readily associates with the adaptor proteins Crk and CrkL via a SH3 domain binding site in the regulatory region of GCKR. A role for GCKR in the oncoprotein Bcr-Abl mediated SAPK activation has also been found.
A third major accomplishment of the BCMIS was the identification of a crucial role for the transcription factor HB9 in both pancreas and motor neuron development and function. HB9 is a homeobox gene, which was first identified as an activation gene in lymphocytes. Again in collaboration with Dr. H. Gu, a targeted deletion of the HB9 gene in mice was accomplished. While the HB9 heterozygous mice are normal in appearance and behavior the HB9 -/- mice die at birth of respiratory failure. In collaboration with Dr. S. Pfaff's laboratory at the Salk Institute, a major defect in motor neuron development and function has been found in these mice. Pancreas development in the HB9 deficient mice is also defective and within the residual pancreas there is a marked reduction in insulin production. These results indicate that the transcriptional program that specifies motor neuron and pancreas development contain overlapping elements.
Current projects include gene targeting of the murine orthologs of several of the RGS and GCK family members and transgenic over-expression in lymphocytes of several RGS family members as well as activated forms of Gα subunits. Other projects include clarification of the role of GCK family members in SAPK activation by the TNF receptor and other TNF receptor family members, complete elucidation of the mechanisms of RGS protein translocation, and an examination of the roles of G12α and G13α in chemokine signaling and lymphocyte function. Finally, we are continuing to study HB9 in the context of pancreas and motor neuron development and function.
Memberships
- Alpha Omega Alpha
- American Federation for Clinical Research
- American Society for Clinical Investigation
- American Association of Immunologists
Editorial Boards
Research Group Members
Astrid Scheschonka, Chong-Shan Shi, Hyeseon Cho, Chantal Moratz, Srikumar Sinnarajah, Deepa Srikumar, and John Yuen
Selected Publications
(View list in PubMed.)
Druey, K.M., Blumer, K.J., Kang, V.H., and Kehrl, J.H. Inhibition of G protein-mediated MAP kinase activation by members of a novel mammalian gene family. Nature. 379: 742-746, 1996.
Druey, K.M. and Kehrl, J.H. Inhibition of regulator of G protein signaling by two mutant RGS4 proteins. Proceedings of the National Academy of Sciences USA. 94: 12851-12856, 1997.
Kehrl, J.H. Heterotrimeric G protein signaling: roles in immune function and fine-tuning by RGS proteins. Immunity. 8: 1-10, 1998.
Shi, C-S. and Kehrl, J.H. Activation of stress-activated protein kinase/c-Jun N-terminal kinase, but not NF-k B, by the tumor necrosis factor (TNF) receptor 1 through a TNF receptor-associated factor-2 and germinal center kinase related-dependent pathway. Journal of Biological Chemistry. 272: 32102-32107, 1997.
Watson, N., Linder, M.E., Druey, K.M., Kehrl, J.H., and Blumer, K.J. RGS family members: GTPase activating proteins for heterotrimeric G protein a subunits. Nature. 383: 172-175, 1996.
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