The non-receptor protein tyrosine kinases p56lck and p59fyn are pivotal regulators of normal signaling processes in lymphocytes. Previous studies have demonstrated that p56lck interacts physically and functionally with numerous T cell receptor structures, including the CD4 and CD8 coreceptors, and the IL-2 receptor beta chain. More recent experiments have defined an exquisitely specific function for this kinase: p56lck directs the development of immature T-lineage cells by sensing the products of functional rearrangement of T cell receptor beta chain genes, and stimulating thymocyte proliferation (and maturation) thereafter. Indeed, interdiction of the lck signaling pathway both blocks thymocyte differentiation and compromises allelic exclusion at the T cell receptor beta loci. This proposal seeks continued support for the elucidation of signaling pathways to which p56lck, and the closely related kinase p59fyn, contribute. First, a series of mouse mutants will be evaluated to learn whether p56lck acts primarily by phosphorylating T cell receptor components. Efforts will then be made to establish a signaling system through which p56lck kinase activity can be experimentally manipulated. The consequences of these manipulations will be investigated in thymocytes, and a parallel analysis will be undertaken in cell lines. A system will also be devised that will permit interference with p56lck function in mature T lymphocytes. Lastly, the function of p59fyn will be addressed through reconstitution of existing mouse mutants. The (very) long-range goal of these studies is the complete dissection of signaling pathways that regulate lymphocyte activation, pathways wherein these two non-receptor protein tyrosine kinases plan crucial roles.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA045682-09
Application #
2091966
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1990-09-30
Project End
2000-05-31
Budget Start
1995-08-01
Budget End
1996-05-31
Support Year
9
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
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