Antigen receptor signaling regulates B cell fate through induction of activated transcription factors. Among the surface immunoglobulin (sIg) -triggered transcription factors are STAT proteins, two of which, STAT1 and STAT3, are phosphorylated late in a manner that depends on do novo protein synthesis. These and other features of STAT1/STAT3 activation suggest that a novel, non-JAK pathway is involved, distinct from the pathway(s) responsible for cytokine-induced STAT activation and the early activation of STAT3 and STAT6 that follows sIg engagement. The goal of the present application is to identify the key molecules that con-stitute the novel, late pathway for STAT1/STAT3 activation. This will be accomplished in two ways: (1) Mutant B cells that fail to activate STAT1 and STAT3 after sIg engagement will be selected and defective cells will be complemented by elements of a cDNA library, after which genes responsible for restoring STAT phosphorylation will be cloned and sequenced. (2) Gene products that directly associate with STAT1 or, separately, STAT3 will be identified through yeast two hybrid analysis screening of a cDNA library. Identification of molecules involved in the novel pathway for STAT activation will validate the pathway's existence, will elucidate new mechanisms by which sIg transmits signals intracellularly, will provide a deeper understanding of autoimmune associated B-1 cells that constitutively express activated STAT1 and STAT3, and will immediately become candidates for manipulation of STAT activity that influences the expression of genes importantly involved in the life, growth and death of cells. This study has the potential to reframe the existing paradigm for STAT activation and to provide new information that will be indispensable to understanding and manipulating STAT-dependent transcriptional outcomes.
| Fan, H; Rothstein, T L (2001) Lymphokine dependence of STAT3 activation produced by surface immunoglobulin cross-linking and by phorbol ester plus calcium ionophore treatment in B cells. Eur J Immunol 31:665-71 |
