Activation of the protein kinase A pathway down regulates spleen tyrosine kinase in human T cells (63.30)

Abstract

Abstract Cyclic adenosine monophosphate (cAMP)-mediated activation of the protein kinase A (PKA) pathway has an overall negative impact on T cell proliferation and down regulates or neutralizes signaling pathways of many genes. Spleen tyrosine kinase (SYK) is an important gene expressed differentially during T cell development and functions by phosphorylating downstream effector molecules in both T and B lymphocytes. We report here that PKA inhibitors promoted, whereas cAMP analogues suppressed SYK expression. Overexpression of a catalytic subunit of PKA significantly abrogated SYK protein and mRNA expression as well as the levels of phosphorylated SYK. A complete cAMP response element (CRE) site on SYK promoter was found functional and capable of binding CREMα and CREB as detected by EMSA and chromatin immunoprecipitation. CREMα overexpression reduced, while disruption of the CRE site enhanced the basal promoter activity of SYK. Collectively, the cAMP-mediated PKA pathway functions as the negative regulator of SYK expression by promoting direct binding of a repressor element to the SYK promoter.