A family of cAMP-binding proteins that directly activate Rap1

cAMP (3',5' cyclic adenosine monophosphate) is a second messenger that in e ukaryotic cells induces physiological responses ranging from growth, differ entiation, and gene expression to secretion and neurotransmission. Most of these effects have been attributed to the binding of cAMP to cAMP-dependent protein kinase A (PKA). Here, a family of cAMP-binding proteins that are d ifferentially distributed in the mammalian brain and body organs and that e xhibit both cAMP-binding and guanine nucleotide exchange factor (GEF) domai ns is reported. These cAMP-regulated GEFs (cAMP-GEFs) bind cAMP and selecti vely activate the Ras superfamily guanine nucleotide binding protein Rap1A in a cAMP-dependent but PKA-independent manner. Our findings suggest the ne ed to reformulate concepts of cAMP-mediated signaling to include direct cou pling to Ras superfamily signaling.