A family of cAMP-binding proteins that directly activate Rap1.
cAMP (3',5' cyclic adenosine monophosphate) is a second messenger that in eukaryotic cells induces physiological responses ranging from growth, differentiation, 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 differentially distributed in the mammalian brain and body organs and that exhibit both cAMP-binding and guanine nucleotide exchange factor (GEF) domains is reported. These cAMP-regulated GEFs (cAMP-GEFs) bind cAMP and selectively activate the Ras superfamily guanine nucleotide binding protein Rap1A in a cAMP-dependent but PKA-independent manner. Our findings suggest the need to reformulate concepts of cAMP-mediated signaling to include direct coupling to Ras superfamily signaling.
Kawasaki
H
H
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology (MIT), Cambridge, MA, 02139, USA.
Springett
G M
GM
Mochizuki
N
N
Toki
S
S
Nakaya
M
M
Matsuda
M
M
Housman
D E
DE
Graybiel
A M
AM
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000311:Adrenal Glands / Q000378:metabolism; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005333:Fetus / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D015870:Gene Expression; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D017403:In Situ Hybridization; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015290:Second Messenger Systems; D017384:Sequence Deletion; D015398:Signal Transduction; D020668:rap GTP-Binding Proteins; D020663:ras Guanine Nucleotide Exchange Factors
D020662:Guanine Nucleotide Exchange Factors; D011506:Proteins; D020663:ras Guanine Nucleotide Exchange Factors; D005576:Colforsin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019204:GTP-Binding Proteins; D020668:rap GTP-Binding Proteins; D015056:1-Methyl-3-isobutylxanthine