Non-kinase second-messenger signaling: new pathways with new promise.
Intercellular signaling by growth factors, hormones and neurotransmitters produces second messenger molecules such as cyclic adenosine monophosphate (cAMP) and diacylglycerol (DAG). Protein Kinase A and Protein Kinase C are the principal effector proteins of these prototypical second messengers in certain cell types. Recently, novel receptors for cAMP and DAG have been identified. These proteins, designated EPAC (Exchange Protein directly Activated by cAMP) or cAMP-GEF (cAMP regulated Guanine nucleotide Exchange Factor) and CalDAG-GEF (Calcium and Diacylglycerol regulated Guanine nucleotide Exchange Factor) or RasGRP (Ras Guanine nucleotide Releasing Protein) are able to mediate some of the physiologic effects of the second messengers in a protein-kinase-independent fashion. These proteins are exchange factors for Ras family GTPases that operate in pathways that run parallel to the classic kinase-dependent pathways. The rapidly emerging recognition of the functions of these "non-kinase" effectors in diverse processes such as insulin secretion, thymocyte development, asthma and malignant transformation creates new opportunities for discovery and identifies potential new therapeutic targets.
Springett
Gregory M
GM
Developmental Chemotherapy Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. Springe1@mskcc.org
Kawasaki
Hiroaki
H
Spriggs
David R
DR
D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008407:Mast Cells / Q000378:metabolism / Q000502:physiology; D015290:Second Messenger Systems / Q000502:physiology*
D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D007328:Insulin; C491790:RASGRP1 protein, human; D000242:Cyclic AMP