Abstract
Rap1 proteins belong to the Ras superfamily of small molecular weight GTP-binding proteins. Although Rap1 and Ras share approximately 50% overall amino acid sequence identity, the effector domains of the two proteins are identical, suggesting either similar or antagonistic signaling roles. Several pathways leading to Ras activation have been defined, including those initiated by agonist binding to tyrosine kinase or Gi-coupled receptors. Nothing is known about such events for Rap1 proteins. The cAMP-mediated inhibition of Ras-dependent MAP kinase activation is well documented and resembles that caused by expression of GTPase-deficient Rap1. We have developed a system whereby signals leading to Rap1b activation, i.e. an increase in Rap1b-bound GTP/GDP ratio, can be measured. We report here that treatment of cells with agents that elevate intracellular cAMP levels result in Rap1b activation. These results demonstrate for the first time agonist-dependent activation of Rap1 proteins.
Highlights
From the IlDivision of Cell Biology, Burroughs Wellcome Co., Research Triangle Park, North Carolina 27709 and the Wepartment of Microbiology, Duke University Medical Center, Durham, North Carolina 27710-0001
We have developed a system whereby signals leading to Rap!b activation, i.e. an increase in Rap!b-bound GTP/GDP ratio, can be measured
We report here that treatment of cells with agents that elevate intracellular cAMP levels result in Rap!b activation
Summary
Rap proteins share 50% sequence identity and basic biochemical properties with Ras [3, 4] Both of these proteins function as molecular switches in which the GTP-bound conformation represents the active form of the molecule while the GDP-bound conformation is the inactive form. Switch I encompasses residues 32-40, defined as the effector domain [11,12,13] These amino acids are identical in Rapl and Ras, raising the possibility that the proteins share similar or antagonistic functions. Experiments performed in vitro suggested that phosphorylation by protein kinase A plays a role in Rapl activation [26] and implicated Rap 1 as one of the effectors of cAMP action. This represents the first demonstration of hormonal regulation of Rap proteins
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