|
|
Blood, 15 April 2005, Vol. 105, No. 8, pp. 3185-3192.
Prepublished online as a Blood First Edition Paper on January 4, 2005; DOI 10.1182/blood-2004-09-3605.
 Previous Article | Table of Contents | Next Article 
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Rap1GAP2 is a new GTPase-activating protein of Rap1 expressed in human platelets
Jan Schultess,
Oliver Danielewski, and
Albert P. Smolenski
From the Institute for Biochemistry II, University of Frankfurt Medical School, Frankfurt/Main, Germany.
The Ras-like guanine-nucleotide–binding protein Rap1 controls integrin  IIb 3 activity and platelet aggregation. Recently, we have found that Rap1 activation can be blocked by the nitric oxide/cyclic guanosine monophosphate (NO/cGMP) signaling pathway by type 1 cGMP-dependent protein kinase (cGKI). In search of possible targets of NO/cGMP/cGKI, we studied the expression of Rap1-specific GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs) in platelets. We could detect mRNAs for a new protein most closely related to Rap1GAP and for postsynaptic density-95 discs-large and zona occludens protein 1 (PDZ)–GEF1 and CalDAG-GEFs I and III. Using 5'–rapid amplification of cDNA ends (RACE), we isolated the complete cDNA of the new GAP encoding a 715-amino acid protein, which we have termed Rap1GAP2. Rap1GAP2 is expressed in at least 3 splice variants, 2 of which are detectable in platelets. Endogenous Rap1GAP2 protein partially colocalizes with Rap1 in human platelets. In transfected cells, we show that Rap1GAP2 exhibits strong GTPase-stimulating activity toward Rap1. Rap1GAP2 is highly phosphorylated, and we have identified cGKI as a Rap1GAP2 kinase. cGKI phosphorylates Rap1GAP2 exclusively on serine 7, a residue present only in the platelet splice variants of Rap1GAP2. Phosphorylation of Rap1GAP2 by cGKI might mediate inhibitory effects of NO/cGMP on Rap1. Rap1GAP2 is the first GTPase-activating protein of Rap1 found in platelets and is likely to have an important regulatory role in platelet aggregation.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
L. Stefanini, R. C. Roden, and W. Bergmeier
CalDAG-GEFI is at the nexus of calcium-dependent platelet activation
Blood,
September 17, 2009;
114(12):
2506 - 2514.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Neumuller, M. Hoffmeister, J. Babica, C. Prelle, K. Gegenbauer, and A. P. Smolenski
Synaptotagmin-like protein 1 interacts with the GTPase-activating protein Rap1GAP2 and regulates dense granule secretion in platelets
Blood,
August 13, 2009;
114(7):
1396 - 1404.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. A. Severson, W. Y. Lee, C. T. Capaldo, A. Nusrat, and C. A. Parkos
Junctional Adhesion Molecule A Interacts with Afadin and PDZ-GEF2 to Activate Rap1A, Regulate {beta}1 Integrin Levels, and Enhance Cell Migration
Mol. Biol. Cell,
April 1, 2009;
20(7):
1916 - 1925.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. M. Cifuni, D. D. Wagner, and W. Bergmeier
CalDAG-GEFI and protein kinase C represent alternative pathways leading to activation of integrin {alpha}IIb{beta}3 in platelets
Blood,
September 1, 2008;
112(5):
1696 - 1703.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. H. Ulfman, V. M. Kamp, C. W. van Aalst, L. P. Verhagen, M. E. Sanders, K. A. Reedquist, M. Buitenhuis, and L. Koenderman
Homeostatic Intracellular-Free Ca2+ Is Permissive for Rap1-Mediated Constitutive Activation of {alpha}4 Integrins on Eosinophils
J. Immunol.,
April 15, 2008;
180(8):
5512 - 5519.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Hoffmeister, P. Riha, O. Neumuller, O. Danielewski, J. Schultess, and A. P. Smolenski
Cyclic Nucleotide-dependent Protein Kinases Inhibit Binding of 14-3-3 to the GTPase-activating Protein Rap1GAP2 in Platelets
J. Biol. Chem.,
January 25, 2008;
283(4):
2297 - 2306.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. S. Isenberg, M. J. Romeo, C. Yu, C. K. Yu, K. Nghiem, J. Monsale, M. E. Rick, D. A. Wink, W. A. Frazier, and D. D. Roberts
Thrombospondin-1 stimulates platelet aggregation by blocking the antithrombotic activity of nitric oxide/cGMP signaling
Blood,
January 15, 2008;
111(2):
613 - 623.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. J. Jeon, D.-J. Lee, S. Lee, G. Weeks, and R. A. Firtel
Regulation of Rap1 activity by RapGAP1 controls cell adhesion at the front of chemotaxing cells
J. Cell Biol.,
December 3, 2007;
179(5):
833 - 843.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. K. de Oliveira, M. Hoffmeister, S. Gambaryan, W. Muller-Esterl, J. A. Guimaraes, and A. P. Smolenski
Phosphodiesterase 2A Forms a Complex with the Co-chaperone XAP2 and Regulates Nuclear Translocation of the Aryl Hydrocarbon Receptor
J. Biol. Chem.,
May 4, 2007;
282(18):
13656 - 13663.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Antl, M.-L. von Bruhl, C. Eiglsperger, M. Werner, I. Konrad, T. Kocher, M. Wilm, F. Hofmann, S. Massberg, and J. Schlossmann
IRAG mediates NO/cGMP-dependent inhibition of platelet aggregation and thrombus formation
Blood,
January 15, 2007;
109(2):
552 - 559.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Holinstat, B. Voss, M. L. Bilodeau, J. N. McLaughlin, J. Cleator, and H. E. Hamm
PAR4, but Not PAR1, Signals Human Platelet Aggregation via Ca2+ Mobilization and Synergistic P2Y12 Receptor Activation
J. Biol. Chem.,
September 8, 2006;
281(36):
26665 - 26674.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Hofmann, R. Feil, T. Kleppisch, and J. Schlossmann
Function of cGMP-Dependent Protein Kinases as Revealed by Gene Deletion
Physiol Rev,
January 1, 2006;
86(1):
1 - 23.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. J. S. Stork and T. J. Dillon
Multiple roles of Rap1 in hematopoietic cells: complementary versus antagonistic functions
Blood,
November 1, 2005;
106(9):
2952 - 2961.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
