Historical Background
Inositol 1,4,5-trisphosphate (IP3) receptor-associated cyclic GMP (cGMP) kinase substrate (IRAG) is a 125-kD type 2 integral endoplasmic reticulum (ER) membrane protein. IRAG is 900 amino acids long and encoded by the Mrvi1 gene. Two splice variants exist in both mouse and humans with the IRAGa isoform containing an extra 84 amino acids in the N-terminus. Both variants contain a C-terminal hydrophobic domain, α-helix coiled-coil domain, basic N-terminal region, and multiple glycosylation and phosphorylation sites (Ammendola et al. 2001; Schlossmann et al. 2000; Shaughnessy et al. 1999). IRAG forms a complex with the inositol 1,4,5-trisphosphate receptor (IP3R) and cGMP kinase I-β (cGKIβ) and is involved in nitric oxide (NO), cGMP, and cGKIβ signaling pathways. IRAG plays a...
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Ammendola A, Geiselhöringer A, Hofmann F, Schlossmann J. Molecular determinants of the interaction between the inositol 1, 4,5-trisphosphate receptor associated cGMP kinase substrate (IRAG) and cGMP kinase Ibeta. J Biol Chem. 2001;276(26):24153–9.
Antl M, von Brühl ML, Eiglsperger C, Werner M, Konrad I, Kocher T, Wilm M, Hofmann F, Massberg S, Schlossmann J. IRAG mediates NO/cGMP-dependent inhibition of platelet aggregation and thrombus formation. Blood. 2007;109(2):552–9.
Casteel DE, Boss GR, Pilz RB. Identification of the interface between cGMP-dependent protein kinase I beta and its interaction partners TFII-I and IRAG reveals a common interaction motif. J Biol Chem. 2005;280(46):38211–8.
Casteel DE, Zhang T, Zhuang S, Pilz RB. cGMP-dependent protein kinase anchoring by IRAG regulates its nuclear translocation and transcriptional activity. Cell Signal. 2008;20(7):1392–9.
Desch M, Sigl K, Hieke B, Salb K, Kees F, Bernhard D, Jochim A, Spiessberger B, Höcherl K, Feil R, Feil S, Lukowski R, Wegener JW, Hofmann F, Schlossmann J. IRAG determines nitric oxide- and atrial natriuretic peptide-mediated smooth muscle relaxation. Cardiovasc Res. 2010;86(3):496–505. Epub 2010 Jan 15
Frei E, Huster M, Smital P, Schlossmann J, Hofmann F, Wegener JW. Calcium-dependent and calcium-independent inhibition of contraction by cGMP/cGKI in intestinal smooth muscle. Am J Physiol Gastrointest Liver Physiol. 2009;297(4):G834–G9 [Epub ahead of print].
Fritsch RM, Saur D, Kurjak M, Oesterle D, Schlossmann J, Geiselhöringer A, Hofmann F, Allescher HD. InsP3R-associated cGMP kinase substrate (IRAG) is essential for nitric oxide-induced inhibition of calcium signaling in human colonic smooth muscle. J Biol Chem. 2004;279(13):12551–9.
Geiselhöringer A, Werner M, Sigl K, Smital P, Wörner R, Acheo L, Stieber J, Weinmeister P, Feil R, Feil S, Wegener J, Hofmann F, Schlossmann J. IRAG is essential for relaxation of receptor-triggered smooth muscle contraction by cGMP kinase. EMBO J. 2004a;23(21):4222–31.
Geiselhöringer A, Gaisa M, Hofmann F, Schlossmann J. Distribution of IRAG and cGKIisoforms in murine tissues. FEBS Lett. 2004b;575(1–3):19–22.
Graham SM, Longoria S, Sarkar P, Koulen P. Inositol 1,4,5-trisphosphate-associated cGMP kinase substrate. UCSD Nat Molecule Pages. 2008. doi:10.1038/mp.a001275.01.
Koller A, Schlossmann J, Ashman K, Uttenweiler-Joseph S, Ruth P, Hofmann F. Association of phospholamban with a cGMP kinase signaling complex. Biochem Biophys Res Commun. 2003;300(1):155–60.
Kusumawidjaja G, Kayed H, Giese N, Bauer A, Erkan M, Giese T, Hoheise JD, Friess H, Kleeff J. Basic transcription factor 3 (BTF3) regulates transcription of tumorassociated genes in pancreatic cancer cells. Cancer Biol Ther. 2007;6(3):367–6.
Masuda W, Betzenhauser MJ, Yule DI. InsP3R-associated cGMP kinase substrate determines inositol 1,4,5-trisphosphate receptor susceptibility to phosphoregulation by cyclic nucleotide-dependent kinases. J Biol Chem. 2010 Nov 26;285(48):37927–37938. PMID: 20876535.
Sausbier M, Zhou XB, Beier C, Sausbier U, Wolpers D, Maget S, Martin C, Dietrich A, Ressmeyer AR, Renz H, Schlossmann J, Hofmann F, Neuhuber W, Gudermann T, Uhlig S, Korth M, Ruth P. Reduced rather than enhanced cholinergic airway constrictionin mice with ablation of the large conductance Ca2+−activated K+ channel. FASEB J. 2007;21:812–22.
Schinner E, Salb K, Schlossmann J. Signaling via IRAG is essential for NO/cGMP-dependent inhibition of platelet activation. Platelets. 2011;22(3):217–27. PMID: 21244222
Schlossmann J, Ammendola A, Ashman K, Zong X, Huber A, Neubauer G, Wang GX, Allescher HD, Korth M, Wilm M, Hofmann F, Ruth P. Regulation of intracellular calcium by a signalling complex of IRAG, IP3 receptor and cGMP kinase Ibeta. Nature. 2000;404(6774):197–201.
Shaughnessy JD, Largaespada DA, Tian E, Fletcher CF, Cho BC, Vyas P, Jenkins NA, Copeland N. Mrvi1, a common MRV integration site in BXH2 myeloid leukemias, encodes a protein with homology to a lymphoid-restricted membrane protein Jaw1. Oncogene. 1999;18(12):2069–84.
Werder Av, Mayr M, Schneider G, Oesterle D, Fritsch RM, Seidler B, Schlossmann J, Hofmann F, Schemann M, Allescher HD, Schmid RM, Saur D. Truncated IRAG variants modulate cGMP-mediated inhibition of human colonic smooth muscle cell contraction. Am J Physiol Cell Physiol. 2011;301(6):C1445–57. doi: 10.1152/ajpcell.00304.2010. Epub 2011 Aug 24.
Yaroslavskiy BB, Turkova I, Wang Y, Robinson LJ, Blair HC. Functional osteoclast attachment requires inositol-1,4,5-trisphosphate receptor-associated cGMP-dependent kinase substrate. Lab Investig. 2010;90(10):1533–42 [Epub ahead of print].
Acknowledgments
This chapter is part of the Encyclopedia of Signaling Molecules, 2nd Edition, and is based on a chapter of the same name previously published in the first edition of Encyclopedia of Signaling Molecules. This study was supported in part by grants EY014227 and EY022774 from NIH/NEI, RR022570 and RR027093 from NIH/NCRR and NIH/NIGMS, and AG010485, AG022550, and AG027956 from NIH/NIA, by the Felix and Carmen Sabates Missouri Endowed Chair in Vision Research (PK). We thank Margaret, Richard, and Sara Koulen for their generous support and encouragement.
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Grillo, M.A., Koulen, P. (2018). Inositol 1,4,5-Trisphosphate-Associated cGMP Kinase Substrate. In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, Cham. https://doi.org/10.1007/978-3-319-67199-4_373
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DOI: https://doi.org/10.1007/978-3-319-67199-4_373
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