Receptor Guanylyl Cyclase C

 

Receptor Guanylyl Cyclase C cGMP Phosphodiesterase Mycobacterial Enzymes

 

GC-C, a member of the family of membrane bound guanylyl cyclases, serves as the receptor for the family of endogenous guanylin peptides and the bacterial heat-stable enterotoxins.  Activation of GC-C by ligand binding results in increases in intracellular cGMP levels, resulting in a cascade of cellular events, including activation of cyclic nucleotide-dependent protein kinases.  The cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel, is phosphorylated by protein kinase A and G, resulting in increases chloride secretion, concomitant fluid efflux from the cell, and transitory diarrhea associated with the stable toxin peptides.  Therefore, it is believed that the role of the guanylin family of peptides is to regulate fluid secretion across the intestinal epithelium, which is the major site for GC-C expression.

 

We have been studying the regulation, expression and down-stream signaling events mediated by GC-C as well as looking into its expression in extra-intestinal tissues.  During the course of these studies, we have performed mutational analysis of the protein kinase-like domain of GC-C, generated polyclonal and monoclonal antibodies to various domains of GC-C, investigated the mechanism of transcriptional regulation of the GC-C gene, and investigated the role of glycosylation of GC-C in terms of its regulation and ligand-binding properties. More recently, we have studied the mechanisms of allosteric regulation of GC-C via the linker region.  Importantly, we have identified cross-talk between c-src and GC-C mediated via tyrosine phosphorylation of GC-C, and this cross-talk regulates colon cell  proliferation.

 

Visit the GC-C mini-molecule page on the Alliance for Cellular Signaling (AfCS) website.

 

 

 

                                                                                                                                                Control                                             PV + HgCl2

                 

                       Cross-Talk between GC-C and c-Src Tyrosine Kinase 

                   

                                                                                                                (Mol. Cell Biol. 2009 Oct;29(19):5277-89)   (J. Mol. Evol. 2009 Jun;68(6):587-602)

 

 

Relevant publications:

 

Müller T, Rasool I, Heinz-Erian P, Mildenberger E, Hülstrunk C, Müller A, Michaud L, Koot BG, Ballauff A, Vodopiutz J, Rosipal S, Petersen BS, Franke A, Fuchs I, Witt H, Zoller H, Janecke AR, Visweswariah SS.

Congenital secretory diarrhoea caused by activating germline mutations in GUCY2C.

 

Basu N, Saha S, Khan I, Ramachandra SG, Visweswariah SS.

Intestinal Cell Proliferation and Senescence Are Regulated by Receptor Guanylyl Cyclase C and p21.

J Biol Chem. 2014 Jan 3;289(1):581-93.

 

Arshad N, Visweswariah SS.

Cyclic nucleotide signaling in intestinal epithelia: getting to the gut of the matter.

 

Arshad N, Ballal S, Visweswariah SS.

Site-specific N-linked glycosylation of receptor guanylyl cyclase C regulates ligand binding, ligand-mediated activation and interaction with vesicular integral membrane protein 36 (VIP36)

J. Biol Chem. 2012  Feb 8;288(6):3907-17.

 

Arshad N, Visweswariah SS.

The multiple and enigmatic roles of guanylyl cyclase C in intestinal homeostasis.

FEBS Lett. 2012 Aug 31;586(18):2835-40.

 

Fiskerstrand T, Arshad N, Haukanes, BI, Tronstad RR, Pham KD, Johansson S, Havik B, Tonder SL, Levy SE, BrackmanD, Boman H, Biswas KH, Apold J, Hovdenak N, Visweswariah SS, Knappskog PM.

Familial Diarrhea Syndrome caused by an activating GUCY2C activating mutation.

N. Engl. J. Med. 2012 Apr 26;366(17): 1586-95.

 

Basu N, Arshad N, Visweswariah SS.

Receptor guanylyl cyclase (GC-C): regulation and signal transduction.

Mol. Cell Biochem. 2009 Jan. 334(1-2):7-80.

 

Saha S, Biswas, KH, Kondapalli C, Isloor N, Visweswariah SS.

The linker region in receptor guanylyl cyclases is a key regulatory module: mutational analysis of guanylyl cyclase C.

J. Biol. Chem. 2009 Oct2;284(40):27135-45.

 

Basu N, Bhandari R, Natarajan VT, Visweswariah SS.

Cross talk between receptor guanylyl cyclase C and c-src tyrosine kinase regulates colon cancer cell cytostasis.

Mol. Cell Biol. 2009 Oct;29(19):5277-89.

 

Biswas, K.H., Shenoy, A.R., Dutta, A. and Visweswariah, S.S.

The evolution of guanylyl cyclases as multidomain proteins: conserved features of kinase-cyclase domain fusions.

 J. Mol. Evol. 2009 Jun;68(6):587-602.

 

Jaleel M, Saha S, Shenoy AR, Visweswariah SS.

The kinase homology domain of receptor guanylyl cyclase C: ATP binding and identification of an adenine nucleotide sensitive site.

Biochemistry. 2006 Feb 14;45(6):1888-98.

Jaleel M, Shenoy AR, Visweswariah SS.
Tyrphostins are inhibitors of guanylyl and adenylyl cyclases.
Biochemistry. 2004 Jun 29;43(25):8247-55.

Ghanekar Y, Chandrashaker A, Tatu U, Visweswariah SS.
Glycosylation of the receptor guanylyl cyclase C: role in ligand binding and catalytic activity.
Biochem J. 2004 May 1;379(Pt 3):653-63.

Ghanekar Y, Chandrashaker A, Visweswariah SS.
Cellular refractoriness to the heat-stable enterotoxin peptide is associated with alterations in levels of the differentially glycosylated forms of guanylyl cyclase C.
Eur J Biochem. 2003 Sep;270(18):3848-57.

Jaleel M, London RM, Eber SL, Forte LR, Visweswariah SS.
Expression of the receptor guanylyl cyclase C and its ligands in reproductive tissues of the rat: a potential role for a novel signaling pathway in the epididymis.
Biol Reprod. 2002 Dec;67(6):1975-80.

Bhandari R, Srinivasan N, Mahaboobi M, Ghanekar Y, Suguna K, Visweswariah SS.
Functional inactivation of the human guanylyl cyclase C receptor: modeling and mutation of the protein kinase-like domain.
Biochemistry. 2001 Aug 7;40(31):9196-206.

Roy N, Guruprasad MR, Kondaiah P, Mann EA, Giannella RA, Visweswariah SS.
Protein kinase C regulates transcription of the human guanylate cyclase C gene.
Eur J Biochem. 2001 Apr;268(7):2160-71.

Vijayachandra K, Guruprasad M, Bhandari R, Manjunath UH, Somesh BP, Srinivasan N, Suguna K, Visweswariah SS.
Biochemical characterization of the intracellular domain of the human guanylyl cyclase C receptor provides evidence for a catalytically active homotrimer.
Biochemistry. 2000 Dec 26;39(51):16075-83.

Bakre MM, Ghanekar Y, Visweswariah SS.
Homologous desensitization of the human guanylate cyclase C receptor. Cell-specific regulation of catalytic activity.
Eur J Biochem. 2000 Jan;267(1):179-87.

Nandi A, Bhandari R, Visweswariah SS.
Epitope conservation and immunohistochemical localization of the guanylin/stable toxin peptide receptor, guanylyl cyclase C.
J Cell Biochem. 1997 Sep 15;66(4):500-11.

 

Receptor Guanylyl Cyclase C cGMP Phosphodiesterase Mycobacterial Enzymes

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Indian Institute of Science • Dept. of MRDG