Skip to content

Advertisement

  • Poster presentation
  • Open Access

Signaling via guanylyl cyclase C: cGMP, Src and p21

  • Nirmalya Basu1,
  • Sayanti Saha2 and
  • Sandhya S Visweswariah1
BMC Pharmacology201111(Suppl 1):P4

https://doi.org/10.1186/1471-2210-11-S1-P4

Published: 1 August 2011

Keywords

Intestinal Epithelial CellGuanylyl CyclaseGuanylyl Cyclase ActivityCyclase DomainAdditional Signalling Pathway

Background

Guanylyl cyclase C (GC-C) is a receptor expressed in intestinal epithelial cells and activation of GCC by its ligands elevates intracellular cGMP which results in an inhibition of cell proliferation [1]. Multiple regulatory mechanisms operate in GC-C to modulate its activity, and include ligand binding to the extracellular domain, ATP binding to the kinase homology domain and additional structural features that link the kinase homology domain to the C-terminal guanylyl cyclase domain [2]. The persistent expression of GC-C in colorectal carcinomas and occult metastases makes it a marker for malignancy.

Results

We have investigated cross-talk of GC-C with additional signalling pathways in the intestinal cell in order to investigate its role in cell proliferation. Activation of c-src in human colonic cells results in down-regulation of cGMP production by GC-C, and through mutational analysis and in vitro and in vivo assays, we show that GC-C is a substrate for phosphorylation by c-src. This phosphorylation now results in a reduction in guanylyl cyclase activity. Phosphorylation of GC-C by c-src allows the docking of the c-src SH2 domain to phosphorylated GC-C, which can now result in further activation of c-src. This feed forward mechanism of activation of c-src, induced by novel cross-talk between a receptor guanylyl cyclase and a tyrosine kinase, may have important implications in colonic tumour progression [3]. To identify other downstream effects of cGMP, we have performed microarray analysis on T84 colon carcinoma cells treated with the heat-stable enterotoxin. One of the genes significantly up-regulated, both at the levels of transcript and protein, was the cell-cycle inhibitor, p21. Treatment of T84 cells with the stable toxin peptide allowed cells to enter a cGMP-dependent senescence programme. The cells show all the hallmarks of senescent cells, including flattened cell morphology, positive staining for SA-ß Gal and formation of senescence-associated heterochromatic foci. Activation of senescence and loss of tumorigenicity in these cells is crucially dependent on the up-regulation of p21 and therefore can contribute to ST induced-cytostasis.

Conclusion

These observations may provide an explanation for the reduced incidence of colon-carcinoma seen in countries where the incidence of ST-mediated diarrhoea is higher. Moreover, our results also highlight the fact that the production of cGMP in intestinal epithelial cells is exquisitely regulated, and cGMP, in turn may regulate a number of pathways with diverse physiological effects.

Authors’ Affiliations

(1)
Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India
(2)
Fox Chase Cancer Center, Philadelphia, USA

References

  1. Basu N, Arshad N, Visweswariah SS: Receptor guanylyl Cyclase C (GC- C): Regulation and Signal Transduction. Mol Cell Biochem. 2010, 334: 67-80. 10.1007/s11010-009-0324-x.View ArticlePubMedGoogle Scholar
  2. 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 guanylylcyclase C (GC-C). J Biol Chem. 2009, 284 (40): 27135-27145.PubMed CentralView ArticlePubMedGoogle Scholar
  3. Basu N, Bhandari R, Tirumlai V, Visweswariah SS: Cross-talk between receptor guanylyl cyclase C and c-src tyrosine kinase. Mol Cell Biol. 2009, 29: 527752-527789.View ArticleGoogle Scholar

Copyright

© Basu et al; licensee BioMed Central Ltd. 2011

This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Advertisement