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This article is part of the supplement: 5th International Conference on cGMP: Generators, Effectors and Therapeutic Implications

Open Access Poster presentation

Signaling via guanylyl cyclase C: cGMP, Src and p21

Nirmalya Basu1*, Sayanti Saha2 and Sandhya S Visweswariah1

  • * Corresponding author: Nirmalya Basu

Author Affiliations

1 Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science,Bangalore 560012, India

2 Fox Chase Cancer Center, Philadelphia, Pa 19111, USA

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BMC Pharmacology 2011, 11(Suppl 1):P4  doi:10.1186/1471-2210-11-S1-P4

The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2210/11/S1/P4


Published:1 August 2011

© 2011 Basu et al; licensee 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.

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 invitro 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.

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. PubMed Abstract | Publisher Full Text OpenURL

  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 Abstract OpenURL

  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. OpenURL