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Molecular and Cellular Biology, October 2009, p. 5277-5289, Vol. 29, No. 19
0270-7306/09/$08.00+0     doi:10.1128/MCB.00001-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Cross Talk between Receptor Guanylyl Cyclase C and c-src Tyrosine Kinase Regulates Colon Cancer Cell Cytostasis{triangledown}

Nirmalya Basu, Rashna Bhandari,{dagger} Vivek T. Natarajan,{ddagger} and Sandhya S. Visweswariah*

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

Received 1 January 2009/ Returned for modification 29 January 2009/ Accepted 13 July 2009

Increased activation of c-src seen in colorectal cancer is an indicator of a poor clinical prognosis, suggesting that identification of downstream effectors of c-src may lead to new avenues of therapy. Guanylyl cyclase C (GC-C) is a receptor for the gastrointestinal hormones guanylin and uroguanylin and the bacterial heat-stable enterotoxin. Though activation of GC-C by its ligands elevates intracellular cyclic GMP (cGMP) levels and inhibits cell proliferation, its persistent expression in colorectal carcinomas and occult metastases makes it a marker for malignancy. We show here that GC-C is a substrate for inhibitory phosphorylation by c-src, resulting in reduced ligand-mediated cGMP production. Consequently, active c-src in colonic cells can overcome GC-C-mediated control of the cell cycle. Furthermore, docking of the c-src SH2 domain to phosphorylated GC-C results in colocalization and further activation of c-src. We therefore propose a novel feed-forward mechanism of activation of c-src that is induced by cross talk between a receptor GC and a tyrosine kinase. Our findings have important implications in understanding the molecular mechanisms involved in the progression and treatment of colorectal cancer.

* Corresponding author. Mailing address: Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India. Phone: 91 80-22932542. Fax: 91 80-23600999. E-mail: sandhya{at}mrdg.iisc.ernet.in

{triangledown} Published ahead of print on 20 July 2009.

{dagger} Present address: Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India.

{ddagger} Present address: National Institute of Immunology, New Delhi, India.

Molecular and Cellular Biology, October 2009, p. 5277-5289, Vol. 29, No. 19
0270-7306/09/$08.00+0     doi:10.1128/MCB.00001-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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