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Carbonic anhydrase IX (CA IX) is a membrane isoenzyme the overexpression of which is associated with the clear cell carcinoma of the kidney. Its overexpression is mainly cancer restricted as it is absent in the corresponding normal tissues making it a potential cancer biomarker. Several recent studies show that CA IX, apart from its classical enzyme activity of reversibly hyrdrating carbon dioxide extracellularly to facilitate the net extrusion of protons from inside to outside the cell, it can also be a key player in the modulation of cell adhesion processes and participate in the regulation of cell proliferation in response to hypoxic environment to ultimately contribute to tumor progression. Here, we show that the sole tyrosine moiety of CA IX present in its intracellular domain can be phosphorylated in an epidermal growth factor (EGF) dependent manner, suggesting that it can feed into the growth factor receptor dependent signaling pathways. Our studies suggest that the tyrosine phosphorylated CA IX can interact with the SH2 domain of the regulatory subunit of PI-3-Kinase, contributing to Akt activation. These studies have revealed a positive feed back loop that can form the basis of a vicious cycle that might contribute to the progression of clear cell renal carcinoma and poor prognosis. These studies show that CA IX signaling may be a part of both the hypoxia driven and hypoxia independent pathways that occur in the cancer cell. Finally, our studies emphasize the need for a more refined strategy using signal transduction therapeutics to inhibit the cell surface carbonic anhydrases for the management of this malignancy. In addition, some of the recent results on the down regulation of E-Cadherin by CA IX and the functional consequences of this phenomenon will be presented in relation to cancer progression.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA