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Carbonic anhydrase IX interacts with bicarbonate transporters in lamellipodia and increases cell migration via its catalytic domain.
J Biol Chem 2012; 287(5):3392-402JB

Abstract

Carbonic anhydrase IX (CA IX) is a hypoxia-induced cell surface enzyme expressed in solid tumors, and functionally involved in acidification of extracellular pH and destabilization of intercellular contacts. Since both extracellular acidosis and reduced cell adhesion facilitate invasion and metastasis, we investigated the role of CA IX in cell migration, which promotes the metastatic cascade. As demonstrated here, ectopically expressed CA IX increases scattering, wound healing and transwell migration of MDCK cells, while an inactive CA IX variant lacking the catalytic domain (ΔCA) fails to do so. Correspondingly, hypoxic HeLa cells exhibit diminished migration upon inactivation of the endogenous CA IX either by forced expression of the dominant-negative ΔCA variant or by treatment with CA inhibitor, implying that the catalytic activity is indispensable for the CA IX function. Interestingly, CA IX improves cell migration both in the absence and presence of hepatocyte growth factor (HGF), an established inducer of epithelial-mesenchymal transition. On the other hand, HGF up-regulates CA IX transcription and triggers CA IX protein accumulation at the leading edge of lamellipodia. In these membrane regions CA IX co-localizes with sodium bicarbonate co-transporter (NBCe1) and anion exchanger 2 (AE2) that are both components of the migration apparatus and form bicarbonate transport metabolon with CA IX. Moreover, CA IX physically interacts with AE2 and NBCe1 in situ, as shown here for the first time. Thus, our findings suggest that CA IX actively contributes to cell migration via its ability to facilitate ion transport and pH control at protruding fronts of moving cells.

Authors+Show Affiliations

Department of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22170054

Citation

Svastova, Eliska, et al. "Carbonic Anhydrase IX Interacts With Bicarbonate Transporters in Lamellipodia and Increases Cell Migration Via Its Catalytic Domain." The Journal of Biological Chemistry, vol. 287, no. 5, 2012, pp. 3392-402.
Svastova E, Witarski W, Csaderova L, et al. Carbonic anhydrase IX interacts with bicarbonate transporters in lamellipodia and increases cell migration via its catalytic domain. J Biol Chem. 2012;287(5):3392-402.
Svastova, E., Witarski, W., Csaderova, L., Kosik, I., Skvarkova, L., Hulikova, A., ... Pastorekova, S. (2012). Carbonic anhydrase IX interacts with bicarbonate transporters in lamellipodia and increases cell migration via its catalytic domain. The Journal of Biological Chemistry, 287(5), pp. 3392-402. doi:10.1074/jbc.M111.286062.
Svastova E, et al. Carbonic Anhydrase IX Interacts With Bicarbonate Transporters in Lamellipodia and Increases Cell Migration Via Its Catalytic Domain. J Biol Chem. 2012 Jan 27;287(5):3392-402. PubMed PMID: 22170054.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Carbonic anhydrase IX interacts with bicarbonate transporters in lamellipodia and increases cell migration via its catalytic domain. AU - Svastova,Eliska, AU - Witarski,Wojciech, AU - Csaderova,Lucia, AU - Kosik,Ivan, AU - Skvarkova,Lucia, AU - Hulikova,Alzbeta, AU - Zatovicova,Miriam, AU - Barathova,Monika, AU - Kopacek,Juraj, AU - Pastorek,Jaromir, AU - Pastorekova,Silvia, Y1 - 2011/12/14/ PY - 2011/12/16/entrez PY - 2011/12/16/pubmed PY - 2012/3/23/medline SP - 3392 EP - 402 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 287 IS - 5 N2 - Carbonic anhydrase IX (CA IX) is a hypoxia-induced cell surface enzyme expressed in solid tumors, and functionally involved in acidification of extracellular pH and destabilization of intercellular contacts. Since both extracellular acidosis and reduced cell adhesion facilitate invasion and metastasis, we investigated the role of CA IX in cell migration, which promotes the metastatic cascade. As demonstrated here, ectopically expressed CA IX increases scattering, wound healing and transwell migration of MDCK cells, while an inactive CA IX variant lacking the catalytic domain (ΔCA) fails to do so. Correspondingly, hypoxic HeLa cells exhibit diminished migration upon inactivation of the endogenous CA IX either by forced expression of the dominant-negative ΔCA variant or by treatment with CA inhibitor, implying that the catalytic activity is indispensable for the CA IX function. Interestingly, CA IX improves cell migration both in the absence and presence of hepatocyte growth factor (HGF), an established inducer of epithelial-mesenchymal transition. On the other hand, HGF up-regulates CA IX transcription and triggers CA IX protein accumulation at the leading edge of lamellipodia. In these membrane regions CA IX co-localizes with sodium bicarbonate co-transporter (NBCe1) and anion exchanger 2 (AE2) that are both components of the migration apparatus and form bicarbonate transport metabolon with CA IX. Moreover, CA IX physically interacts with AE2 and NBCe1 in situ, as shown here for the first time. Thus, our findings suggest that CA IX actively contributes to cell migration via its ability to facilitate ion transport and pH control at protruding fronts of moving cells. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/22170054/Carbonic_anhydrase_IX_interacts_with_bicarbonate_transporters_in_lamellipodia_and_increases_cell_migration_via_its_catalytic_domain_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=22170054 DB - PRIME DP - Unbound Medicine ER -