This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Artym, V. V. Articles by Mueller, S. C. Search for Related Content PubMed PubMed Citation Articles by Artym, V. V. Articles by Mueller, S. C.

Dynamic Interactions of Cortactin and Membrane Type 1 Matrix Metalloproteinase at Invadopodia: Defining the Stages of Invadopodia Formation and Function

¹ Department of Oncology and ² Division of Biostatistics and Bioinformatics, Lombardi Comprehensive Cancer Center, Georgetown University Medical School, Washington, District of Columbia; and ³ Craniofacial Developmental Biology and Regeneration Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland

Requests for reprints: Susette C. Mueller, Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, E301 Research Building, Box 571469, Washington, DC 20057-1469. E-mail: muellers{at}georgetown.edu.

Metastatic tumor cells that actively migrate and invade surrounding tissues rely on invadopodia to degrade extracellular matrix (ECM) barriers. Invadopodia are membrane protrusions that localize enzymes required for ECM degradation. Little is known about the formation, function, and regulation of invadopodia. Here, we show that invadopodia have two distinct aspects: (a) structural for organizing the cellular actin cytoskeleton to form membrane protrusions and (b) functional for using proteolytic enzyme(s) for ECM degradation. Small interfering RNA (siRNA) inhibition established that organization of invadopodia structure requires cortactin, whereas protease inhibitor studies identified membrane type 1 matrix metalloproteinase (MT1-MMP) as the key invadopodial enzyme responsible for gelatin matrix degradation in the breast carcinoma cell line MDA-MB-231. The inhibition of invadopodial structure assembly by cortactin depletion resulted in a block of matrix degradation due to failure of invadopodia formation. Either protease inhibition or MT1-MMP siRNA depletion moderately decreased the formation of invadopodial structures that were identified as actin-cortactin accumulations at the ventral cell membrane adherent to matrix. The invadopodia that were able to form upon MT1-MMP inhibition or depletion retained actin-cortactin accumulations but were unable to degrade matrix. Examination of cells at different time points as well as live-cell imaging revealed four distinct invadopodial stages: membrane cortactin aggregation at membranes adherent to matrix, MT1-MMP accumulation at the region of cortactin accumulation, matrix degradation at the invadopodia region, and subsequent cortactin dissociation from the area of continued MT1-MMP accumulation associated with foci of degraded matrix. Based on these results, we propose a stepwise model of invadopodia formation and function. (Cancer Res 2006; 66(6): 3034-43)

This article has been cited by other articles:

				T. Oikawa, T. Itoh, and T. Takenawa Sequential signals toward podosome formation in NIH-src cells J. Cell Biol., July 14, 2008; 182(1): 157 - 169. [Abstract] [Full Text] [PDF]

				M. Sakurai-Yageta, C. Recchi, G. Le Dez, J.-B. Sibarita, L. Daviet, J. Camonis, C. D'Souza-Schorey, and P. Chavrier The interaction of IQGAP1 with the exocyst complex is required for tumor cell invasion downstream of Cdc42 and RhoA J. Cell Biol., June 16, 2008; 181(6): 985 - 998. [Abstract] [Full Text] [PDF]

				B. Desai, T. Ma, and M. A. Chellaiah Invadopodia and Matrix Degradation, a New Property of Prostate Cancer Cells during Migration and Invasion J. Biol. Chem., May 16, 2008; 283(20): 13856 - 13866. [Abstract] [Full Text] [PDF]

				C. L. Cortesio, K. T. Chan, B. J. Perrin, N. O. Burton, S. Zhang, Z.-Y. Zhang, and A. Huttenlocher Calpain 2 and PTP1B function in a novel pathway with Src to regulate invadopodia dynamics and breast cancer cell invasion J. Cell Biol., March 5, 2008; 180(5): 957 - 971. [Abstract] [Full Text] [PDF]

				I. Ayala, M. Baldassarre, G. Giacchetti, G. Caldieri, S. Tete, A. Luini, and R. Buccione Multiple regulatory inputs converge on cortactin to control invadopodia biogenesis and extracellular matrix degradation J. Cell Sci., February 1, 2008; 121(3): 369 - 378. [Abstract] [Full Text] [PDF]

				C. Badowski, G. Pawlak, A. Grichine, A. Chabadel, C. Oddou, P. Jurdic, M. Pfaff, C. Albiges-Rizo, and M. R. Block Paxillin Phosphorylation Controls Invadopodia/Podosomes Spatiotemporal Organization Mol. Biol. Cell, February 1, 2008; 19(2): 633 - 645. [Abstract] [Full Text] [PDF]

				M. Baumgartner, G. Radziwill, M. Lorger, A. Weiss, and K. Moelling c-Src-Mediated Epithelial Cell Migration and Invasion Regulated by PDZ Binding Site Mol. Cell. Biol., January 15, 2008; 28(2): 642 - 655. [Abstract] [Full Text] [PDF]

				S. Tournaviti, S. Hannemann, S. Terjung, T. M. Kitzing, C. Stegmayer, J. Ritzerfeld, P. Walther, R. Grosse, W. Nickel, and O. T. Fackler SH4-domain-induced plasma membrane dynamization promotes bleb-associated cell motility J. Cell Sci., November 1, 2007; 120(21): 3820 - 3829. [Abstract] [Full Text] [PDF]

				S. Tehrani, N. Tomasevic, S. Weed, R. Sakowicz, and J. A. Cooper Src phosphorylation of cortactin enhances actin assembly PNAS, July 17, 2007; 104(29): 11933 - 11938. [Abstract] [Full Text] [PDF]

				E. Furmaniak-Kazmierczak, S. W. Crawley, R. L. Carter, D. H. Maurice, and G. P. Cote Formation of Extracellular Matrix-Digesting Invadopodia by Primary Aortic Smooth Muscle Cells Circ. Res., May 11, 2007; 100(9): 1328 - 1336. [Abstract] [Full Text] [PDF]

				E. S. Clark, A. S. Whigham, W. G. Yarbrough, and A. M. Weaver Cortactin Is an Essential Regulator of Matrix Metalloproteinase Secretion and Extracellular Matrix Degradation in Invadopodia Cancer Res., May 1, 2007; 67(9): 4227 - 4235. [Abstract] [Full Text] [PDF]

				O. M. Tirado, S. Mateo-Lozano, J. Villar, L. E. Dettin, A. Llort, S. Gallego, J. Ban, H. Kovar, and V. Notario Caveolin-1 (CAV1) Is a Target of EWS/FLI-1 and a Key Determinant of the Oncogenic Phenotype and Tumorigenicity of Ewing's Sarcoma Cells. Cancer Res., October 15, 2006; 66(20): 9937 - 9947. [Abstract] [Full Text] [PDF]

				L. I. Cosen-Binker and A. Kapus Cortactin: The Gray Eminence of the Cytoskeleton. Physiology, October 1, 2006; 21(5): 352 - 361. [Abstract] [Full Text] [PDF]

				B. L. Rothschild, A. H. Shim, A. G. Ammer, L. C. Kelley, K. B. Irby, J. A. Head, L. Chen, M. Varella-Garcia, P. G. Sacks, B. Frederick, et al. Cortactin Overexpression Regulates Actin-Related Protein 2/3 Complex Activity, Motility, and Invasion in Carcinomas with Chromosome 11q13 Amplification Cancer Res., August 15, 2006; 66(16): 8017 - 8025. [Abstract] [Full Text] [PDF]