Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text PDF (Full Text) PPT slides of all figures Supplemental Material Index Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Cho, S. Y. Articles by Klemke, R. L. Search for Related Content PubMed PubMed Citation Articles by Cho, S. Y. Articles by Klemke, R. L. Related Collections Related Article Social Bookmarking                      What's this?

Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037

Address correspondence to Richard L. Klemke, Dept. of Immunology, SP231, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037. Tel.: (858) 784-7750. Fax: (858) 784-7785. E-mail: klemke{at}scripps.edu

Initiation of cell migration requires morphological polarization with formation of a dominant leading pseudopodium and rear compartment. A molecular understanding of this process has been limited, due to the inability to biochemically separate the leading pseudopodium from the rear of the cell. Here we examine the spatio-temporal localization and activation of cytoskeletal-associated signals in purified pseudopodia directed to undergo growth or retraction. Pseudopodia growth requires assembly of a p130Crk-associated substrate (CAS)/c-CrkII (Crk) scaffold, which facilitates translocation and activation of Rac1. Interestingly, Rac1 activation then serves as a positive-feedback loop to maintain CAS/Crk coupling and pseudopodia extension. Conversely, disassembly of this molecular scaffold is critical for export and down regulation of Rac1 activity and induction of pseudopodia retraction. Surprisingly, the uncoupling of Crk from CAS during pseudopodium retraction is independent of changes in focal adhesion kinase activity and CAS tyrosine phosphorylation. These findings establish CAS/Crk as an essential scaffold for Rac1-mediated pseudopodia growth and retraction, and illustrate spatio-temporal segregation of cytoskeletal signals during cell polarization.

Key Words: cell migration; chemotaxis; signal transduction; pseudopodium; Rac GTPase

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

Related Article

The sound of one foot walking

Alan W. Dove
J. Cell Biol. 2002 156: 586-587. [Full Text] [PDF]

This article has been cited by other articles:

• Spiczka, K. S., Yeaman, C. (2008). Ral-regulated interaction between Sec5 and paxillin targets Exocyst to focal complexes during cell migration. J. Cell Sci. 121: 2880-2891 [Abstract] [Full Text]  
• Mercure, M. Z., Ginnan, R., Singer, H. A. (2008). CaM kinase II{delta}2-dependent regulation of vascular smooth muscle cell polarization and migration. Am. J. Physiol. Cell Physiol. 294: C1465-C1475 [Abstract] [Full Text]  
• Jacob, M., Todd, L., Sampson, M. F., Pure, E. (2008). Dual role of Cbl links critical events in BCR endocytosis. Int Immunol 20: 485-497 [Abstract] [Full Text]  
• Tan, N. S., Icre, G., Montagner, A., Heggeler, B. B.-t., Wahli, W., Michalik, L. (2007). The Nuclear Hormone Receptor Peroxisome Proliferator-Activated Receptor {beta}/{delta} Potentiates Cell Chemotactism, Polarization, and Migration. Mol. Cell. Biol. 27: 7161-7175 [Abstract] [Full Text]  
• Wang, Y., Ding, S.-J., Wang, W., Yang, F., Jacobs, J. M., Camp, D. II, Smith, R. D., Klemke, R. L. (2007). Methods for Pseudopodia Purification and Proteomic Analysis. Sci Signal 2007: pl4-pl4 [Abstract] [Full Text]  
• Gupton, S. L., Gertler, F. B. (2007). Filopodia: The Fingers That Do the Walking. Sci Signal 2007: re5-re5 [Abstract] [Full Text]  
• Anfinogenova, Y., Wang, R., Li, Q.-f., Spinelli, A. M., Tang, D. D. (2007). Abl Silencing Inhibits CAS-Mediated Process and Constriction in Resistance Arteries. Circ. Res. 101: 420-428 [Abstract] [Full Text]  
• Lester, R. D., Jo, M., Montel, V., Takimoto, S., Gonias, S. L. (2007). uPAR induces epithelial mesenchymal transition in hypoxic breast cancer cells. J. Cell Biol. 178: 425-436 [Abstract] [Full Text]  
• Schrecengost, R. S., Riggins, R. B., Thomas, K. S., Guerrero, M. S., Bouton, A. H. (2007). Breast Cancer Antiestrogen Resistance-3 Expression Regulates Breast Cancer Cell Migration through Promotion of p130Cas Membrane Localization and Membrane Ruffling. Cancer Res. 67: 6174-6182 [Abstract] [Full Text]  
• Avraamides, C., Bromberg, M. E., Gaughan, J. P., Thomas, S. M., Tsygankov, A. Y., Panetti, T. S. (2007). Hic-5 promotes endothelial cell migration to lysophosphatidic acid. Am. J. Physiol. Heart Circ. Physiol. 293: H193-H203 [Abstract] [Full Text]  
• Wang, Y., Ding, S.-J., Wang, W., Jacobs, J. M., Qian, W.-J., Moore, R. J., Yang, F., Camp, D. G. II, Smith, R. D., Klemke, R. L. (2007). Profiling signaling polarity in chemotactic cells. Proc. Natl. Acad. Sci. USA 104: 8328-8333 [Abstract] [Full Text]  
• Cho, Y. J., Cunnick, J. M., Yi, S.-J., Kaartinen, V., Groffen, J., Heisterkamp, N. (2007). Abr and Bcr, Two Homologous Rac GTPase-Activating Proteins, Control Multiple Cellular Functions of Murine Macrophages. Mol. Cell. Biol. 27: 899-911 [Abstract] [Full Text]  
• Burridge, K., Sastry, S. K., Sallee, J. L. (2006). Regulation of Cell Adhesion by Protein-tyrosine Phosphatases: I. CELL-MATRIX ADHESION. J. Biol. Chem. 281: 15593-15596 [Abstract] [Full Text]  
• Kostic, A., Sheetz, M. P. (2006). Fibronectin Rigidity Response through Fyn and p130Cas Recruitment to the Leading Edge. Mol. Biol. Cell 17: 2684-2695 [Abstract] [Full Text]  
• Ghosh, S., Johnson, J. J., Sen, R., Mukhopadhyay, S., Liu, Y., Zhang, F., Wei, Y., Chapman, H. A., Stack, M. S. (2006). Functional Relevance of Urinary-type Plasminogen Activator Receptor-{alpha}3beta1 Integrin Association in Proteinase Regulatory Pathways. J. Biol. Chem. 281: 13021-13029 [Abstract] [Full Text]  
• Sastry, S. K., Rajfur, Z., Liu, B. P., Cote, J.-F., Tremblay, M. L., Burridge, K. (2006). PTP-PEST Couples Membrane Protrusion and Tail Retraction via VAV2 and p190RhoGAP. J. Biol. Chem. 281: 11627-11636 [Abstract] [Full Text]  
• Holcomb, M., Rufini, A., Barila, D., Klemke, R. L. (2006). Deregulation of Proteasome Function Induces Abl-mediated Cell Death by Uncoupling p130CAS and c-CrkII. J. Biol. Chem. 281: 2430-2440 [Abstract] [Full Text]  
• Sloan, K. E., Stewart, J. K., Treloar, A. F., Matthews, R. T., Jay, D. G. (2005). CD155/PVR Enhances Glioma Cell Dispersal by Regulating Adhesion Signaling and Focal Adhesion Dynamics. Cancer Res. 65: 10930-10937 [Abstract] [Full Text]  
• Howe, A. K., Baldor, L. C., Hogan, B. P. (2005). Spatial regulation of the cAMP-dependent protein kinase during chemotactic cell migration. Proc. Natl. Acad. Sci. USA 102: 14320-14325 [Abstract] [Full Text]  
• Cascone, I., Napione, L., Maniero, F., Serini, G., Bussolino, F. (2005). Stable interaction between {alpha}5{beta}1 integrin and Tie2 tyrosine kinase receptor regulates endothelial cell response to Ang-1. J. Cell Biol. 170: 993-1004 [Abstract] [Full Text]  
• Kisseleva, M., Feng, Y., Ward, M., Song, C., Anderson, R. A., Longmore, G. D. (2005). The LIM Protein Ajuba Regulates Phosphatidylinositol 4,5-Bisphosphate Levels in Migrating Cells through an Interaction with and Activation of PIPKI{alpha}. Mol. Cell. Biol. 25: 3956-3966 [Abstract] [Full Text]  
• Danen, E. H.J., van Rheenen, J., Franken, W., Huveneers, S., Sonneveld, P., Jalink, K., Sonnenberg, A. (2005). Integrins control motile strategy through a Rho-cofilin pathway. J. Cell Biol. 169: 515-526 [Abstract] [Full Text]  
• Rodrigues, S. P., Fathers, K. E., Chan, G., Zuo, D., Halwani, F., Meterissian, S., Park, M. (2005). CrkI and CrkII Function as Key Signaling Integrators for Migration and Invasion of Cancer Cells. Mol Cancer Res 3: 183-194 [Abstract] [Full Text]  
• Pratt, S. J., Epple, H., Ward, M., Feng, Y., Braga, V. M., Longmore, G. D. (2005). The LIM protein Ajuba influences p130Cas localization and Rac1 activity during cell migration. J. Cell Biol. 168: 813-824 [Abstract] [Full Text]  
• Wozniak, M. A., Kwong, L., Chodniewicz, D., Klemke, R. L., Keely, P. J. (2005). R-Ras Controls Membrane Protrusion and Cell Migration through the Spatial Regulation of Rac and Rho. Mol. Biol. Cell 16: 84-96 [Abstract] [Full Text]  
• Ge, L., Shenoy, S. K., Lefkowitz, R. J., DeFea, K. (2004). Constitutive Protease-activated Receptor-2-mediated Migration of MDA MB-231 Breast Cancer Cells Requires Both {beta}-Arrestin-1 and -2. J. Biol. Chem. 279: 55419-55424 [Abstract] [Full Text]  
• Arthur, W. T., Quilliam, L. A., Cooper, J. A. (2004). Rap1 promotes cell spreading by localizing Rac guanine nucleotide exchange factors. J. Cell Biol. 167: 111-122 [Abstract] [Full Text]  
• Zhou, R.-H., Yao, M., Lee, T.-S., Zhu, Y., Martins-Green, M., Shyy, J. Y.-J. (2004). Vascular Endothelial Growth Factor Activation of Sterol Regulatory Element Binding Protein: A Potential Role in Angiogenesis. Circ. Res. 95: 471-478 [Abstract] [Full Text]  
• Choma, D. P., Pumiglia, K., DiPersio, C. M. (2004). Integrin {alpha}3{beta}1 directs the stabilization of a polarized lamellipodium in epithelial cells through activation of Rac1. J. Cell Sci. 117: 3947-3959 [Abstract] [Full Text]  
• Gustavsson, A., Yuan, M., Fallman, M. (2004). Temporal Dissection of {beta}1-Integrin Signaling Indicates a Role for p130Cas-Crk in Filopodia Formation. J. Biol. Chem. 279: 22893-22901 [Abstract] [Full Text]  
• Lin, Y. H., Park, Z.-Y., Lin, D., Brahmbhatt, A. A., Rio, M.-C., Yates, J. R. III, Klemke, R. L. (2004). Regulation of cell migration and survival by focal adhesion targeting of Lasp-1. J. Cell Biol. 165: 421-432 [Abstract] [Full Text]  
• Grimsley, C. M., Kinchen, J. M., Tosello-Trampont, A.-C., Brugnera, E., Haney, L. B., Lu, M., Chen, Q., Klingele, D., Hengartner, M. O., Ravichandran, K. S. (2004). Dock180 and ELMO1 Proteins Cooperate to Promote Evolutionarily Conserved Rac-dependent Cell Migration. J. Biol. Chem. 279: 6087-6097 [Abstract] [Full Text]  
• Goldberg, G. S., Alexander, D. B., Pellicena, P., Zhang, Z.-Y., Tsuda, H., Miller, W. T. (2003). Src Phosphorylates Cas on Tyrosine 253 to Promote Migration of Transformed Cells. J. Biol. Chem. 278: 46533-46540 [Abstract] [Full Text]  
• Joy, A. M., Beaudry, C. E., Tran, N. L., Ponce, F. A., Holz, D. R., Demuth, T., Berens, M. E. (2003). Migrating glioma cells activate the PI3-K pathway and display decreased susceptibility to apoptosis. J. Cell Sci. 116: 4409-4417 [Abstract] [Full Text]  
• van Hennik, P. B., Klooster, J. P. t., Halstead, J. R., Voermans, C., Anthony, E. C., Divecha, N., Hordijk, P. L. (2003). The C-terminal Domain of Rac1 Contains Two Motifs That Control Targeting and Signaling Specificity. J. Biol. Chem. 278: 39166-39175 [Abstract] [Full Text]  
• Ge, L., Ly, Y., Hollenberg, M., DeFea, K. (2003). A {beta}-Arrestin-dependent Scaffold Is Associated with Prolonged MAPK Activation in Pseudopodia during Protease-activated Receptor-2-induced Chemotaxis. J. Biol. Chem. 278: 34418-34426 [Abstract] [Full Text]  
• Goldfinger, L. E., Han, J., Kiosses, W. B., Howe, A. K., Ginsberg, M. H. (2003). Spatial restriction of {alpha}4 integrin phosphorylation regulates lamellipodial stability and {alpha}4{beta}1-dependent cell migration. J. Cell Biol. 162: 731-741 [Abstract] [Full Text]  
• Lin, Y., Ceacareanu, A. C., Hassid, A. (2003). Nitric oxide-induced inhibition of aortic smooth muscle cell motility: role of PTP-PEST and adaptor proteins p130cas and Crk. Am. J. Physiol. Heart Circ. Physiol. 285: H710-H721 [Abstract] [Full Text]  
• Woodring, P. J., Hunter, T., Wang, J. Y. J. (2003). Regulation of F-actin-dependent processes by the Abl family of tyrosine kinases. J. Cell Sci. 116: 2613-2626 [Abstract] [Full Text]  
• Brahmbhatt, A. A., Klemke, R. L. (2003). ERK and RhoA Differentially Regulate Pseudopodia Growth and Retraction during Chemotaxis. J. Biol. Chem. 278: 13016-13025 [Abstract] [Full Text]  
• Vonna, L., Wiedemann, A., Aepfelbacher, M., Sackmann, E. (2003). Local force induced conical protrusions of phagocytic cells. J. Cell Sci. 116: 785-790 [Abstract] [Full Text]  
• Jo, M., Thomas, K. S., O'Donnell, D. M., Gonias, S. L. (2003). Epidermal Growth Factor Receptor-dependent and -independent Cell-signaling Pathways Originating from the Urokinase Receptor. J. Biol. Chem. 278: 1642-1646 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents