CoChat
Sign Up
Cited by 287

The DOI matches its Crossref record.

Integrins regulate GTP-Rac localized effector interactions through dissociation of Rho-GDI

Del Pozo, Miguel Angel, Kiosses, William B., Alderson, Nazilla B., Meller, Nahum, Hahn, Klaus M., Schwartz, Martin Alexander·2002·Nature Cell Biology
DOI 10.1038/ncb759
Open this paper in CoChat — free account

Abstract

The proper function of Rho GTPases requires precise spatial and temporal regulation of effector interactions. Integrin-mediated cell adhesion modulates the interaction of GTP-Rac with its effectors by controlling GTP-Rac membrane targeting. Here, we show that the translocation of GTP-Rac to membranes is independent of effector interactions, but instead requires the polybasic sequence near the carboxyl terminus. Cdc42 also requires integrin-mediated adhesion for translocation to membranes. A recently developed fluorescence resonance energy transfer (FRET)-based assay yields the surprising result that, despite its uniform distribution, the interaction of activated V12-Rac with a soluble, cytoplasmic effector domain is enhanced at specific regions near cell edges and is induced locally by integrin stimulation. This enhancement requires Rac membrane targeting. We show that Rho-GDI, which associates with cytoplasmic GTP-Rac, blocks effector binding. Release of Rho-GDI after membrane translocation allows Rac to bind to effectors. Thus, Rho-GDI confers spatially restricted regulation of Rac-effector interactions.

Overview

Integrity signals

Registry

Crossref · 10.1038/ncb759

Cites

Statistics

Recomputing p-values needs the paper’s full text.

Verification

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Citations

Cites

No references could be resolved yet.

Research works printed but not linked: 47

  1. de Curtis, I. Cell migration: GAPs between membrane traffic and the cytoskeleton. EMBO Rep. 2, 277–281 (2001). · DOI
  2. Hall, A. Rho GTPases and the actin cytoskeleton. Science 279, 509–514 (1998). · DOI
  3. Lauffenburger, D. A. & Horwitz, A. F. Cell migration: a physically integrated molecular process. Cell 84, 359–369 (1996). · DOI · Paper page
  4. Bishop, A. L. & Hall, A. Rho GTPases and their effector proteins. Biochem. J. 348 Pt 2, 241–255 (2000). · DOI · Paper page
  5. Olofsson, B. Rho guanine dissociation inhibitors: pivotal molecules in cellular signalling. Cell Signal. 11, 545–554 (1999). · DOI
  6. Seabra, M. C. Membrane association and targeting of prenylated Ras-like GTPases. Cell Signal. 10, 167–172 (1998). · DOI · Paper page
  7. Keep, N. H. et al. A modulator of rho family G proteins, Rho-GDI, binds these G proteins via an immunoglobulin-like domain and a flexible N-terminal arm. Structure 5, 623–633 (1997). · DOI
  8. del Pozo, M. A., Price, L. S., Alderson, N. B., Ren, X. D. & Schwartz, M. A. Adhesion to the extracellular matrix regulates the coupling of the small GTPase Rac to its effector PAK. EMBO J. 19, 2008–2014 (2000). · DOI
  9. Symons, M. Adhesion signalling: PAK meets Rac on solid ground. Curr. Biol. 10, R535–R537 (2000). · DOI
  10. Kraynov, V. S. et al. Localized Rac activation dynamics visualized in living cells. Science 290, 333–337 (2000). · DOI
  11. Dharmawardhane, S., Sanders, L. C., Martin, S. S., Daniels, R. H. & Bokoch, G. M. Localization of p21-Activated Kinase 1 (PAK1) to pinocytic vesicles and cortical actin structures in stimulated cells. J. Cell Biol. 138, 1–14 (1997). · DOI
  12. Lamarche, N. et al. Rac and cdc42 induce actin polymerization and G1 cell cycle progression independently of p65PAK and the JNK/SAPK MAP kinase cascade. Cell 87, 519–529 (1996). · DOI
  13. Westwick, J. K. et al. Rac regulation of transformation, gene expression, and actin organization by multiple, PAK-independent pathways. Mol. Cell. Biol. 17, 1324–1335 (1997). · DOI
  14. Price, L. S., Leng, J., Schwartz, M. A. & Bokoch, G. M. Activation of rac and cdc42 by integrins mediates cell spreading. Mol. Biol. Cell 9, 1863–1871 (1998). · DOI
  15. Hancock, J. F., Paterson, H. & Marshall, C. J. A polybasic domain or palmitoylation is required in addition to the CAAX motif to localize p21ras to the plasma membrane. Cell 63, 133–139 (1990). · DOI
  16. Knaus, U. G., Wang, Y., Reilly, A. M., Warnock, D. & Jackson, J. H. Structural requirements for PAK activation by Rac GTPases. J. Biol. Chem. 273, 21512–21518 (1998). · DOI · Paper page
  17. Kozma, R., Ahmed, S., Best, A. & Lim, L. The Ras-related protein Cdc42Hs and bradykinin promote formation of peripheral actin microspikes and filopodia in Swiss 3T3 fibroblasts. Mol. Cell. Biol. 15, 1942–1952 (1995). · DOI
  18. Jordan, J. D., Landau, E. M. & Iyengar, R. Signalling networks: the origins of cellular multitasking. Cell 103, 193–200 (2000). · DOI
  19. Teruel, M. N. & Meyer, T. Translocation and reversible localization of signalling proteins: a dynamic future for signal transduction. Cell 103, 181–184 (2000). · DOI
  20. Kiosses, W. B., Shattil, S. J., Pampori, N. & Schwartz, M. A. Rac recruits high-affinity integrin αvβ3 to lamellipodia in endothelial cell migration. Nature Cell Biol. 3, 316–320 (2001). · DOI
  21. Miyamoto, S. et al. Integrin function: molecular hierarchies of cytoskeletal and signalling proteins. J. Cell Biol. 131, 791–805 (1995). · DOI
  22. Schwartz, M. A., Lechene, C. & Ingber, D. E. Insoluble fibronectin activates the Na/H antiporter by clustering and immobilizing integrin α5β1, independent of cell shape. Proc. Natl Acad. Sci. USA 88, 7849–7853 (1991). · DOI
  23. Lewis, J. M. & Schwartz, M. A. Mapping in vivo associations of cytoplasmic proteins with integrin β1 cytoplasmic domain mutants. Mol. Biol. Cell 6, 151–160 (1995). · DOI
  24. Bourguignon, L. Y., Zhu, H., Shao, L. & Chen, Y. W. CD44 interaction with tiam1 promotes Rac1 signalling and hyaluronic acid-mediated breast tumor cell migration. J. Biol. Chem. 275, 1829–1838 (2000). · DOI
  25. Woods, A. & Couchman, J. R. Syndecan 4 heparan sulfate proteoglycan is a selectively enriched and widespread focal adhesion component. Mol. Biol. Cell 5, 183–192 (1994). · DOI
  26. Scheffzek, K., Stephan, I., Jensen, O. N., Illenberger, D. & Gierschik, P. The Rac–Rho-GDI complex and the structural basis for the regulation of Rho proteins by Rho-GDI. Nature Struct. Biol. 7, 122–126 (2000). · DOI
  27. Hoffman, G. R., Nassar, N. & Cerione, R. A. Structure of the Rho family GTP-binding protein Cdc42 in complex with the multifunctional regulator Rho-GDI. Cell 100, 345–356 (2000). · DOI
  28. Lian, L. Y. et al. Mapping the binding site for the GTP-binding protein Rac-1 on its inhibitor Rho-GDI-1. Structure Fold Des. 8, 47–55 (2000). · DOI
  29. Longenecker, K. et al. How Rho-GDI binds Rho. Acta Crystallogr. D. Biol. Crystallogr. 55, 1503–1515 (1999). · DOI
  30. Read, P. W. et al. Human RhoA/Rho-GDI complex expressed in yeast: GTP exchange is sufficient for translocation of RhoA to liposomes. Protein Sci. 9, 376–386 (2000). · DOI
  31. Dirac-Svejstrup, A. B., Sumizawa, T. & Pfeffer, S. R. Identification of a GDI displacement factor that releases endosomal Rab GTPases from Rab-GDI. EMBO J. 16, 465–472 (1997). · DOI
  32. Chant, J. Cell polarity in yeast. Annu. Rev. Cell Dev. Biol. 15, 365–391 (1999). · DOI
  33. Johnson, D. I. & Pringle, J. R. Molecular characterization of CDC42, a Saccharomyces cerevisiae gene involved in the development of cell polarity. J. Cell Biol. 111, 143–152 (1990). · DOI
  34. Leng, J., Klemke, R. L., Reddy, A. C. & Cheresh, D. A. Potentiation of cell migration by adhesion-dependent cooperative signals from the GTPase Rac and Raf kinase. J. Biol. Chem. 274, 37855–37861 (1999). · DOI
  35. Habets, G. G. et al. Identification of an invasion-inducing gene, Tiam-1, that encodes a protein with homology to GDP-GTP exchangers for Rho-like proteins. Cell 77, 537–549 (1994). · DOI
  36. Michiels, F., Habets, G. G. M., Stam, J. C., vanderKammen, R. A. & Collard, J. G. A function for rac in Tiam1-induced membrane ruffling and invasion. Nature 375, 338–340 (1995). · DOI
  37. Fukumoto, Y. et al. Molecular cloning and characterization of a novel type of regulatory protein (GDI) for the rho proteins, ras p21-like small GTP-binding proteins. Oncogene 5, 1321–1328 (1990).
  38. Moriyoshi, K., Richards, L. J., Akazawa, C., O'Leary, D. D. & Nakanishi, S. Labeling neural cells using adenoviral gene transfer of membrane- targeted GFP. Neuron 16, 255–260 (1996). · DOI
  39. del Pozo, M. A., Vicente-Manzanares, M., Tejedor, R., Serrador, J. M. & Sanchez-Madrid, F. Rho GTPases control migration and polarization of adhesion molecules and cytoskeletal ERM components in T lymphocytes. Eur. J. Immunol. 29, 3609–3620 (1999). · DOI
  40. Chamberlain, C. E., Kraynov, V. S. & Hahn, K. M. Imaging spatiotemporal dynamics of Rac activation in vivo with FLAIR. Methods Enzymol. 325, 389–400 (2000). · DOI
  41. Glaven, J. A., Whitehead, I., Bagrodia, S., Kay, R. & Cerione, R. A. The Dbl-related protein, Lfc, localizes to microtubules and mediates the activation of Rac signalling pathways in cells. J. Biol. Chem. 274, 2279–2285 (1999). · DOI · Paper page
  42. Gong, M. C. et al. Regulation by GDI of RhoA/Rho-kinase-induced Ca2+ sensitization of smooth muscle myosin II. Am. J. Physiol. Cell Physiol. 281, C257–C269 (2001). · DOI
  43. Read, P. W. & Nakamoto, R. K. Expression and purification of Rho/Rho-GDI complexes. Methods Enzymol. 325, 15–25 (2000). · DOI
  44. Renshaw, M. W., Ren, X.-D. & Schwartz, M. A. Growth factor activation of MAP kinase requires cell adhesion. EMBO J. 16, 5592–5599 (1997). · DOI
  45. Kiosses, W. B., Daniels, R. H., Otey, C., Bokoch, G. M. & Schwartz, M. A. A function for p21-activated kinase in endothelial cell migration. J. Cell. Biol. 147, 831–844 (1999). · DOI
  46. Chamberlain, C. & Hahn, K. M. Watching proteins in the wild: fluorescence methods to study protein dynamics in living cells. Traffic 1, 755–762 (2000). · DOI
  47. Chong, L. D., Traynor-Kaplan, A., Bokoch, G. M. & Schwartz, M. A. The small GTP-binding protein Rho regulates a phosphatidylinositol 4-phosphate 5-kinase in mammalian cells. Cell 79, 507–513 (1994). · DOI

Cited by

See all 287

Metadata

Authors
Del Pozo, M. A., Kiosses, W. B., Alderson, N. B., Meller, N., Hahn, K. M., & Schwartz, M. A.
Venue
Nature Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2002-02-25
Volume
4
Issue
3
Pages
232-239
ISSN
  • 1465-7392
  • 1476-4679
DOI
10.1038/ncb759
Cited by
287
References
0
Language
en
Licence
www.springer.com/tdm (tdm)

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

How to cite

Cite CoChat for the checks on this page, and the paper for its own findings.

This page
CoChat. (2026). Citation check: Integrins regulate GTP-Rac localized effector interactions through dissociation of Rho-GDI. https://app.cochat.ai/papers/10.1038/ncb759
The paper
Del Pozo, M. A., Kiosses, W. B., Alderson, N. B., Meller, N., Hahn, K. M., & Schwartz, M. A. (2002). Integrins regulate GTP-Rac localized effector interactions through dissociation of Rho-GDI. Nature Cell Biology. https://doi.org/10.1038/ncb759