Home LiteratureArticle Details
PMID: 10938112 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Coupling of PAK-interacting exchange factor PIX to GIT1 promotes focal complex disassembly.

Molecular and cellular biology ·Vol. 20 ·No. 17 ·2000-09-00 ·Pages 6354-63

Zhao ZS, Manser E, Loo TH, Lim L

Abstract

The p21-activated kinase PAK is targeted to focal complexes (FCs) through interactions with the SH3 domains of the PAK-interacting exchange factor PIX and Nck. PIX is a Rac GTP exchange factor that also binds the G-protein-coupled receptor kinase-interacting protein known as GIT1. Overexpression of GIT1 in fibroblasts or epithelial cells causes a loss of paxillin from FCs and stimulates cell motility. This is due to the direct interaction of a C-terminal 125-residue domain of GIT1 with paxillin, under the regulation of PIX. In its activated state, GIT1 can promote FC disassembly independent of actin-myosin contractile events. Additionally, GIT directly couples to a key component of FCs, focal adhesion kinase (FAK), via a conserved Spa2 homology domain. We propose that GIT1 and FAK cooperate to promote motility both by directly regulating focal complex dynamics and by the activation of Rac.

MeSH Terms
Adaptor Proteins, Signal Transducing Animals COS Cells Cell Cycle Proteins/chemistry,metabolism Cell Movement Chickens Cytoskeletal Proteins/metabolism Cytoskeleton/metabolism DNA, Complementary/metabolism Epithelial Cells/metabolism Fibroblasts/metabolism Fungal Proteins/metabolism GTPase-Activating Proteins/chemistry,metabolism,physiology Glutathione Transferase/metabolism Guanine Nucleotide Exchange Factors/metabolism HeLa Cells Humans Microscopy, Phase-Contrast Models, Biological Oncogene Proteins/metabolism Paxillin Phosphoproteins/metabolism Plasmids/metabolism Precipitin Tests Protein Binding Protein Serine-Threonine Kinases/metabolism Protein Structure, Tertiary Rho Guanine Nucleotide Exchange Factors Saccharomyces cerevisiae Proteins Signal Transduction Transfection p21-Activated Kinases rac GTP-Binding Proteins/metabolism src Homology Domains
Chemicals
Adaptor Proteins, Signal Transducing Cell Cycle Proteins Cytoskeletal Proteins DNA, Complementary Fungal Proteins GIT1 protein, human GTPase-Activating Proteins Guanine Nucleotide Exchange Factors Nck protein Oncogene Proteins PXN protein, human Paxillin Phosphoproteins Rho Guanine Nucleotide Exchange Factors SPA2 protein, S cerevisiae Saccharomyces cerevisiae Proteins Glutathione Transferase PAK1 protein, human Protein Serine-Threonine Kinases p21-Activated Kinases rac GTP-Binding Proteins
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Zhao Z S
Glaxo-IMCB Group, Institute of Molecular and Cell Biology, Singapore 117609, Singapore.
Manser E
Loo T H
Lim L
References (41)
41 references, click to expand
  1. Paxillin LD4 motif binds PAK and PIX through a novel 95-kD ankyrin repeat, ARF-GAP protein: A role in cytoskeletal remodeling.
    J Cell Biol. 1999 May 17;145(4):851-63 PMID: 10330411
  2. Serine and threonine phosphorylation of the paxillin LIM domains regulates paxillin focal adhesion localization and cell adhesion to fibronectin.
    Mol Biol Cell. 1998 Jul;9(7):1803-16 PMID: 9658172
  3. Required role of focal adhesion kinase (FAK) for integrin-stimulated cell migration.
    J Cell Sci. 1999 Aug;112 ( Pt 16):2677-91 PMID: 10413676
  4. A tyrosine-phosphorylated protein that binds to an important regulatory region on the cool family of p21-activated kinase-binding proteins.
    J Biol Chem. 1999 Aug 6;274(32):22393-400 PMID: 10428811
  5. Pak to the future.
    Trends Cell Biol. 1999 Sep;9(9):350-5 PMID: 10461188
  6. alphaPIX nucleotide exchange factor is activated by interaction with phosphatidylinositol 3-kinase.
    Oncogene. 1999 Oct 7;18(41):5680-90 PMID: 10523848
  7. A new paxillin-binding protein, PAG3/Papalpha/KIAA0400, bearing an ADP-ribosylation factor GTPase-activating protein activity, is involved in paxillin recruitment to focal adhesions and cell migration.
    Mol Biol Cell. 2000 Apr;11(4):1315-27 PMID: 10749932
  8. The Arf GTPase-activating protein ASAP1 regulates the actin cytoskeleton.
    Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4011-6 PMID: 10725410
  9. Interaction between PAK and nck: a template for Nck targets and role of PAK autophosphorylation.
    Mol Cell Biol. 2000 Jun;20(11):3906-17 PMID: 10805734
  10. Predicting coiled coils from protein sequences.
    Science. 1991 May 24;252(5009):1162-4 PMID: 2031185
  11. A brain serine/threonine protein kinase activated by Cdc42 and Rac1.
    Nature. 1994 Jan 6;367(6458):40-6 PMID: 8107774
  12. Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia.
    Cell. 1995 Apr 7;81(1):53-62 PMID: 7536630
  13. Overexpression of the focal adhesion kinase (p125FAK) in invasive human tumors.
    Cancer Res. 1995 Jul 1;55(13):2752-5 PMID: 7796399
  14. Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice.
    Nature. 1995 Oct 12;377(6549):539-44 PMID: 7566154
  15. Direct association of pp125FAK with paxillin, the focal adhesion-targeting mechanism of pp125FAK.
    J Exp Med. 1995 Oct 1;182(4):1089-99 PMID: 7561682
  16. Paxillin, a tyrosine phosphorylated focal adhesion-associated protein binds to the carboxyl terminal domain of focal adhesion kinase.
    Mol Biol Cell. 1995 Jun;6(6):637-47 PMID: 7579684
  17. A Drosophila homolog of the Rac- and Cdc42-activated serine/threonine kinase PAK is a potential focal adhesion and focal complex protein that colocalizes with dynamic actin structures.
    Mol Cell Biol. 1996 May;16(5):1896-908 PMID: 8628256
  18. Actin-based cell motility and cell locomotion.
    Cell. 1996 Feb 9;84(3):371-9 PMID: 8608590
  19. The p160 RhoA-binding kinase ROK alpha is a member of a kinase family and is involved in the reorganization of the cytoskeleton.
    Mol Cell Biol. 1996 Oct;16(10):5313-27 PMID: 8816443
  20. Inhibition of focal adhesion kinase (FAK) signaling in focal adhesions decreases cell motility and proliferation.
    Mol Biol Cell. 1996 Aug;7(8):1209-24 PMID: 8856665
  21. Identification of LIM3 as the principal determinant of paxillin focal adhesion localization and characterization of a novel motif on paxillin directing vinculin and focal adhesion kinase binding.
    J Cell Biol. 1996 Nov;135(4):1109-23 PMID: 8922390
  22. Expression of constitutively active alpha-PAK reveals effects of the kinase on actin and focal complexes.
    Mol Cell Biol. 1997 Mar;17(3):1129-43 PMID: 9032240
  23. Focal adhesion kinase: at the crossroads of signal transduction.
    J Cell Sci. 1997 Feb;110 ( Pt 4):401-7 PMID: 9067592
  24. Cell migration: may the force be with you.
    Curr Biol. 1997 May 1;7(5):R292-4 PMID: 9115390
  25. Mitosis specific serine phosphorylation and downregulation of one of the focal adhesion protein, paxillin.
    Oncogene. 1997 Oct 9;15(15):1753-61 PMID: 9362441
  26. Myotonic dystrophy kinase-related Cdc42-binding kinase acts as a Cdc42 effector in promoting cytoskeletal reorganization.
    Mol Cell Biol. 1998 Jan;18(1):130-40 PMID: 9418861
  27. Identification of p130Cas as a mediator of focal adhesion kinase-promoted cell migration.
    J Cell Biol. 1998 Jan 12;140(1):211-21 PMID: 9425168
  28. PAK promotes morphological changes by acting upstream of Rac.
    EMBO J. 1998 Aug 3;17(15):4328-39 PMID: 9687501
  29. Paxillin LD motifs may define a new family of protein recognition domains.
    Nat Struct Biol. 1998 Aug;5(8):677-8 PMID: 9699628
  30. A novel regulator of p21-activated kinases.
    J Biol Chem. 1998 Sep 11;273(37):23633-6 PMID: 9726964
  31. Integrin associated proteins.
    Curr Opin Cell Biol. 1998 Oct;10(5):578-85 PMID: 9818167
  32. beta2-Adrenergic receptor regulation by GIT1, a G protein-coupled receptor kinase-associated ADP ribosylation factor GTPase-activating protein.
    Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14082-7 PMID: 9826657
  33. The COOH-terminal domain of the focal adhesion kinase induces loss of adhesion and cell death in human tumor cells.
    Cell Growth Differ. 1998 Dec;9(12):999-1005 PMID: 9869300
  34. ARF1 mediates paxillin recruitment to focal adhesions and potentiates Rho-stimulated stress fiber formation in intact and permeabilized Swiss 3T3 fibroblasts.
    J Cell Biol. 1998 Dec 28;143(7):1981-95 PMID: 9864369
  35. Expression of the focal adhesion protein paxillin in lung cancer and its relation to cell motility.
    Oncogene. 1999 Jan 7;18(1):67-77 PMID: 9926921
  36. Inhibition of myosin light chain kinase by p21-activated kinase.
    Science. 1999 Mar 26;283(5410):2083-5 PMID: 10092231
  37. Bidirectional signaling between the cytoskeleton and integrins.
    Curr Opin Cell Biol. 1999 Apr;11(2):274-86 PMID: 10209151
  38. A conserved negative regulatory region in alphaPAK: inhibition of PAK kinases reveals their morphological roles downstream of Cdc42 and Rac1.
    Mol Cell Biol. 1998 Apr;18(4):2153-63 PMID: 9528787
  39. Spa2p interacts with cell polarity proteins and signaling components involved in yeast cell morphogenesis.
    Mol Cell Biol. 1998 Jul;18(7):4053-69 PMID: 9632790
  40. PAK kinases are directly coupled to the PIX family of nucleotide exchange factors.
    Mol Cell. 1998 Jan;1(2):183-92 PMID: 9659915
  41. Pak functions downstream of Dock to regulate photoreceptor axon guidance in Drosophila.
    Cell. 1999 Jun 25;97(7):853-63 PMID: 10399914
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.20.17.6354-6363.2000
Published
2000-09-00
Pages
6354-63
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC86110
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.20.17.6354-6363.2000 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2