Cytoskeleton remodeling - Fibronectin-binding integrins in cell motility

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Fibronectin-binding integrins in cell motility

Fibronectin-binding integrins such as alpha-5/beta-1 and alpha-V/beta-3 can promote different aspects of cell migration. Adhesion to fibronectin by alpha-V/beta-3 integrins supports persistent migration, whereas alpha-5/beta-1 integrins promote random migration [1].

Integrin clustering induces focal adhesion kinase (FAK1) autophosphorylation, which creates a binding site for the proto-oncogene tyrosine-protein kinase Src (c-Src). c-Src-mediated phosphorylation of FAK1 promotes its maximal catalytic activity. The integrin-binding protein talin recruits FAK1 and vinculin to focal contacts. Alpha-actinin is a cytoskeletal protein that binds to vinculin and crosslinks actin in actomyosin stress fibres and tethers them to the focal contacts. Phosphorylation of alpha-actinin by FAK1 reduces the crosslinking of stress fibres and prevents the maturation of focal contacts [2]. Vinculin transiently recruits the actin-related protein complex Arp2/3 to new sites of integrin aggregation [3]. Arp2/3 complex nucleates new actin filaments from the sides of preexisting filaments. This interaction requires phosphorylation of Arp2/3 complex by PAK1 (p21-activated kinase 1), which promotes actin polymerization [4], [5].

FAK1 plays a key role in the control of focal adhesion dynamics and cell migration under the regulation of small GTPases of Rho family (Rac1, Cdc42 and Rho-A) [2], [6]. RhoA downstream effector ROCK (protein Rho-associated kinase) directly phosphorylates LIMK1 and LIMK2 (LIM-kinases), which in turn phosphorylate cofilin (actin-associated protein). Cofilin exhibits actin-depolymerizing activity followed by reorganization of the actin cytoskeleton [7].

Activity of LIMK1 is also regulated by PAK1, the downstream effector of Rac1 and Cdc42 [8]. Cdc42 effector N-WASP (a homolog to the Wiskott-Aldrich syndrome protein) [9] regulates actin polymerization by stimulating the actin-nucleating activity of the Arp2/3 complex [5].

The Arp2/3 complex and cofilin are involved in the generation of propulsive force at the leading edge: the severing activity of cofilin and the branching activity of Arp2/3 act in synergy to drive the extension of lamellipodia. Cofilin is also required for the maintenance of a polarized cytoskeleton and thus for directional cell migration [1].

It was shown that the persistent mode of migration of cells bound to fibronectin by alpha-V/beta-3 integrins is associated with relatively high levels of cofilin activity and low levels of RhoA activity. Adhesion by alpha-5/beta-1 instead stimulates an increase in RhoA-mediated phosphorylation of cofilin and supports random cell migration [1].

Integrin signaling is mediated by distinct and separable interactions of the integrin beta tails. c-Src was shown to bind constitutively and selectively to beta3 integrins [10]. c-Src could, in turn, phosphorylate and stimulate GTPase-activating protein (GAP) p190 RhoGAP. The GAP activity of RhoGAP is specific for RhoA inhibition [11].

Vav1, a guanine nucleotide exchange factor for Rac1, Cdc42 and Rho-A, that stimulates the exchange of bound GDP for GTP, was shown to stimulate preferentially Rac1 and RhoA under integrin alpha-v/beta-3-mediated adhesion of hematopoietic cells, but this effect was investigated on vitronectin substrate [12].

Tyrosine kinase Fyn could phosphorylate and activate Vav1 [13]. Caveolin-1 was shown to function as a membrane adaptor to link the integrin alpha-5 or alpha-v subunit to the Fyn [14]. Vav1 activity is directly controlled by substrates and products of phosphatidylinositol 3-kinase (PI3K). Phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) inhibits activation of Vav1, whereas the product phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3) enhances phosphorylation and activation of Vav1 [15]. FAK1 activation may lead to its association with the regulatory subunit of PI3K (PI3K reg p85), which can subsequently activate PI3K during cell adhesion [16], [17]. PI3K reg p85 could also associate with Vav1 in some types of cells [18].

The protein Nischarin was found to bind preferentially to the cytoplasmic tail of the integrin alpha-5 subunit and to inhibit cell migration [19]. Nischarin was not found in focal adhesion sites, suggesting that it binds to integrins when they are not ligated by the proteins of the extracellular matrix. Once the integrins enter into adhesion sites, Nischarin is released, allowing it to bind to the activated PAK1. This binding is enhanced by active Rac1. Interaction with Nischarin strongly inhibits the ability of PAK1 to phosphorylate substrates and this effect closely parallels Nischarin's ability to inhibit cell motility [20], [21].

References:

  1. Danen EH, van Rheenen J, Franken W, Huveneers S, Sonneveld P, Jalink K, Sonnenberg A
    Integrins control motile strategy through a Rho-cofilin pathway. The Journal of cell biology 2005 May 9;169(3):515-26
  2. Mitra SK, Hanson DA, Schlaepfer DD
    Focal adhesion kinase: in command and control of cell motility. Nature reviews. Molecular cell biology 2005 Jan;6(1):56-68
  3. DeMali KA, Barlow CA, Burridge K
    Recruitment of the Arp2/3 complex to vinculin: coupling membrane protrusion to matrix adhesion. The Journal of cell biology 2002 Dec 9;159(5):881-91
  4. Vadlamudi RK, Li F, Barnes CJ, Bagheri-Yarmand R, Kumar R
    p41-Arc subunit of human Arp2/3 complex is a p21-activated kinase-1-interacting substrate. EMBO reports 2004 Feb;5(2):154-60
  5. Dayel MJ, Mullins RD
    Activation of Arp2/3 complex: addition of the first subunit of the new filament by a WASP protein triggers rapid ATP hydrolysis on Arp2. PLoS biology 2004 Apr;2(4):E91
  6. Parsons JT, Martin KH, Slack JK, Taylor JM, Weed SA
    Focal adhesion kinase: a regulator of focal adhesion dynamics and cell movement. Oncogene 2000 Nov 20;19(49):5606-13
  7. Maekawa M, Ishizaki T, Boku S, Watanabe N, Fujita A, Iwamatsu A, Obinata T, Ohashi K, Mizuno K, Narumiya S
    Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science (New York, N.Y.) 1999 Aug 6;285(5429):895-8
  8. Sumi T, Matsumoto K, Nakamura T
    Specific activation of LIM kinase 2 via phosphorylation of threonine 505 by ROCK, a Rho-dependent protein kinase. The Journal of biological chemistry 2001 Jan 5;276(1):670-6
  9. Parsons M, Monypenny J, Ameer-Beg SM, Millard TH, Machesky LM, Peter M, Keppler MD, Schiavo G, Watson R, Chernoff J, Zicha D, Vojnovic B, Ng T
    Spatially distinct binding of Cdc42 to PAK1 and N-WASP in breast carcinoma cells. Molecular and cellular biology 2005 Mar;25(5):1680-95
  10. Arias-Salgado EG, Lizano S, Sarkar S, Brugge JS, Ginsberg MH, Shattil SJ
    Src kinase activation by direct interaction with the integrin beta cytoplasmic domain. Proceedings of the National Academy of Sciences of the United States of America 2003 Nov 11;100(23):13298-302
  11. Roof RW, Haskell MD, Dukes BD, Sherman N, Kinter M, Parsons SJ
    Phosphotyrosine (p-Tyr)-dependent and -independent mechanisms of p190 RhoGAP-p120 RasGAP interaction: Tyr 1105 of p190, a substrate for c-Src, is the sole p-Tyr mediator of complex formation. Molecular and cellular biology 1998 Dec;18(12):7052-63
  12. Gao C, Schaefer E, Lakkis M, Blystone SD
    Beta3 tyrosine phosphorylation and alphavbeta3-mediated adhesion are required for Vav1 association and Rho activation in leukocytes. The Journal of biological chemistry 2005 Apr 15;280(15):15422-9
  13. Michel F, Grimaud L, Tuosto L, Acuto O
    Fyn and ZAP-70 are required for Vav phosphorylation in T cells stimulated by antigen-presenting cells. The Journal of biological chemistry 1998 Nov 27;273(48):31932-8
  14. Wary KK, Mariotti A, Zurzolo C, Giancotti FG
    A requirement for caveolin-1 and associated kinase Fyn in integrin signaling and anchorage-dependent cell growth. Cell 1998 Sep 4;94(5):625-34
  15. Han J, Luby-Phelps K, Das B, Shu X, Xia Y, Mosteller RD, Krishna UM, Falck JR, White MA, Broek D
    Role of substrates and products of PI 3-kinase in regulating activation of Rac-related guanosine triphosphatases by Vav. Science (New York, N.Y.) 1998 Jan 23;279(5350):558-60
  16. Chen HC, Appeddu PA, Isoda H, Guan JL
    Phosphorylation of tyrosine 397 in focal adhesion kinase is required for binding phosphatidylinositol 3-kinase. The Journal of biological chemistry 1996 Oct 18;271(42):26329-34
  17. Shen TL, Guan JL
    Differential regulation of cell migration and cell cycle progression by FAK complexes with Src, PI3K, Grb7 and Grb2 in focal contacts. FEBS letters 2001 Jun 15;499(1-2):176-81
  18. Weng WK, Jarvis L, LeBien TW
    Signaling through CD19 activates Vav/mitogen-activated protein kinase pathway and induces formation of a CD19/Vav/phosphatidylinositol 3-kinase complex in human B cell precursors. The Journal of biological chemistry 1994 Dec 23;269(51):32514-21
  19. Alahari SK, Lee JW, Juliano RL
    Nischarin, a novel protein that interacts with the integrin alpha5 subunit and inhibits cell migration. The Journal of cell biology 2000 Dec 11;151(6):1141-54
  20. Juliano RL, Reddig P, Alahari S, Edin M, Howe A, Aplin A
    Integrin regulation of cell signalling and motility. Biochemical Society transactions 2004 Jun;32(Pt3):443-6
  21. Alahari SK, Reddig PJ, Juliano RL
    The integrin-binding protein Nischarin regulates cell migration by inhibiting PAK. The EMBO journal 2004 Jul 21;23(14):2777-88

  1. Danen EH, van Rheenen J, Franken W, Huveneers S, Sonneveld P, Jalink K, Sonnenberg A
    Integrins control motile strategy through a Rho-cofilin pathway. The Journal of cell biology 2005 May 9;169(3):515-26
  2. Mitra SK, Hanson DA, Schlaepfer DD
    Focal adhesion kinase: in command and control of cell motility. Nature reviews. Molecular cell biology 2005 Jan;6(1):56-68
  3. DeMali KA, Barlow CA, Burridge K
    Recruitment of the Arp2/3 complex to vinculin: coupling membrane protrusion to matrix adhesion. The Journal of cell biology 2002 Dec 9;159(5):881-91
  4. Vadlamudi RK, Li F, Barnes CJ, Bagheri-Yarmand R, Kumar R
    p41-Arc subunit of human Arp2/3 complex is a p21-activated kinase-1-interacting substrate. EMBO reports 2004 Feb;5(2):154-60
  5. Dayel MJ, Mullins RD
    Activation of Arp2/3 complex: addition of the first subunit of the new filament by a WASP protein triggers rapid ATP hydrolysis on Arp2. PLoS biology 2004 Apr;2(4):E91
  6. Parsons JT, Martin KH, Slack JK, Taylor JM, Weed SA
    Focal adhesion kinase: a regulator of focal adhesion dynamics and cell movement. Oncogene 2000 Nov 20;19(49):5606-13
  7. Maekawa M, Ishizaki T, Boku S, Watanabe N, Fujita A, Iwamatsu A, Obinata T, Ohashi K, Mizuno K, Narumiya S
    Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science (New York, N.Y.) 1999 Aug 6;285(5429):895-8
  8. Sumi T, Matsumoto K, Nakamura T
    Specific activation of LIM kinase 2 via phosphorylation of threonine 505 by ROCK, a Rho-dependent protein kinase. The Journal of biological chemistry 2001 Jan 5;276(1):670-6
  9. Parsons M, Monypenny J, Ameer-Beg SM, Millard TH, Machesky LM, Peter M, Keppler MD, Schiavo G, Watson R, Chernoff J, Zicha D, Vojnovic B, Ng T
    Spatially distinct binding of Cdc42 to PAK1 and N-WASP in breast carcinoma cells. Molecular and cellular biology 2005 Mar;25(5):1680-95
  10. Arias-Salgado EG, Lizano S, Sarkar S, Brugge JS, Ginsberg MH, Shattil SJ
    Src kinase activation by direct interaction with the integrin beta cytoplasmic domain. Proceedings of the National Academy of Sciences of the United States of America 2003 Nov 11;100(23):13298-302
  11. Roof RW, Haskell MD, Dukes BD, Sherman N, Kinter M, Parsons SJ
    Phosphotyrosine (p-Tyr)-dependent and -independent mechanisms of p190 RhoGAP-p120 RasGAP interaction: Tyr 1105 of p190, a substrate for c-Src, is the sole p-Tyr mediator of complex formation. Molecular and cellular biology 1998 Dec;18(12):7052-63
  12. Gao C, Schaefer E, Lakkis M, Blystone SD
    Beta3 tyrosine phosphorylation and alphavbeta3-mediated adhesion are required for Vav1 association and Rho activation in leukocytes. The Journal of biological chemistry 2005 Apr 15;280(15):15422-9
  13. Michel F, Grimaud L, Tuosto L, Acuto O
    Fyn and ZAP-70 are required for Vav phosphorylation in T cells stimulated by antigen-presenting cells. The Journal of biological chemistry 1998 Nov 27;273(48):31932-8
  14. Wary KK, Mariotti A, Zurzolo C, Giancotti FG
    A requirement for caveolin-1 and associated kinase Fyn in integrin signaling and anchorage-dependent cell growth. Cell 1998 Sep 4;94(5):625-34
  15. Han J, Luby-Phelps K, Das B, Shu X, Xia Y, Mosteller RD, Krishna UM, Falck JR, White MA, Broek D
    Role of substrates and products of PI 3-kinase in regulating activation of Rac-related guanosine triphosphatases by Vav. Science (New York, N.Y.) 1998 Jan 23;279(5350):558-60
  16. Chen HC, Appeddu PA, Isoda H, Guan JL
    Phosphorylation of tyrosine 397 in focal adhesion kinase is required for binding phosphatidylinositol 3-kinase. The Journal of biological chemistry 1996 Oct 18;271(42):26329-34
  17. Shen TL, Guan JL
    Differential regulation of cell migration and cell cycle progression by FAK complexes with Src, PI3K, Grb7 and Grb2 in focal contacts. FEBS letters 2001 Jun 15;499(1-2):176-81
  18. Weng WK, Jarvis L, LeBien TW
    Signaling through CD19 activates Vav/mitogen-activated protein kinase pathway and induces formation of a CD19/Vav/phosphatidylinositol 3-kinase complex in human B cell precursors. The Journal of biological chemistry 1994 Dec 23;269(51):32514-21
  19. Alahari SK, Lee JW, Juliano RL
    Nischarin, a novel protein that interacts with the integrin alpha5 subunit and inhibits cell migration. The Journal of cell biology 2000 Dec 11;151(6):1141-54
  20. Juliano RL, Reddig P, Alahari S, Edin M, Howe A, Aplin A
    Integrin regulation of cell signalling and motility. Biochemical Society transactions 2004 Jun;32(Pt3):443-6
  21. Alahari SK, Reddig PJ, Juliano RL
    The integrin-binding protein Nischarin regulates cell migration by inhibiting PAK. The EMBO journal 2004 Jul 21;23(14):2777-88

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