How is integrin activation regulated?2017-12-26T15:35:23+00:00

How is integrin activation regulated?

Regulation of Integrin Activation

The following classes of proteins/ events are known to enhance or inhibit integrin activation in various contexts. It must be noted that this list provides just a few examples of proteins that regulate the activation of integrin.

Regulators of talin recruitment

Proteins with membrane targeting motif that bind to talin reviewed in [1]

i. Rap1 -RIAM (Talin activation) [2] [3][4]

ii. WAVE [5]

iii. Fam38A / r-Ras (Talin activation by calpain cleavage) [6]

Phosphorylation of integrin cytoplasmic domains

i. Tyr Phosphorylation -promote reduce talin affinity, promote Dok1 binding or other PTB domain proteins [7][8][9]

ii. PKA mediated Ser phosphorylation- α4β1 recruitment and activation at the leading edge [10][11]

iii. Src-kinase -mediated Tyr phosphorylation of beta integrin  ([8],reviewed in [12])- may not have downstream effect always [13]

Competitors for talin

i. Filamin and migfilin [14][15][16]

ii. CIB1 and its paralogues binding to α cytoplasmic tail [17][18]

iii. PIPKIγ90 [19][20][21]

ERK1 and ERK2

Trans-dominant inhibition of activation [22]

View All

Latest Findings

Protein Info

References

  1. Shattil SJ, Kim C, and Ginsberg MH. The final steps of integrin activation: the end game. Nat. Rev. Mol. Cell Biol. 2010; 11(4):288-300. [PMID: 20308986]
  2. Lafuente EM, van Puijenbroek AAFL, Krause M, Carman CV, Freeman GJ, Berezovskaya A, Constantine E, Springer TA, Gertler FB, and Boussiotis VA. RIAM, an Ena/VASP and Profilin ligand, interacts with Rap1-GTP and mediates Rap1-induced adhesion. Dev. Cell 2004; 7(4):585-95. [PMID: 15469846]
  3. Bos JL. Linking Rap to cell adhesion. Curr. Opin. Cell Biol. 2005; 17(2):123-8. [PMID: 15780587]
  4. Han J, Lim CJ, Watanabe N, Soriani A, Ratnikov B, Calderwood DA, Puzon-McLaughlin W, Lafuente EM, Boussiotis VA, Shattil SJ, and Ginsberg MH. Reconstructing and deconstructing agonist-induced activation of integrin alphaIIbbeta3. Curr. Biol. 2006; 16(18):1796-806. [PMID: 16979556]
  5. Nolz JC, Medeiros RB, Mitchell JS, Zhu P, Freedman BD, Shimizu Y, and Billadeau DD. WAVE2 regulates high-affinity integrin binding by recruiting vinculin and talin to the immunological synapse. Mol. Cell. Biol. 2007; 27(17):5986-6000. [PMID: 17591693]
  6. McHugh BJ, Buttery R, Lad Y, Banks S, Haslett C, and Sethi T. Integrin activation by Fam38A uses a novel mechanism of R-Ras targeting to the endoplasmic reticulum. J. Cell. Sci. 2010; 123(Pt 1):51-61. [PMID: 20016066]
  7. Tadokoro S, Shattil SJ, Eto K, Tai V, Liddington RC, de Pereda JM, Ginsberg MH, and Calderwood DA. Talin binding to integrin beta tails: a final common step in integrin activation. Science 2003; 302(5642):103-6. [PMID: 14526080]
  8. Anthis NJ, Haling JR, Oxley CL, Memo M, Wegener KL, Lim CJ, Ginsberg MH, and Campbell ID. Beta integrin tyrosine phosphorylation is a conserved mechanism for regulating talin-induced integrin activation. J. Biol. Chem. 2009; 284(52):36700-10. [PMID: 19843520]
  9. Oxley CL, Anthis NJ, Lowe ED, Vakonakis I, Campbell ID, and Wegener KL. An integrin phosphorylation switch: the effect of beta3 integrin tail phosphorylation on Dok1 and talin binding. J. Biol. Chem. 2007; 283(9):5420-6. [PMID: 18156175]
  10. Goldfinger LE, Han J, Kiosses WB, Howe AK, and Ginsberg MH. Spatial restriction of alpha4 integrin phosphorylation regulates lamellipodial stability and alpha4beta1-dependent cell migration. J. Cell Biol. 2003; 162(4):731-41. [PMID: 12913113]
  11. Lim CJ, Kain KH, Tkachenko E, Goldfinger LE, Gutierrez E, Allen MD, Groisman A, Zhang J, and Ginsberg MH. Integrin-mediated protein kinase A activation at the leading edge of migrating cells. Mol. Biol. Cell 2008; 19(11):4930-41. [PMID: 18784251]
  12. Gahmberg CG, Fagerholm SC, Nurmi SM, Chavakis T, Marchesan S, and Grönholm M. Regulation of integrin activity and signalling. Biochim. Biophys. Acta 2009; 1790(6):431-44. [PMID: 19289150]
  13. Meves A, Geiger T, Zanivan S, DiGiovanni J, Mann M, and Fässler R. Beta1 integrin cytoplasmic tyrosines promote skin tumorigenesis independent of their phosphorylation. Proc. Natl. Acad. Sci. U.S.A. 2011; 108(37):15213-8. [PMID: 21876123]
  14. Kiema T, Lad Y, Jiang P, Oxley CL, Baldassarre M, Wegener KL, Campbell ID, Ylänne J, and Calderwood DA. The molecular basis of filamin binding to integrins and competition with talin. Mol. Cell 2006; 21(3):337-47. [PMID: 16455489]
  15. Lad Y, Jiang P, Ruskamo S, Harburger DS, Ylänne J, Campbell ID, and Calderwood DA. Structural basis of the migfilin-filamin interaction and competition with integrin beta tails. J. Biol. Chem. 2008; 283(50):35154-63. [PMID: 18829455]
  16. Ithychanda SS, Das M, Ma Y, Ding K, Wang X, Gupta S, Wu C, Plow EF, and Qin J. Migfilin, a molecular switch in regulation of integrin activation. J. Biol. Chem. 2008; 284(7):4713-22. [PMID: 19074766]
  17. Yuan W, Leisner TM, McFadden AW, Wang Z, Larson MK, Clark S, Boudignon-Proudhon C, Lam SC, and Parise LV. CIB1 is an endogenous inhibitor of agonist-induced integrin alphaIIbbeta3 activation. J. Cell Biol. 2006; 172(2):169-75. [PMID: 16418530]
  18. Denofrio JC, Yuan W, Temple BR, Gentry HR, and Parise LV. Characterization of calcium- and integrin-binding protein 1 (CIB1) knockout platelets: potential compensation by CIB family members. Thromb. Haemost. 2008; 100(5):847-56. [PMID: 18989529]
  19. Martel V, Racaud-Sultan C, Dupe S, Marie C, Paulhe F, Galmiche A, Block MR, and Albiges-Rizo C. Conformation, localization, and integrin binding of talin depend on its interaction with phosphoinositides. J. Biol. Chem. 2001; 276(24):21217-27. [PMID: 11279249]
  20. Ling K, Doughman RL, Iyer VV, Firestone AJ, Bairstow SF, Mosher DF, Schaller MD, and Anderson RA. Tyrosine phosphorylation of type Igamma phosphatidylinositol phosphate kinase by Src regulates an integrin-talin switch. J. Cell Biol. 2003; 163(6):1339-49. [PMID: 14691141]
  21. Calderwood DA, Tai V, Di Paolo G, De Camilli P, and Ginsberg MH. Competition for talin results in trans-dominant inhibition of integrin activation. J. Biol. Chem. 2004; 279(28):28889-95. [PMID: 15143061]
  22. Harburger DS, Bouaouina M, and Calderwood DA. Kindlin-1 and -2 directly bind the C-terminal region of beta integrin cytoplasmic tails and exert integrin-specific activation effects. J. Biol. Chem. 2009; 284(17):11485-97. [PMID: 19240021]