Skip to main content

Advertisement

SpringerLink
Log in

Cooperative signaling between integrins and growth factor receptors in fibrosis

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Fibrosis is a pathological process characterized by accumulation of fibrous connective tissue in organs, leading to organ malfunction and failure. At the cellular level, tissue injury or cellular stress results in aberrant and/or sustained fibroblast “activation” leading to excessive extracellular matrix (ECM) accumulation and remodeling, as well as abnormal crosstalk with other cell types. Fibroblast functions within the fibrotic milieu are broad and complex, but among the most prominent are regulation of tissue architecture via modulation of ECM deposition and synthesis, and production of, activation of, and response to growth factors. Thus, both integrins and growth factor receptors (GFRs) play critical roles in fibroblast orchestration of tissue remodeling. However, the interplay between integrins and GFRs in this context is not fully understood. Their interaction has been described for other diseases, such as cancer. Here, we review the literature relevant to integrin/GFR interactions in the context of fibrosis, classify the known interactions into broad categories, and discuss research opportunities that may yield novel therapeutic targets for a broad range of debilitating chronic diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Protein and gene information for Fig. 3 were obtained from the UniProt database (https://www.uniprot.org). The software used to develop networking analysis was Cytoscape 3.7 (free source https://cytoscape.org/).

References

  1. Wynn TA (2008) Cellular and molecular mechanisms of fibrosis. J Pathol 214(2):199–210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wynn TA, Ramalingam TR (2012) Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med 18(7):1028–1040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Olson AL, Gifford AH, Inase N, Fernández Pérez ER, Suda T (2018) The epidemiology of idiopathic pulmonary fibrosis and interstitial lung diseases at risk of a progressive-fibrosing phenotype. Eur Respir Rev 27(150):180077

    Article  PubMed  Google Scholar 

  4. Kendall RT, Feghali-Bostwick CA (2014) Fibroblasts in fibrosis: novel roles and mediators. Front Pharmacol 5:123–123

    Article  PubMed  PubMed Central  Google Scholar 

  5. Darby IA, Hewitson TD (2007) Fibroblast differentiation in wound healing and fibrosis, International Review of Cytology, Academic Press, pp. 143–179

  6. Waters DW, Blokland KEC, Pathinayake PS, Burgess JK, Mutsaers SE, Prele CM, Schuliga M, Grainge CL, Knight DA (2018) Fibroblast senescence in the pathology of idiopathic pulmonary fibrosis. Am J Phys Lung Cell Mol Phys 315(2):L162–l172

    CAS  Google Scholar 

  7. Fiore VF, Strane PW, Bryksin AV, White ES, Hagood JS, Barker TH (2015) Conformational coupling of integrin and Thy-1 regulates Fyn priming and fibroblast mechanotransduction. J Cell Biol 211(1):173–190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Fiore VF, Wong SS, Tran C, Tan C, Xu W, Sulchek T, White ES, Hagood JS, Barker TH (2018) αvβ3 integrin drives fibroblast contraction and strain stiffening of soft provisional matrix during progressive fibrosis. JCI insight 3(20):e97597

    Article  PubMed Central  Google Scholar 

  9. DeLeon-Pennell KY, Barker TH, Lindsey ML (2020) Fibroblasts: the arbiters of extracellular matrix remodeling. Matrix Biol 91-92:1–7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Barker TH, Engler AJ (2017) The provisional matrix: setting the stage for tissue repair outcomes. Matrix Biol 60-61:1–4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Saied EM, Bediwy AS (2011) Expression of epidermal growth factor receptor (EGFR) in the bronchial epithelium of patients with chronic obstructive pulmonary disease (COPD). Eur Respir J 38(Suppl 55):p3823

    Google Scholar 

  12. Vallath S, Hynds RE, Succony L, Janes SM, Giangreco A (2014) Targeting EGFR signalling in chronic lung disease: therapeutic challenges and opportunities. Eur Respir J 44(2):513–522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Henderson NC, Sheppard D (2013) Integrin-mediated regulation of TGFβ in fibrosis. Biochim Biophys Acta 1832(7):891–896

    Article  CAS  PubMed  Google Scholar 

  14. Margadant C, Sonnenberg A (2010) Integrin-TGF-beta crosstalk in fibrosis, cancer and wound healing. EMBO Rep 11(2):97–105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chen X, Whiting C, Borza C, Hu W, Mont S, Bulus N, Zhang M-Z, Harris RC, Zent R, Pozzi A (2010) Integrin alpha1beta1 regulates epidermal growth factor receptor activation by controlling peroxisome proliferator-activated receptor gamma-dependent caveolin-1 expression. Mol Cell Biol 30(12):3048–3058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ivaska J, Heino J (2011) Cooperation between integrins and growth factor receptors in signaling and endocytosis. Annu Rev Cell Dev Biol 27(1):291–320

    Article  CAS  PubMed  Google Scholar 

  17. Takada Y, Takada YK, Fujita M (2017) Crosstalk between insulin-like growth factor (IGF) receptor and integrins through direct integrin binding to IGF1. Cytokine Growth Factor Rev 34:67–72

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Thomas JR, Paul NR, Morgan MR (2019) Adhesion and growth factor receptor crosstalk mechanisms controlling cell migration. Essays Biochem 63(5):553–567

    Article  CAS  PubMed  Google Scholar 

  19. Hynes RO (2002) Integrins: bidirectional. Allosteric Signaling Machines, Cell 110(6):673–687

    CAS  PubMed  Google Scholar 

  20. Harburger DS, Calderwood DA (2009) Integrin signalling at a glance. J Cell Sci 122(2):159–163

    Article  CAS  PubMed  Google Scholar 

  21. Kechagia JZ, Ivaska J, Roca-Cusachs P (2019) Integrins as biomechanical sensors of the microenvironment. Nat Rev Mol Cell Biol 20(8):457–473

    Article  CAS  PubMed  Google Scholar 

  22. Hermosilla T, Muñoz D, Herrera-Molina R, Valdivia A, Muñoz N, Nham SU, Schneider P, Burridge K, Quest AF, Leyton L (2008) Direct Thy-1/alphaVbeta3 integrin interaction mediates neuron to astrocyte communication. Biochim Biophys Acta 1783(6):1111–1120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Manninen A, Varjosalo M (2017) A proteomics view on integrin-mediated adhesions. Proteomics 17(3–4)

  24. Humphries JD, Byron A, Humphries MJ (2006) Integrin ligands at a glance. J Cell Sci 119(19):3901–3903

    Article  CAS  PubMed  Google Scholar 

  25. Leyton L, Díaz J, Martínez S, Palacios E, Pérez LA, Pérez RD (2019) Thy-1/CD90 a bidirectional and lateral signaling scaffold. Front Cell Dev Biol 7:132

    Article  PubMed  PubMed Central  Google Scholar 

  26. Maldonado H, Calderon C, Burgos-Bravo F, Kobler O, Zuschratter W, Ramirez O, Härtel S, Schneider P, Quest AF, Herrera-Molina R, Leyton L (2017) Astrocyte-to-neuron communication through integrin-engaged Thy-1/CBP/Csk/Src complex triggers neurite retraction via the RhoA/ROCK pathway. Biochim Biophys Acta, Mol Cell Res 1864(2):243–254

    Article  CAS  Google Scholar 

  27. Avalos AM, Valdivia AD, Muñoz N, Herrera-Molina R, Tapia JC, Lavandero S, Chiong M, Burridge K, Schneider P, Quest AF, Leyton L (2009) Neuronal Thy-1 induces astrocyte adhesion by engaging syndecan-4 in a cooperative interaction with alphavbeta3 integrin that activates PKCalpha and RhoA. J Cell Sci 122(Pt 19):3462–3471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jiao Y, Feng X, Zhan Y, Wang R, Zheng S, Liu W, Zeng X (2012) Matrix metalloproteinase-2 promotes αvβ3 integrin-mediated adhesion and migration of human melanoma cells by cleaving fibronectin. PLoS One 7(7):e41591–e41591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Borrirukwanit K, Lafleur MA, Mercuri FA, Blick T, Price JT, Fridman R, Pereira JJ, Leardkamonkarn V, Thompson EW (2007) The type I collagen induction of MT1-MMP-mediated MMP-2 activation is repressed by alphaVbeta3 integrin in human breast cancer cells. Matrix Biol 26(4):291–305

    Article  CAS  PubMed  Google Scholar 

  30. Morozevich G, Kozlova N, Cheglakov I, Ushakova N, Berman A (2009) Integrin α5β1 controls invasion of human breast carcinoma cells by direct and indirect modulation of MMP-2 collagenase activity. Cell Cycle 8(14):2219–2225

    Article  CAS  PubMed  Google Scholar 

  31. Abdalla M, Thompson L, Gurley E, Burke S, Ujjin J, Newsome R, Somanath PR (2015) Dasatinib inhibits TGFβ-induced myofibroblast differentiation through Src-SRF pathway. Eur J Pharmacol 769:134–142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lawson C, Schlaepfer DD (2012) Integrin adhesions: who’s on first? What’s on second? Connections between FAK and talin, Cell Adhes Migr 6(4) 302–306

  33. Nagano M, Hoshino D, Koshikawa N, Akizawa T, Seiki M (2012) Turnover of focal adhesions and cancer cell migration. Int J Cell Biol 2012:310616

    Article  PubMed  PubMed Central  Google Scholar 

  34. Nardone G, Oliver-De La Cruz J, Vrbsky J, Martini C, Pribyl J, Skládal P, Pešl M, Caluori G, Pagliari S, Martino F, Maceckova Z, Hajduch M, Sanz-Garcia A, Pugno NM, Stokin GB, Forte G (2017) YAP regulates cell mechanics by controlling focal adhesion assembly. Nat Commun 8:15321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Rausch V, Hansen CG (2020) The hippo pathway, YAP/TAZ, and the plasma membrane. Trends Cell Biol 30(1):32–48

    Article  CAS  PubMed  Google Scholar 

  36. Balasubramanian S, Quinones L, Kasiganesan H, Zhang Y, Pleasant DL, Sundararaj KP, Zile MR, Bradshaw AD, Kuppuswamy D (2012) β3 integrin in cardiac fibroblast is critical for extracellular matrix accumulation during pressure overload hypertrophy in mouse. PLoS One 7(9):e45076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chen C, Li R, Ross RS, Manso AM (2016) Integrins and integrin-related proteins in cardiac fibrosis. J Mol Cell Cardiol 93:162–174

    Article  CAS  PubMed  Google Scholar 

  38. Conroy KP, Kitto LJ, Henderson NC (2016) alphav integrins: key regulators of tissue fibrosis. Cell Tissue Res 365(3):511–519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Perrucci GL, Barbagallo VA, Corliano M, Tosi D, Santoro R, Nigro P, Poggio P, Bulfamante G, Lombardi F, Pompilio G (2018) Integrin alphanubeta5 in vitro inhibition limits pro-fibrotic response in cardiac fibroblasts of spontaneously hypertensive rats. J Transl Med 16(1):352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Perrucci GL, Barbagallo VA, Corlianò M, Tosi D, Santoro R, Nigro P, Poggio P, Bulfamante G, Lombardi F, Pompilio G (2018) Integrin ανβ5 in vitro inhibition limits pro-fibrotic response in cardiac fibroblasts of spontaneously hypertensive rats. J Transl Med 16(1):352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Schnittert J, Bansal R, Storm G, Prakash J (2018) Integrins in wound healing, fibrosis and tumor stroma: high potential targets for therapeutics and drug delivery. Adv Drug Deliv Rev 129:37–53

    Article  CAS  PubMed  Google Scholar 

  42. Coelho NM, McCulloch CA (2016) Contribution of collagen adhesion receptors to tissue fibrosis. Cell Tissue Res 365(3):521–538

    Article  CAS  PubMed  Google Scholar 

  43. Heino J (2014) Cellular signaling by collagen-binding integrins, in: D. Gullberg (Ed.), I Domain integrins, Springer Netherlands, Dordrecht, pp. 143–155

  44. Lu P, Takai K, Weaver VM, Werb Z (2011) Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb Perspect Biol 3(12):a005058

    Article  PubMed  PubMed Central  Google Scholar 

  45. Kagami S, Kondo S, Löster K, Reutter W, Kuhara T, Yasutomo K, Kuroda Y (1999) α1β1 integrin-mediated collagen matrix remodeling by rat mesangial cells is differentially regulated by transforming growth factor-β and platelet-derived growth factor-BB. J Am Soc Nephrol 10(4):779–789

    Article  CAS  PubMed  Google Scholar 

  46. Yang C, Zeisberg M, Lively JC, Nyberg P, Afdhal N, Kalluri R (2003) Integrin α1β1 and α2β1 are the key regulators of hepatocarcinoma cell invasion across the fibrotic matrix microenvironment. Cancer Res 63(23):8312–8317

    CAS  PubMed  Google Scholar 

  47. Gardner H, Broberg A, Pozzi A, Laato M, Heino J (1999) Absence of integrin alpha1beta1 in the mouse causes loss of feedback regulation of collagen synthesis in normal and wounded dermis. J Cell Sci 112(Pt 3):263–272

    Article  CAS  PubMed  Google Scholar 

  48. Chen X, Abair TD, Ibanez MR, Su Y, Frey MR, Dise RS, Polk DB, Singh AB, Harris RC, Zent R, Pozzi A (2007) Integrin alpha1beta1 controls reactive oxygen species synthesis by negatively regulating epidermal growth factor receptor-mediated Rac activation. Mol Cell Biol 27(9):3313–3326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Rubel D, Frese J, Martin M, Leibnitz A, Girgert R, Miosge N, Eckes B, Müller G-A, Gross O (2014) Collagen receptors integrin alpha2beta1 and discoidin domain receptor 1 regulate maturation of the glomerular basement membrane and loss of integrin alpha2beta1 delays kidney fibrosis in COL4A3 knockout mice. Matrix Biol 34:13–21

    Article  CAS  PubMed  Google Scholar 

  50. Chen X, Moeckel G, Morrow JD, Cosgrove D, Harris RC, Fogo AB, Zent R, Pozzi A (2004) Lack of integrin alpha1beta1 leads to severe glomerulosclerosis after glomerular injury. Am J Pathol 165(2):617–630

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Borok Z (2009) Role for alpha3 integrin in EMT and pulmonary fibrosis. J Clin Invest 119(1):7–10

    CAS  PubMed  Google Scholar 

  52. Bansal R, Nakagawa S, Yazdani S, van Baarlen J, Venkatesh A, Koh AP, Song W-M, Goossens N, Watanabe H, Beasley MB, Powell CA, Storm G, Kaminski N, van Goor H, Friedman SL, Hoshida Y, Prakash J (2017) Integrin alpha 11 in the regulation of the myofibroblast phenotype: implications for fibrotic diseases. Exp Mol Med 49(11):e396–e396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Dewidar B, Meyer C, Dooley S, Meindl B, Nadja (2019) TGF-β in hepatic stellate cell activation and liver fibrogenesis-updated 2019. Cells 8(11):1419

    Article  CAS  PubMed Central  Google Scholar 

  54. Giannandrea M, Parks WC (2014) Diverse functions of matrix metalloproteinases during fibrosis. Dis Model Mech 7(2):193–203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ravanti L, Heino J, López-Otinin C, Kähäri V-M (1999) Induction of collagenase-3 (MMP-13) expression in human skin fibroblasts by three-dimensional collagen is mediated by p38 mitogen-activated protein kinase. J Biol Chem 274(4):2446–2455

    Article  CAS  PubMed  Google Scholar 

  56. Zigrino P, Drescher C, Mauch C (2001) Collagen-induced proMMP-2 activation by MT1-MMP in human dermal fibroblasts and the possible role of α2β1 integrins. Eur J Cell Biol 80(1):68–77

    Article  CAS  PubMed  Google Scholar 

  57. Brilha S, Chong DLW, Khawaja AA, Ong CWM, Guppy NJ, Porter JC, Friedland JS (2018) Integrin α2β1 expression regulates matrix metalloproteinase-1-dependent bronchial epithelial repair in pulmonary tuberculosis. Front Immunol 9:1348–1348

    Article  PubMed  PubMed Central  Google Scholar 

  58. Hung CF, Wilson CL, Chow Y-H, Schnapp LM (2018) Role of integrin alpha8 in murine model of lung fibrosis. PLoS One 13(5):e0197937–e0197937

    Article  PubMed  PubMed Central  Google Scholar 

  59. Song K-H, Cho S-J, Song J-Y (2016) αvβ1 integrin as a novel therapeutic target for tissue fibrosis. Ann Transl Med 4(20):411–411

    Article  PubMed  PubMed Central  Google Scholar 

  60. Tatler AL, Goodwin AT, Gbolahan O, Saini G, Porte J, John AE, Clifford RL, Violette SM, Weinreb PH, Parfrey H, Wolters PJ, Gauldie J, Kolb M, Jenkins G (2016) Amplification of TGFβ induced ITGB6 gene transcription may promote pulmonary fibrosis. PLoS One 11(8):e0158047–e0158047

    Article  PubMed  PubMed Central  Google Scholar 

  61. Gian L. Bagnato, N. Irrera, G. Pizzino, D. Santoro, William N. Roberts, G. Bagnato, G. Pallio, M. Vaccaro, F. Squadrito, A. Saitta, D. Altavilla, A. Bitto, Dual αvβ3 and αvβ5 blockade attenuates fibrotic and vascular alterations in a murine model of systemic sclerosis, Clin Sci 132(2) (2018) 231–242

  62. McCarty JH (2020) αvβ8 integrin adhesion and signaling pathways in development, physiology and disease. J Cell Sci 133(12):jcs239434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Annes JP, Chen Y, Munger JS, Integrin DBR (2004) αVβ6-mediated activation of latent TGF-β requires the latent TGF-β binding protein-1. J Cell Biol 165(5):723–734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Huang XZ, Wu JF, Cass D, Erle DJ, Corry D, Young SG, Farese RV Jr, Sheppard D (1996) Inactivation of the integrin beta 6 subunit gene reveals a role of epithelial integrins in regulating inflammation in the lung and skin. J Cell Biol 133(4):921–928

    Article  CAS  PubMed  Google Scholar 

  65. Hahm K, Lukashev ME, Luo Y, Yang WJ, Dolinski BM, Weinreb PH, Simon KJ, Chun Wang L, Leone DR, Lobb RR, McCrann DJ, Allaire NE, Horan GS, Fogo A, Kalluri R, Shield CF 3rd, Sheppard D, Gardner HA, Violette SM (2007) Alphav beta6 integrin regulates renal fibrosis and inflammation in Alport mouse. Am J Pathol 170(1):110–125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Puthawala K, Hadjiangelis N, Jacoby SC, Bayongan E, Zhao Z, Yang Z, Devitt ML, Horan GS, Weinreb PH, Lukashev ME, Violette SM, Grant KS, Colarossi C, Formenti SC, Munger JS (2008) Inhibition of integrin alpha(v)beta6, an activator of latent transforming growth factor-beta, prevents radiation-induced lung fibrosis. Am J Respir Crit Care Med 177(1):82–90

    Article  CAS  PubMed  Google Scholar 

  67. Munger JS, Huang X, Kawakatsu H, Griffiths MJ, Dalton SL, Wu J, Pittet JF, Kaminski N, Garat C, Matthay MA, Rifkin DB, Sheppard D (1999) The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96(3):319–328

    Article  CAS  PubMed  Google Scholar 

  68. Bandyopadhyay A, Raghavan S (2009) Defining the role of integrin alphavbeta6 in cancer. Curr Drug Targets 10(7):645–652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Liu H, Wu Y, Wang F, Liu Z (2014) Molecular imaging of integrin αvβ6 expression in living subjects. Am J Nucl Med Mol Imaging 4(4):333–345

    PubMed  PubMed Central  Google Scholar 

  70. Nishimura SL (2009) Integrin-mediated transforming growth factor-beta activation, a potential therapeutic target in fibrogenic disorders. Am J Pathol 175(4):1362–1370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Tan C, Jiang M, Wong SS, Espinoza CR, Kim C, Li X, Connors E, Hagood JS (2019) Soluble Thy-1 reverses lung fibrosis via its integrin-binding motif. JCI Insight 4(21)

  72. Khanna D, Tashkin D, Wells A, Goldin J, Lubell M, Wax S, Damian D, Denton C (2017) Randomized controlled trial of abituzumab in systemic sclerosis-associated interstitial lung disease. Eur Respir J 50(suppl 61):OA2930

    Google Scholar 

  73. Hersey P, Sosman J, O’Day S, Richards J, Bedikian A, Gonzalez R, Sharfman W, Weber R, Logan T, Buzoianu M, Hammershaimb L, Kirkwood JM (2010) A randomized phase 2 study of etaracizumab, a monoclonal antibody against integrin alpha(v)beta(3), + or - dacarbazine in patients with stage IV metastatic melanoma. Cancer 116(6):1526–1534

    Article  CAS  PubMed  Google Scholar 

  74. Ritzenthaler JD, Zhang M, Torres-Gonzalez E, Roman J (2020) The integrin inhibitor cilengitide and bleomycin-induced pulmonary fibrosis : cilengitide and bleomycin-induced pulmonary fibrosis. Lung 198:947–955

    Article  CAS  PubMed  Google Scholar 

  75. Guzy RD, Li L, Smith C, Dorry SJ, Koo HY, Chen L, Ornitz DM (2017) Pulmonary fibrosis requires cell-autonomous mesenchymal fibroblast growth factor (FGF) signaling. J Biol Chem 292(25):10364–10378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Joannes A, Brayer S, Besnard V, Marchal-Somme J, Jaillet M, Mordant P, Mal H, Borie R, Crestani B, Mailleux AA (2016) FGF9 and FGF18 in idiopathic pulmonary fibrosis promote survival and migration and inhibit myofibroblast differentiation of human lung fibroblasts in vitro. Am J Phys Lung Cell Mol Phys 310(7):L615–L629

    Google Scholar 

  77. Singh B, Carpenter G, Coffey RJ (2016) EGF receptor ligands: recent advances, F1000Res 5

    Google Scholar 

  78. Huang F, Chen Y-G (2012) Regulation of TGF-β receptor activity. Cell Biosci 2:9–9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Guan S, Zhou J (2017) Frizzled-7 mediates TGF-β-induced pulmonary fibrosis by transmitting non-canonical Wnt signaling. Exp Cell Res 359(1):226–234

    Article  CAS  PubMed  Google Scholar 

  80. Huang H-C, Klein PS (2004) The Frizzled family: receptors for multiple signal transduction pathways. Genome Biol 5(7):234–234

    Article  PubMed  PubMed Central  Google Scholar 

  81. Smith ER, Holt SG, Hewitson TD (2017) FGF23 activates injury-primed renal fibroblasts via FGFR4-dependent signalling and enhancement of TGF-beta autoinduction. Int J Biochem Cell Biol 92:63–78

    Article  CAS  PubMed  Google Scholar 

  82. Piersma B, R.A. Bank, Boersema M (2015) Signaling in fibrosis: TGF-β, WNT, and YAP/TAZ converge. Front Med 2(59)

  83. Gauldie J, Kolb M, Ask K, Martin G, Bonniaud P, Warburton D (2006) Smad3 signaling involved in pulmonary fibrosis and emphysema. Proc Am Thorac Soc 3(8):696–702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Walton KL, Johnson KE, Harrison CA (2017) Targeting TGF-β mediated SMAD signaling for the prevention of fibrosis. Front Pharmacol 8(461)

  85. Liu F, Wang L, Qi H, Wang J, Wang Y, Jiang W, Xu L, Liu N, Zhuang S (2017) Nintedanib, a triple tyrosine kinase inhibitor, attenuates renal fibrosis in chronic kidney disease. Clin Sci 131(16):2125–2143

    Article  CAS  Google Scholar 

  86. Wollin L, Maillet I, Quesniaux V, Ryffel B (2013) Nintedanib reduces bleomycin-induced lung inflammation and fibrosis in mice. Eur Respir J 42(Suppl 57):P682

    Google Scholar 

  87. Wollin L, Wex E, Pautsch A, Schnapp G, Hostettler KE, Stowasser S, Kolb M (2015) Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis, Eur Respir J ERJ-01749-2014

  88. Ju W, Zhihong Y, Zhiyou Z, Qin H, Dingding W, Li S, Baowei Z, Xing W, Ying H, An H (2012) Inhibition of α-SMA by the ectodomain of FGFR2c attenuates lung fibrosis. Mol Med 18(1):992–1002

    Article  PubMed  PubMed Central  Google Scholar 

  89. Tang J, Liu N, Tolbert E, Ponnusamy M, Ma L, Gong R, Bayliss G, Yan H, Zhuang S (2013) Sustained activation of EGFR triggers renal fibrogenesis after acute kidney injury. Am J Pathol 183(1):160–172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Fuchs BC, Hoshida Y, Fujii T, Wei L, Yamada S, Lauwers GY, McGinn CM, DePeralta DK, Chen X, Kuroda T, Lanuti M, Schmitt AD, Gupta S, Crenshaw A, Onofrio R, Taylor B, Winckler W, Bardeesy N, Caravan P, Golub TR, Tanabe KK (2014) Epidermal growth factor receptor inhibition attenuates liver fibrosis and development of hepatocellular carcinoma. Hepatology 59(4):1577–1590

    Article  CAS  PubMed  Google Scholar 

  91. Liu N, Guo J-K, Pang M, Tolbert E, Ponnusamy M, Gong R, Bayliss G, Dworkin LD, Yan H, Zhuang S (2012) Genetic or pharmacologic blockade of EGFR inhibits renal fibrosis. J Am Soc Nephrol 23(5):854–867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Shu DY, Wojciechowski M, Lovicu FJ (2019) ERK1/2-mediated EGFR-signaling is required for TGFβ-induced lens epithelial-mesenchymal transition. Exp Eye Res 178:108–121

    Article  CAS  PubMed  Google Scholar 

  93. Faress JA, Nethery DE, Kern EFO, Eisenberg R, Jacono FJ, Allen CL, Kern JA (2007) Bleomycin-induced pulmonary fibrosis is attenuated by a monoclonal antibody targeting HER2. J Appl Physiol 103(6):2077–2083

    Article  CAS  PubMed  Google Scholar 

  94. Tzouvelekis A, Ntolios P, Karameris A, Vilaras G, Boglou P, Koulelidis A, Archontogeorgis K, Kaltsas K, Zacharis G, Sarikloglou E, Steiropoulos P, Mikroulis D, Koutsopoulos A, Froudarakis M, Bouros D (2013) Increased expression of epidermal growth factor receptor (EGF-R) in patients with different forms of lung fibrosis. Biomed Res Int 2013:654354

    Article  PubMed  PubMed Central  Google Scholar 

  95. Weiskirchen R, Weiskirchen S, Tacke F (2019) Organ and tissue fibrosis: molecular signals, cellular mechanisms and translational implications. Mol Asp Med 65:2–15

    Article  CAS  Google Scholar 

  96. de Heus C, Kagie N, Heukers R, van Bergen en Henegouwen PMP, Gerritsen HC (2013) Chapter 16 - analysis of EGF receptor oligomerization by homo-FRET, in: P.M. Conn (Ed.), Methods in cell biology, Academic Press, pp. 305–321

  97. Lemmon MA, Schlessinger J (2010) Cell signaling by receptor tyrosine kinases. Cell 141(7):1117–1134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Karimizadeh E, Motamed N, Mahmoudi M, Jafarinejad-Farsangi S, Jamshidi A, Faridani H, Gharibdoost F (2015) Attenuation of fibrosis with selective inhibition of c-Abl by siRNA in systemic sclerosis dermal fibroblasts. Arch Dermatol Res 307(2):135–142

    Article  CAS  PubMed  Google Scholar 

  99. Kinoshita K, Aono Y, Azuma M, Kishi J, Takezaki A, Kishi M, Makino H, Okazaki H, Uehara H, Izumi K, Sone S, Nishioka Y (2013) Antifibrotic effects of focal adhesion kinase inhibitor in bleomycin-induced pulmonary fibrosis in mice. Am J Respir Cell Mol Biol 49(4):536–543

    Article  CAS  PubMed  Google Scholar 

  100. Xu S-w, Liu S, Eastwood M, Sonnylal S, Denton CP, Abraham DJ, Leask A (2009) Rac inhibition reverses the phenotype of fibrotic fibroblasts. PLoS One 4(10):e7438–e7438

    Article  PubMed  Google Scholar 

  101. Andrikopoulos P, Kieswich J, Pacheco S, Nadarajah L, Harwood SM, O’Riordan CE, Thiemermann C, Yaqoob MM (2019) The MEK inhibitor trametinib ameliorates kidney fibrosis by suppressing ERK1/2 and mTORC1 signaling. J Am Soc Nephrol 30(1):33–49

    Article  CAS  PubMed  Google Scholar 

  102. Wen J, Lin X, Gao W, Qu B, Ling Y, Liu R, Yu M (2019) MEK inhibition prevents TGF-β1-induced myofibroblast transdifferentiation in human tenon fibroblasts. Mol Med Rep 19(1):468–476

    CAS  PubMed  Google Scholar 

  103. Madala SK, Edukulla R, Phatak M, Schmidt S, Davidson C, Acciani TH, Korfhagen TR, Medvedovic M, LeCras TD, Wagner K, Hardie WD (2014) Dual targeting of MEK and PI3K pathways attenuates established and progressive pulmonary fibrosis. PLoS One 9(1):e86536

    Article  PubMed  PubMed Central  Google Scholar 

  104. Laplante P, Raymond M-A, Gagnon G, Vigneault N, Sasseville AM-J, Langelier Y, Bernard M, Raymond Y, Hébert M-J (2005) Novel fibrogenic pathways are activated in response to endothelial apoptosis: implications in the pathophysiology of systemic sclerosis. J Immunol 174(9):5740–5749

    Article  CAS  PubMed  Google Scholar 

  105. Hu M, Che P, Han X, Cai G-Q, Liu G, Antony V, Luckhardt T, Siegal GP, Zhou Y, Liu R-m, Desai LP, O’Reilly PJ, Thannickal VJ, Ding Q (2014) Therapeutic targeting of SRC kinase in myofibroblast differentiation and pulmonary fibrosis. J Pharmacol Exp Ther 351(1):87–95

    Article  PubMed  PubMed Central  Google Scholar 

  106. Lu Y-Y, Zhao X-K, Yu L, Qi F, Zhai B, Gao C-Q, Ding Q (2017) Interaction of Src and alpha-V integrin regulates fibroblast migration and modulates lung fibrosis in a preclinical model of lung fibrosis. Sci Rep 7:46357–46357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Massip Copiz MM, Santa Coloma TA (2016) c- Src and its role in cystic fibrosis. Eur J Cell Biol 95(10):401–413

    Article  CAS  PubMed  Google Scholar 

  108. Tice DA, Biscardi JS, Nickles AL, Parsons SJ (1999) Mechanism of biological synergy between cellular Src and epidermal growth factor receptor. Proc Natl Acad Sci U S A 96(4):1415–1420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Maa MC, Leu TH, McCarley DJ, Schatzman RC, Parsons SJ (1995) Potentiation of epidermal growth factor receptor-mediated oncogenesis by c-Src: implications for the etiology of multiple human cancers. Proc Natl Acad Sci U S A 92(15):6981–6985

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Mitra AK, Sawada K, Tiwari P, Mui K, Gwin K, Lengyel E (2011) Ligand-independent activation of c-Met by fibronectin and α(5)β(1)-integrin regulates ovarian cancer invasion and metastasis. Oncogene 30(13):1566–1576

    Article  CAS  PubMed  Google Scholar 

  111. Moro L, Dolce L, Cabodi S, Bergatto E, Erba EB, Smeriglio M, Turco E, Retta SF, Giuffrida MG, Venturino M, Godovac-Zimmermann J, Conti A, Schaefer E, Beguinot L, Tacchetti C, Gaggini P, Silengo L, Tarone G, Defilippi P (2002) Integrin-induced epidermal growth factor (EGF) receptor activation requires c-Src and p130Cas and leads to phosphorylation of specific EGF receptor tyrosines. J Biol Chem 277(11):9405–9414

    Article  CAS  PubMed  Google Scholar 

  112. Somanath PR, Malinin NL, Byzova TV (2009) Cooperation between integrin alphavbeta3 and VEGFR2 in angiogenesis. Angiogenesis 12(2):177–185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Borges E, Jan Y, Ruoslahti E (2000) Platelet-derived growth factor receptor β and vascular endothelial growth factor receptor 2 bind to the β3 integrin through its extracellular domain. J Biol Chem 275(51):39867–39873

    Article  CAS  PubMed  Google Scholar 

  114. Woodard AS, García-Cardeña G, Leong M, Madri JA, Sessa WC, Languino LR (1998) The synergistic activity of alphavbeta3 integrin and PDGF receptor increases cell migration. J Cell Sci 111(Pt 4):469–478

    Article  CAS  PubMed  Google Scholar 

  115. Mori S, Takada Y (2013) Crosstalk between fibroblast growth factor (FGF) receptor and integrin through direct integrin binding to FGF and resulting integrin-FGF-FGFR ternary complex formation. Medi Sci 1(1):20–36

    Google Scholar 

  116. Mori S, Wu CY, Yamaji S, Saegusa J, Shi B, Ma Z, Kuwabara Y, Lam KS, Isseroff RR, Takada YK, Takada Y (2008) Direct binding of integrin alphavbeta3 to FGF1 plays a role in FGF1 signaling. J Biol Chem 283(26):18066–18075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Avalos AM, Valdivia AD, Muñoz N, Herrera-Molina R, Tapia JC, Lavandero S, Chiong M, Burridge K, Schneider P, Quest AFG, Leyton L (2009) Neuronal Thy-1 induces astrocyte adhesion by engaging syndecan-4 in a cooperative interaction with alphavbeta3 integrin that activates PKCalpha and RhoA. J Cell Sci 122(Pt 19):3462–3471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Hagood JS (2019) Thy-1 as an integrator of diverse extracellular signals. Front Cell Dev Biol 7:26–26

    Article  PubMed  PubMed Central  Google Scholar 

  119. Leyton L, Díaz J, Martínez S, Palacios E, Pérez LA, Pérez RD (2019) Thy-1/CD90 a bidirectional and lateral signaling scaffold. Front Cell Dev Biol 7(132)

  120. Hagood JS, Prabhakaran P, Kumbla P, Salazar L, MacEwen MW, Barker TH, Ortiz LA, Schoeb T, Siegal GP, Alexander CB, Pardo A, Selman M (2005) Loss of fibroblast Thy-1 expression correlates with lung fibrogenesis. Am J Pathol 167(2):365–379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Aluwihare P, Mu Z, Zhao Z, Yu D, Weinreb PH, Horan GS, Violette SM, Munger JS (2009) Mice that lack activity of alphavbeta6- and alphavbeta8-integrins reproduce the abnormalities of Tgfb1- and Tgfb3-null mice. J Cell Sci 122(Pt 2):227–232

    Article  CAS  PubMed  Google Scholar 

  122. Ning Y, Buranda T, Hudson LG (2007) Activated epidermal growth factor receptor induces integrin alpha2 internalization via caveolae/raft-dependent endocytic pathway. J Biol Chem 282(9):6380–6387

    Article  CAS  PubMed  Google Scholar 

  123. Paul NR, Thomas JR, Maldonado H, Wolanska KI, Koper EJ, Humphries JD, Byron A, George A, Allen N, Prior IA, Streuli CH, Humphries MJ, Morgan MR (2018) Eps8 is a convergence point integrating EGFR and integrin trafficking and crosstalk, bioRxiv 405043

  124. Lindsay AJ, Hendrick AG, Cantalupo G, Senic-Matuglia F, Goud B, Bucci C, McCaffrey MW (2002) Rab coupling protein (RCP), a novel Rab4 and Rab11 effector protein. J Biol Chem 277(14):12190–12199

    Article  CAS  PubMed  Google Scholar 

  125. Caswell PT, Chan M, Lindsay AJ, McCaffrey MW, Boettiger D, Norman JC (2008) Rab-coupling protein coordinates recycling of α5β1 integrin and EGFR1 to promote cell migration in 3D microenvironments. J Cell Biol 183(1):143–155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This review was supported by The UNC Catalyst for Rare Disease, Eshelman School of Pharmacy at the University of North Carolina at Chapel Hill Foundation (to J.S.H.).

Author information

Authors and Affiliations

  1. Department of Pediatrics, Pulmonology Division, Program for Rare and Interstitial Lung Disease, University of North Carolina at Chapel Hill, 450 MacNider, CB# 7217, 333 S. Columbia St., Chapel Hill, NC, 27599-7217, USA

    Horacio Maldonado & James S. Hagood

  2. UNC Catalyst for Rare Disease, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Horacio Maldonado

Authors
  1. Horacio Maldonado
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James S. Hagood
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Both authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Horacio Maldonado and James Hagood. The first draft of the manuscript was written by Horacio Maldonado and James Hagood; both authors commented on previous versions of the manuscript. Both authors read and approved the final manuscript.

Corresponding author

Correspondence to James S. Hagood.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Maldonado, H., Hagood, J.S. Cooperative signaling between integrins and growth factor receptors in fibrosis. J Mol Med 99, 213–224 (2021). https://doi.org/10.1007/s00109-020-02026-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-020-02026-2

Keywords

Search

Navigation