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Kindlin-1 and Its Role in Kindler Syndrome

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Blistering Diseases

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Abstract

Kindlin-1 is a member of the conserved protein family of kindlins, intracellular adaptor components of the integrin-linked adhesion sites, the focal adhesions, which serve as supramolecular signalling and actin-anchoring platforms. Together with talin, kindlins directly bind to integrin β subunit cytoplasmic tails and are responsible for integrin activation. Mutations in the kindlin-1 gene cause the Kindler syndrome, a rare genodermatosis characterised by skin blistering, photosensitivity, poikiloderma, mucosal involvement and propensity to mucocutaneous squamous cell carcinomas. Fragility and atrophy of the skin in patients with Kindler syndrome correlate with reduced adhesion and proliferation of keratinocytes in culture, but the underlying molecular pathways are not fully elucidated. Kindlin-1-deficient keratinocytes demonstrate pronounced response to stress factors, which may launch autocrine and paracrine signals and explain the dermal fibrosis and photosensitivity. A subgroup of patients with Kindler syndrome demonstrates a disseminated pattern of revertant mosaicism, which may serve as a basis for cell-based therapies.

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References

  1. Karakose E, Schiller HB, Fassler R. The kindlins at a glance. J Cell Sci. 2010;123(Pt 14):2353–6.

    Article  PubMed  Google Scholar 

  2. Jobard F, Bouadjar B, Caux F, Hadj-Rabia S, Has C, Matsuda F, et al. Identification of mutations in a new gene encoding a FERM family protein with a pleckstrin homology domain in Kindler syndrome. Hum Mol Genet. 2003;12(8):925–35.

    Article  CAS  PubMed  Google Scholar 

  3. Siegel DH, Ashton GH, Penagos HG, Lee JV, Feiler HS, Wilhelmsen KC, et al. Loss of kindlin-1, a human homolog of the Caenorhabditis elegans actin-extracellular-matrix linker protein UNC-112, causes Kindler syndrome. Am J Hum Genet. 2003;73(1):174–87.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Kindler T. Congenital poikiloderma with traumatic bulla formation and progressive cutaneous atrophy. Br J Dermatol. 1954;66(3):104–11.

    Article  CAS  PubMed  Google Scholar 

  5. Fine JD, Eady RA, Bauer EA, Bauer JW, Bruckner-Tuderman L, Heagerty A, et al. The classification of inherited epidermolysis bullosa (EB): report of the Third International Consensus Meeting on diagnosis and classification of EB. J Am Acad Dermatol. 2008;58(6):931–50.

    Article  PubMed  Google Scholar 

  6. Ussar S, Wang HV, Linder S, Fassler R, Moser M. The Kindlins: subcellular localization and expression during murine development. Exp Cell Res. 2006;312(16):3142–51.

    Article  CAS  PubMed  Google Scholar 

  7. Kern JS, Herz C, Haan E, Moore D, Nottelmann S, von Lilien T, et al. Chronic colitis due to an epithelial barrier defect: the role of kindlin-1 isoforms. J Pathol. 2007;213(4):462–70.

    Article  CAS  PubMed  Google Scholar 

  8. Lai-Cheong JE, Ussar S, Arita K, Hart IR, McGrath JA. Colocalization of kindlin-1, kindlin-2, and migfilin at keratinocyte focal adhesion and relevance to the pathophysiology of Kindler syndrome. J Invest Dermatol. 2008;128(9):2156–65.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Petricca G, Leppilampi M, Jiang G, Owen GR, Wiebe C, Tu Y, et al. Localization and potential function of kindlin-1 in periodontal tissues. Eur J Oral Sci. 2009;117(5):518–27.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Bandyopadhyay A, Rothschild G, Kim S, Calderwood DA, Raghavan S. Uncovering functional differences between kindlin-1 and kindlin-2 in keratinocytes. J Cell Sci. 2012;125:2172–84.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Ussar S, Moser M, Widmaier M, Rognoni E, Harrer C, Genzel-Boroviczeny O, et al. Loss of kindlin-1 causes skin atrophy and lethal neonatal intestinal epithelial dysfunction. PLoS Genet. 2008;4(12):e1000289.

    Article  PubMed Central  PubMed  Google Scholar 

  12. Herz C, Aumailley M, Schulte C, Schlotzer-Schrehardt U, Bruckner-Tuderman L, Has C. Kindlin-1 is a phosphoprotein involved in regulation of polarity, proliferation, and motility of epidermal keratinocytes. J Biol Chem. 2006;281(47):36082–90.

    Article  CAS  PubMed  Google Scholar 

  13. Kloeker S, Major MB, Calderwood DA, Ginsberg MH, Jones DA, Beckerle MC. The Kindler syndrome protein is regulated by transforming growth factor-beta and involved in integrin-mediated adhesion. J Biol Chem. 2004;279(8):6824–33.

    Article  CAS  PubMed  Google Scholar 

  14. Larjava H, Plow EF, Wu C. Kindlins: essential regulators of integrin signalling and cell-matrix adhesion. EMBO Rep. 2008;9(12):1203–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Moser M, Legate KR, Zent R, Fassler R. The tail of integrins, talin, and kindlins. Science. 2009;324(5929):895–9.

    Article  CAS  PubMed  Google Scholar 

  16. Goult BT, Bouaouina M, Harburger DS, Bate N, Patel B, Anthis NJ, et al. The structure of the N-terminus of kindlin-1: a domain important for alphaiibbeta3 integrin activation. J Mol Biol. 2009;394(5):944–56.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Bouaouina M, Goult BT, Huet-Calderwood C, Bate N, Brahme NN, Barsukov IL, et al. A conserved lipid-binding loop in the kindlin FERM F1 domain is required for kindlin-mediated alphaIIbbeta3 integrin coactivation. J Biol Chem. 2012;287(10):6979–90.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Bottcher RT, Lange A, Fassler R. How ILK and kindlins cooperate to orchestrate integrin signaling. Curr Opin Cell Biol. 2009;21(5):670–5.

    Article  PubMed  Google Scholar 

  19. Harburger DS, Bouaouina M, 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Has C, Herz C, Zimina E, Qu HY, He Y, Zhang ZG, et al. Kindlin-1 is required for RhoGTPase-mediated lamellipodia formation in keratinocytes. Am J Pathol. 2009;175(4):1442–52.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Dephoure N, Zhou C, Villen J, Beausoleil SA, Bakalarski CE, Elledge SJ, et al. A quantitative atlas of mitotic phosphorylation. Proc Natl Acad Sci U S A. 2008;105(31):10762–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Wegener KL, Partridge AW, Han J, Pickford AR, Liddington RC, Ginsberg MH, et al. Structural basis of integrin activation by talin. Cell. 2007;128(1):171–82.

    Article  CAS  PubMed  Google Scholar 

  23. Montanez E, Ussar S, Schifferer M, Bosl M, Zent R, Moser M, et al. Kindlin-2 controls bidirectional signaling of integrins. Genes Dev. 2008;22(10):1325–30.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Dowling JJ, Gibbs E, Russell M, Goldman D, Minarcik J, Golden JA, et al. Kindlin-2 is an essential component of intercalated discs and is required for vertebrate cardiac structure and function. Circ Res. 2008;102(4):423–31.

    Article  CAS  PubMed  Google Scholar 

  25. Svensson L, Howarth K, McDowall A, Patzak I, Evans R, Ussar S, et al. Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3 affecting integrin activation. Nat Med. 2009;15(3):306–12.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Malinin NL, Zhang L, Choi J, Ciocea A, Razorenova O, Ma YQ, et al. A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humans. Nat Med. 2009;15(3):313–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Lai-Cheong JE, Parsons M, Tanaka A, Ussar S, South AP, Gomathy S, et al. Loss-of-function FERMT1 mutations in Kindler syndrome implicate a role for fermitin family homolog-1 in integrin activation. Am J Pathol. 2009;175(4):1431–41.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. He Y, Esser P, Heinemann A, Bruckner-Tuderman L, Has C. Kindlin-1 and -2 have overlapping functions in epithelial cells implications for phenotype modification. Am J Pathol. 2011;178(3):975–82.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Lefort CT, Rossaint J, Moser M, Petrich BG, Zarbock A, Monkley SJ, et al. Distinct roles for talin-1 and kindlin-3 in LFA-1 extension and affinity regulation. Blood. 2012;119(18):4275–82.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Margadant C, Kreft M, de Groot DJ, Norman JC, Sonnenberg A. Distinct roles of talin and kindlin in regulating integrin alpha5beta1 function and trafficking. Curr Biol. 2012;22:1554–63.

    Article  CAS  PubMed  Google Scholar 

  31. Tan CL, Andrews MR, Kwok JC, Heintz TG, Gumy LF, Fassler R, et al. Kindlin-1 enhances axon growth on inhibitory chondroitin sulfate proteoglycans and promotes sensory axon regeneration. J Neurosci. 2012;32(21):7325–35.

    Article  CAS  PubMed  Google Scholar 

  32. Weinstein EJ, Bourner M, Head R, Zakeri H, Bauer C, Mazzarella R. URP1: a member of a novel family of PH and FERM domain-containing membrane-associated proteins is significantly over-expressed in lung and colon carcinomas. Biochim Biophys Acta. 2003;1637(3):207–16.

    Article  CAS  PubMed  Google Scholar 

  33. Landemaine T, Jackson A, Bellahcene A, Rucci N, Sin S, Abad BM, et al. A six-gene signature predicting breast cancer lung metastasis. Cancer Res. 2008;68(15):6092–9.

    Article  CAS  PubMed  Google Scholar 

  34. Sin S, Bonin F, Petit V, Meseure D, Lallemand F, Bieche I, et al. Role of the focal adhesion protein kindlin-1 in breast cancer growth and lung metastasis. J Natl Cancer Inst. 2011;103:1323–37.

    Article  CAS  PubMed  Google Scholar 

  35. Has C, Castiglia D, del Rio M, Diez MG, Piccinni E, Kiritsi D, et al. Kindler syndrome: extension of FERMT1 mutational spectrum and natural history. Hum Mutat. 2011;32(11):1204–12.

    Article  CAS  PubMed  Google Scholar 

  36. Lai-Cheong JE, Parsons M, McGrath JA. The role of kindlins in cell biology and relevance to human disease. Int J Biochem Cell Biol. 2010;42(5):595–603.

    Article  CAS  PubMed  Google Scholar 

  37. Lai-Cheong JE, McGrath JA, Uitto J. Revertant mosaicism in skin: natural gene therapy. Trends Mol Med. 2010;17(3):140–8.

    Article  PubMed Central  PubMed  Google Scholar 

  38. Kiritsi D, He Y, Pasmooij AM, Onder M, Happle R, Jonkman MF, et al. Revertant mosaicism in a human skin fragility disorder results from slipped mispairing and mitotic recombination. J Clin Invest. 2012;122(5):1742–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Lai-Cheong JE, Moss C, Parsons M, Almaani N, McGrath JA. Revertant mosaicism in Kindler syndrome. J Invest Dermatol. 2011;132(3 Pt 1):730–2.

    PubMed  Google Scholar 

  40. Qu H, Wen T, Pesch M, Aumailley M. Partial loss of epithelial phenotype in kindlin-1-deficient keratinocytes. Am J Pathol. 2012;180(4):1581–92.

    Article  CAS  PubMed  Google Scholar 

  41. Heinemann A, He Y, Zimina E, Boerries M, Busch H, Chmel N, et al. Induction of phenotype modifying cytokines by FERMT1 mutations. Hum Mutat. 2011;32(4):397–406.

    Article  CAS  PubMed  Google Scholar 

  42. Ng YZ, Pourreyron C, Salas-Alanis JC, Dayal JH, Cepeda-Valdes R, Yan W, et al. Fibroblast-derived dermal matrix drives development of aggressive cutaneous squamous cell carcinoma in patients with recessive dystrophic epidermolysis bullosa. Cancer Res. 2012;72:3522–34.

    Article  CAS  PubMed  Google Scholar 

  43. Purdie KJ, Pourreyron C, Fassihi H, Cepeda-Valdes R, Frew JW, Volz A, et al. No evidence that human papillomavirus is responsible for the aggressive nature of recessive dystrophic epidermolysis bullosa-associated squamous cell carcinoma. J Invest Dermatol. 2010;130(12):2853–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Pourreyron C, Cox G, Mao X, Volz A, Baksh N, Wong T, et al. Patients with recessive dystrophic epidermolysis bullosa develop squamous-cell carcinoma regardless of type VII collagen expression. J Invest Dermatol. 2007;127(10):2438–44.

    Article  CAS  PubMed  Google Scholar 

  45. South AP, O’Toole EA. Understanding the pathogenesis of recessive dystrophic epidermolysis bullosa squamous cell carcinoma. Dermatol Clin. 2010;28(1):171–8.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Dermatology, University Freiburg Medical Center, Freiburg, Germany

    Cristina Has MD

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  1. Cristina Has MD
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Correspondence to Cristina Has MD .

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Editors and Affiliations

  1. Department of Dermatology, St George Hospital, University of New South Wales, Sydney, New South Wales, Australia

    Dédée F. Murrell

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Has, C. (2015). Kindlin-1 and Its Role in Kindler Syndrome. In: Murrell, D. (eds) Blistering Diseases. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-45698-9_10

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  • DOI: https://doi.org/10.1007/978-3-662-45698-9_10

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