20
Cell News 1/2015
Research news
structures to bind and regulate growth factor bioavailability.
Therefore it is becoming clear that the ECM-remodeling func-
tion of ILK is central to its role as an essential regulator of cell
and tissue behavior. It will be of great interest to evaluate how
force-induced fibril assembly driven by ILK impacts these pro-
cesses and what is the role of ECM remodeling in the various
phenotypes of ILK-deficient mice.
ILK in dermal tissue repair and fibrosis
ECM deposition is an indispensible, but transient and reversible
process during wound healing. When disturbed, it can convert
tissue repair into a progressive and irreversible fibrotic response,
leading to hypertrophic scarring, keloids or fibrosis. This results
in destruction of normal tissue architecture and compromised
organ function (Gabrielli et al., 2009; Hunzelmann and Krieg,
2010; Wynn and Ramalingam, 2012). ILK has important func-
tions both during physiological tissue repair as well as in fibrosis.
Deletion of ILK in dermal fibroblasts in mice results in impaired
myofibroblast generation during wound healing, compromising
matrix remodeling and subsequently tissue repair (Blumbach et
al., 2010; Vi et al., 2011).
Interestingly, ILK, due to its kinase fold, is a substrate of the
chaperone Heat shock protein 90 (Hsp90) that is required to
stabilize ILK. Inhibition of Hsp90 activity in fibroblasts therefore
leads to degradation and subsequent depletion of ILK protein,
inducing a cellular phenotype closely resembling ILK-deficient
cells (Radovanac et al., 2013). Consequently, blocking Hsp90
activity severely attenuates myofibroblast generation and the
development of skin fibrosis in mice (Radovanac et al., 2013).
This might provide a potential therapeutic strategy to treat fi-
brotic disease.
Interestingly, rigidity and mechanical stability of the matrix,
in conjunction with the key profibrotic mediator transforming
growth factor
β
1 (TGF
β
1), act as the primary stimulus for myo-
fibroblast differentiation and persistence (Tomasek et al., 2002;
Nakamura-Wakatsuki et al., 2012). Furthermore, myofibroblasts
can activate latent TGF
β
1 that is bound to the ECM using integ-
rin-mediated contraction, suggesting that activation of TGF
β
1 is
driven by a mechanical mode of action. In this respect it is inte-
resting to note that ILK-deficient fibroblasts show impaired dif-
ferentiation into myofibroblasts, and decreased release of TGF
β
1
(Blumbach et al., 2010; Vi et al., 2011; Radovanac et al., 2013).
Concluding remarks
To conclude, recent work from our lab and others has identi-
fied mechanisms by which integrins, through adaptors such
as ILK, transduce traction forces that are central to adhesion
maturation, regulation of cell shape and migration as well as
ECM remodeling. In addition, this work has revealed exciting
new mechanisms by which kinase domains can be utilized as
specific protein-protein interaction domains by pseudokinases.
An important aim for future work is to understand the precise
mechanisms by which cellular behavior is regulated by the dy-
namic crosstalk between cells and their immediate ECM micro-
environment.
Acknowledgements
The ILK work in the Wickström lab is supported by the Max
Planck Society and by the DFG (SFB 829, WI 4177/2).
References
Blumbach, K., Zweers, M.C., Brunner, G., Peters, A.S., Schmitz, M., Schulz, J.N., Schild, A.,
Denton, C.P., Sakai, T., Fassler, R., Krieg, T., and Eckes, B. (2010). Defective granulation tissue
formation in mice with specific ablation of integrin-linked kinase in fibroblasts - role of
TGFbeta1 levels and RhoA activity. Journal of cell science 123, 3872-3883.
Boudeau, J., Miranda-Saavedra, D., Barton, G.J., and Alessi, D.R. (2006). Emerging roles of
pseudokinases. Trends Cell Biol 16, 443-452.
Boulter, E., Grall, D., Cagnol, S., and Van Obberghen-Schilling, E. (2006). Regulation of cell-
matrix adhesion dynamics and Rac-1 by integrin linked kinase. FASEB journal : official pu-
blication of the Federation of American Societies for Experimental Biology 20, 1489-1491.
Chiswell, B.P., Zhang, R., Murphy, J.W., Boggon, T.J., and Calderwood, D.A. (2008). The struc-
tural basis of integrin-linked kinase-PINCH interactions. Proc Natl Acad Sci U S A 105,
20677-20682.
Clark, K., Pankov, R., Travis, M.A., Askari, J.A., Mould, A.P., Craig, S.E., Newham, P., Yamada,
K.M., and Humphries, M.J. (2005). A specific alpha5beta1-integrin conformation promotes
directional integrin translocation and fibronectin matrix formation. Journal of cell science
118, 291-300.
Daley, W.P., and Yamada, K.M. (2013). ECM-modulated cellular dynamics as a driving force
for tissue morphogenesis. Current opinion in genetics & development 23, 408-414.
Frantz, C., Stewart, K.M., and Weaver, V.M. (2010). The extracellular matrix at a glance.
Journal of cell science 123, 4195-4200.
Fukuda, K., Gupta, S., Chen, K., Wu, C., and Qin, J. (2009). The pseudoactive site of ILK is
essential for its binding to alpha-Parvin and localization to focal adhesions. Mol Cell 36,
819-830.
Fukuda, K., Knight, J.D., Piszczek, G., Kothary, R., and Qin, J. (2011). Biochemical, proteomic,
structural, and thermodynamic characterizations of integrin-linked kinase (ILK): cross-vali-
dation of the pseudokinase. J Biol Chem 286, 21886-21895.
Gabrielli, A., Avvedimento, E.V., and Krieg, T. (2009). Scleroderma. N Engl J Med 360, 1989-
2003.
Gattazzo, F., Urciuolo, A., and Bonaldo, P. (2014). Extracellular matrix: a dynamic microen-
vironment for stem cell niche. Biochim Biophys Acta 1840, 2506-2519.
Hannigan, G.E., Leung-Hagesteijn, C., Fitz-Gibbon, L., Coppolino, M.G., Radeva, G., Filmus,
J., Bell, J.C., and Dedhar, S. (1996). Regulation of cell adhesion and anchorage-dependent
growth by a new beta 1-integrin-linked protein kinase. Nature 379, 91-96.
Hunzelmann, N., and Krieg, T. (2010). Scleroderma: from pathophysiology to novel thera-
peutic approaches. Exp Dermatol 19, 393-400.
Huveneers, S., Truong, H., Fassler, R., Sonnenberg, A., and Danen, E.H. (2008). Binding of
soluble fibronectin to integrin alpha5 beta1 - link to focal adhesion redistribution and
contractile shape. Journal of cell science 121, 2452-2462.
Hynes, R.O. (2002). Integrins: bidirectional, allosteric signaling machines. Cell 110, 673-687.
Kinsey, R., Williamson, M.R., Chaudhry, S., Mellody, K.T., McGovern, A., Takahashi, S., Shut-
tleworth, C.A., and Kielty, C.M. (2008). Fibrillin-1 microfibril deposition is dependent on
fibronectin assembly. Journal of cell science 121, 2696-2704.
Kogata, N., Tribe, R.M., Fassler, R., Way, M., and Adams, R.H. (2009). Integrin-linked kina-
se controls vascular wall formation by negatively regulating Rho/ROCK-mediated vascular
smooth muscle cell contraction. Genes Dev 23, 2278-2283.
Lange, A., Wickström, S.A., Jakobson, M., Zent, R., Sainio, K., and Fässler, R. (2009). Integrin-
linked kinase is an adaptor with essential functions during mouse development. Nature
461, 1002-1006.
Legate, K.R., Wickström, S.A., and Fässler, R. (2009). Genetic and cell biological analysis of
integrin outside-in signaling. Genes Dev 23, 397-418.
Mackinnon, A.C., Qadota, H., Norman, K.R., Moerman, D.G., and Williams, B.D. (2002). C.
elegans PAT-4/ILK functions as an adaptor protein within integrin adhesion complexes.
Current biology 12, 787-797.
Nakamura-Wakatsuki, T., Oyama, N., and Yamamoto, T. (2012). Local injection of latency-
associated peptide, a linker propeptide specific for active form of transforming growth
factor-beta1, inhibits dermal sclerosis in bleomycin-induced murine scleroderma. Exp Der-
matology 21, 189-194.
Ohashi, T., Kiehart, D.P., and Erickson, H.P. (2002). Dual labeling of the fibronectin matrix
and actin cytoskeleton with green fluorescent protein variants. Journal of cell science 115,
1221-1229.
Olorundare, O.E., Peyruchaud, O., Albrecht, R.M., and Mosher, D.F. (2001). Assembly of a
fibronectin matrix by adherent platelets stimulated by lysophosphatidic acid and other ago-
nists. Blood 98, 117-124.
Olski, T.M., Noegel, A.A., and Korenbaum, E. (2001). Parvin, a 42 kDa focal adhesion protein,
related to the alpha-actinin superfamily. Journal of cell science 114, 525-538.
Pankov, R., Cukierman, E., Katz, B.Z., Matsumoto, K., Lin, D.C., Lin, S., Hahn, C., and Yamada,
K.M. (2000). Integrin dynamics and matrix assembly: tensin-dependent translocation of
