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non-integrin mediated signaling pathways such as growth fac-
tor signaling. “Outside-in” signaling regulates cellular responses
induced by ligand binding to integrin receptors that regulate
cell spreading, migration and proliferation (Hynes, 2002). Upon
ligand binding, integrins cluster at the plasma membrane and
various integrin-binding proteins are recruited to their cytoplas-
mic tails to form FAs. These core FA components subsequently
recruit a large number of actin-modulatory proteins and signa-
ling molecules allowing actin stress fiber formation, FA matura-
tion, and propagation of intracellular signaling cascades (Legate
et al., 2009; Wickström et al., 2011).
Integrin-linked kinase – a pseudokinase with adaptor
function
ILK is a central component of
β1
- and possibly also of
β3
-
integrin adhesion complexes. It is ubiquitously expressed, con-
sists of 452 amino acids, and has a molecular weight of 52 kDa.
ILK was originally identified in a yeast two-hybrid screen as a
direct binding partner of
β1
-integrin (Hannigan et al., 1996).
Due to its sequence homology to protein kinases as well as in
vitro observations showing that ILK is capable of phosphoryla-
ting substrates such as GSK-
3β
and PKB/AKT and
β1
-integrin, it
was initially reported to be a serine/threonine kinase (Hannigan
et al., 1996).
ILK is composed of five N-terminal ankyrin repeat (ANK) do-
mains, followed by a pleckstrin homology (PH)-like sequence
and an N-terminal kinase domain (KD). Together the five ANK
domains form a superhelical spiral that serves as a binding do-
main for PINCH, another important integrin adaptor (Chiswell
et al., 2008). The PH-like sequence of ILK is integrated into the
ILK-KD and is in fact not capable of binding the second messen-
ger phosphatidylinositol 3-phosphate (PIP3). The KD of ILK func-
tions as a protein-protein interaction domain that binds among
others the calponin homology 2 (CH2) domain of parvin (Fukuda
et al., 2009; Stiegler et al., 2013). In cells, ILK, PINCH and parvin
are mostly present in a ternary complex within FAs (Fig. 1).
Despite initial in vitro observations of kinase activity, inspection
of the KD sequence already raised doubts about its catalytic
activity. During phosphotransfer, the DFG (Asp-Phe-Gly) motif
that is conserved in most eukaryotic kinases mediates the align-
ment of the
γ
-phosphate, but in ILK this motif is replaced by
DVK (Asp-Val-Lys). Phosphotransfer further requires the proton
acceptance from the hydroxyl group catalyzed by the aspartate
residue in the HRD (His-Arg-Asp) motif that is also lacking in ILK
(Wickström et al., 2010a). It is generally presumed that the pre-
sence of both DFG and HRD motif is required for kinase activity,
and no kinase with reported activity lacks both of the motifs
(Boudeau et al., 2006).
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