Integrin-linked kinase: Not so ‘pseudo’ after all

Hannigan, Gregory E.; McDonald, Paul C.; Walsh, Michael P.; Dedhar, Shoukat

doi:10.1038/onc.2011.177

Cited by 126 publications

(114 citation statements)

References 84 publications

(136 reference statements)

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“…2a). Inactivation of GSK-3b through phosphorylation at Ser9 (pGSK-3b) is cytoprotective in the myocardium 25,26 and is a common readout of ILK activation 27,28 . ILK overexpression caused an increase in phosphorylation of GSK-3b, whereas ILK knockdown by short interfering RNA (siRNA) caused a relative de-phosphorylation of GSK-3b (Fig.…”

Section: Resultsmentioning

confidence: 99%

Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function

Traister

Aafaqi

et al. 2014

Nat Commun

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Human dilated cardiomyopathy (DCM) manifests as a profound reduction in biventricular cardiac function that typically progresses to death or cardiac transplantation. There is no effective mechanism-based therapy currently available for DCM, in part because the transduction of mechanical load into dynamic changes in cardiac contractility (termed mechanotransduction) remains an incompletely understood process during both normal cardiac function and in disease states. Here we show that the mechanoreceptor protein integrin-linked kinase (ILK) mediates cardiomyocyte force transduction through regulation of the key calcium regulatory protein sarcoplasmic/endoplasmic reticulum Ca 2 þ ATPase isoform 2a (SERCA-2a) and phosphorylation of phospholamban (PLN) in the human heart. A non-oncogenic ILK mutation with a synthetic point mutation in the pleckstrin homology-like domain (ILK R211A ) is shown to enhance global cardiac function through SERCA-2a/PLN. Thus, ILK serves to link mechanoreception to the dynamic modulation of cardiac contractility through a previously undiscovered interaction with the functional SERCA-2a/PLN module that can be exploited to rescue impaired mechanotransduction in DCM.

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Section: Resultsmentioning

confidence: 99%

Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function

Traister

Aafaqi

et al. 2014

Nat Commun

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“…Approximately 50% of cellular ILK was retained in Triton-skinned smooth muscle and may be associated with MLCP because purified phosphatase preparations contain co-purifying ILK (19). It should be noted that ILK has often been described as a pseudokinase (25), but the evidence for its bona fide kinase activity is substantial (26,27). Zipper-interacting protein kinase (ZIPK) has also been implicated in the diphosphorylation of LC 20 (18,28), although inhibition of ZIPK activity in Triton-skinned rat caudal arterial smooth muscle did not affect microcystin-induced LC 20 diphosphorylation or contraction (19), suggesting that ILK is likely the responsible kinase in these conditions.…”

mentioning

confidence: 99%

Myosin Regulatory Light Chain Diphosphorylation Slows Relaxation of Arterial Smooth Muscle

Sutherland

Walsh

2012

Journal of Biological Chemistry

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“…The activity of ILK is antagonized by phosphatases such as ILKAP and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) (McDonald et al, 2008a). Important downstream targets of ILK signaling include PKB/Akt, GSK-3, β-catenin, p44/p42 MAP kinases, the myosin light chain (MLC) (Hannigan et al, 2011) and the Hippo pathway through Merlin's phosphatase MYPT1 (Serrano et al, 2013c). AKT is a regulator of cell survival and apoptosis.…”

Section: Functionmentioning

confidence: 99%