Modulation of integrin signal transduction by ILKAP, a protein phosphatase 2C associating with the integrin-linked kinase, ILK1.
ILKAP, a protein serine/threonine (S/T) phosphatase of the PP2C family, was isolated in a yeast two-hybrid screen baited with integrin-linked kinase, ILK1. Association of ILK1 and ILKAP was independent of the catalytic activity of either partner, as assayed in co-precipitation and two-hybrid experiments. Condi tional expression of ILKAP in HEK ... 293 cells resulted in selective inhibition of ECM- and growth factor-stimulated ILK1 activity, but did not inhibit Raf-1 kinase activity. A catalytic mutant of ILKAP, H154D, did not inhibit ILK1 kinase activity. Two cellular targets of ILK1, glycogen synthase kinase 3 beta (GSK3beta) and protein kinase B (PKB)/AKT, were differentially affected by ILKAP-mediated inhibition of ILK1. Catalytically active, but not mutant ILKAP, strongly inhibited insulin-like growth factor-1-stimulated GSK3beta phosphorylation on Ser9, but did not affect phosphorylation of PKB on Ser473, suggesting that ILKAP selectively affects ILK-mediated GSK3beta signalling. Consistent with this, active, but not H154D mutant or the related PP2Calpha, selectively inhibited transactivation of a Tcf/Lef reporter gene, TOPFlash, in 293 cells. We propose that ILKAP regulates ILK1 activity, targeting ILK1 signalling of Wnt pathway components via modulation of GSK3beta phosphorylation.
Mesh Terms:
Calcium-Calmodulin-Dependent Protein Kinases, Carrier Proteins, Catalysis, Cell Line, Gene Expression, Genes, Reporter, Glycogen Synthase Kinase 3, Glycogen Synthase Kinases, Humans, Insulin-Like Growth Factor I, Integrins, Isoenzymes, Kidney, Molecular Sequence Data, Mutagenesis, Site-Directed, Phosphoprotein Phosphatases, Phosphorylation, Protein Phosphatase 2, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-raf, Saccharomyces cerevisiae Proteins, Sequence Homology, Amino Acid, Signal Transduction, Transcriptional Activation, Transfection, Two-Hybrid System Techniques
Calcium-Calmodulin-Dependent Protein Kinases, Carrier Proteins, Catalysis, Cell Line, Gene Expression, Genes, Reporter, Glycogen Synthase Kinase 3, Glycogen Synthase Kinases, Humans, Insulin-Like Growth Factor I, Integrins, Isoenzymes, Kidney, Molecular Sequence Data, Mutagenesis, Site-Directed, Phosphoprotein Phosphatases, Phosphorylation, Protein Phosphatase 2, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-raf, Saccharomyces cerevisiae Proteins, Sequence Homology, Amino Acid, Signal Transduction, Transcriptional Activation, Transfection, Two-Hybrid System Techniques
EMBO J.
Date: May. 01, 2001
PubMed ID: 11331582
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