PKCepsilon is a permissive link in integrin-dependent IFN-gamma signalling that facilitates JAK phosphorylation of STAT1.
The critical dependence of receptor-triggered signals on integrin-mediated cell-substrate interactions represents a fundamental biological paradigm in health and disease. However, the molecular connections of these permissive inputs, which operate through integrin-matrix interactions, has remained largely obscure. Here we show that the serine-threonine kinase protein kinase C epsilon (PKCepsilon) functions as a signal integrator between cytokine and integrin signalling pathways. Integrins are shown to control PKCepsilon phosphorylation acutely by determining complex formation with protein phosphatase 2A (PP2A) and the upstream kinase PDK1 (phosphoinositide-dependent kinase 1). The PP2A-induced loss of PKCepsilon function results in attenuated interferon gamma (INF-gamma)-induced phosphorylation of STAT1 (signal transducer and activator of transcription 1) downstream of Janus kinase 1/2 (JAK1/2). PKCepsilon function and the IFN-gamma response can be recovered by inhibition of PP2A if PDK1 is associated with PKCepsilon in this complex. More directly, a PP2A-resistant mutant of PKCepsilon is sufficient for restoration of the IFN-gamma response in suspension culture. Thus, PKCepsilon functions as a central point of integration through which integrin engagement exerts a permissive input on IFN-gamma signalling.
Ivaska
Johanna
J
Protein Phosphorylation Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Bosca
Lisardo
L
Parker
Peter J
PJ
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005057:Eukaryotic Cells / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D053613:Janus Kinase 1; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000172:deficiency* / Q000235:genetics; D051744:Protein Kinase C-epsilon; D054648:Protein Phosphatase 2; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D016023:Integrins; D011956:Receptors, Cell Surface; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D007371:Interferon-gamma; C497256:Prkce protein, mouse; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578562:PDPK1 protein, human; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; C497255:PRKCE protein, human; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2