Plectin-controlled keratin cytoarchitecture affects MAP kinases involved in cellular stress response and migration.
Plectin is a major intermediate filament (IF)-based cytolinker protein that stabilizes cells and tissues mechanically, regulates actin filament dynamics, and serves as a scaffolding platform for signaling molecules. In this study, we show that plectin deficiency is a cause of aberrant keratin cytoskeleton organization caused by a lack of orthogonal IF cross-linking. Keratin networks in plectin-deficient cells were more susceptible to osmotic shock-induced retraction from peripheral areas, and their okadaic acid-induced disruption (paralleled by stress-activated MAP kinase p38 activation) proceeded faster. Basal activities of the MAP kinase Erk1/2 and of the membrane-associated upstream protein kinases c-Src and PKCdelta were significantly elevated, and increased migration rates, as assessed by in vitro wound-closure assays and time-lapse microscopy, were observed. Forced expression of RACK1, which is the plectin-binding receptor protein for activated PKCdelta, in wild-type keratinocytes elevated their migration potential close to that of plectin-null cells. These data establish a link between cytolinker-controlled cytoarchitecture/scaffolding functions of keratin IFs and specific MAP kinase cascades mediating distinct cellular responses.
Osmanagic-Myers
Selma
S
Department of Molecular Cell Biology, Max F. Perutz Laboratories, University of Vienna, A-1030 Vienna, Austria.
Gregor
Martin
M
Walko
Gernot
G
Burgstaller
Gerald
G
Reipert
Siegfried
S
Wiche
Gerhard
G
D000818:Animals; D002465:Cell Movement / Q000502:physiology; D003599:Cytoskeleton / Q000378:metabolism* / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007381:Intermediate Filament Proteins / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism / Q000648:ultrastructure; D007633:Keratins / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism; D009479:Neuropeptides / Q000187:drug effects / Q000378:metabolism; D019319:Okadaic Acid / Q000494:pharmacology; D009997:Osmotic Pressure; D051179:Plakins / Q000235:genetics / Q000378:metabolism*; D051190:Plectin / Q000235:genetics / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000187:drug effects / Q000378:metabolism; D000075370:Receptors for Activated C Kinase; D013312:Stress, Physiological / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D019061:src-Family Kinases / Q000187:drug effects / Q000378:metabolism
D004791:Enzyme Inhibitors; D007381:Intermediate Filament Proteins; D009479:Neuropeptides; D051179:Plakins; C495333:Plec protein, mouse; D051190:Plectin; C090294:RACK1 protein, mouse; D000075370:Receptors for Activated C Kinase; D019319:Okadaic Acid; D007633:Keratins; D019061:src-Family Kinases; D051745:Protein Kinase C-delta; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases