Dephosphorylation of cofilin is regulated through Ras and requires the combined activities of the Ras-effectors MEK and PI3K.
Remodeling of the actin cytoskeleton is crucial for a multitude of cellular functions including cell movement, intracellular transport as well as signal transduction and gene expression processes. Cofilin has been identified as a key mediator of actin reorganization. Its activity is regulated via reversible phosphorylation of ser-3. In a variety of cell types stimulation through particular surface receptors fastly induces the dephosphorylation/activation of cofilin. Yet, the signal transduction cascades linking receptor stimulation with cofilin activation have not been identified so far. Here we show that the GTPase Ras acts as a central regulator of the cofilin dephosphorylation pathway. Thus, stimulation of Ras through platelet-derived growth factor (PDGF) or transient expression of activated Ras-proteins induces the dephosphorylation of cofilin. Importantly, the cooperation of two Ras-initiated signaling pathways is required to induce cofilin dephosphorylation: a Ras-Raf-MAPkinase/Erk-kinase (MEK)- and a Ras-phosphatidylinositol-3-kinase (PI3K)-effector cascade.
Nebl
Gabriele
G
Institute for Immunology, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany. o66@ix.urz.uni-heidelberg.de
Fischer
Sabine
S
Penzel
Roland
R
Samstag
Yvonne
Y
D051339:Actin Depolymerizing Factors; D000199:Actins / Q000378:metabolism; D000818:Animals; D003599:Cytoskeleton / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D041681:NIH 3T3 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D018631:ras Proteins / Q000378:metabolism*
D051339:Actin Depolymerizing Factors; D000199:Actins; D004791:Enzyme Inhibitors; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; D008840:Microfilament Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010982:Platelet-Derived Growth Factor; D019908:Proto-Oncogene Proteins c-raf; D018631:ras Proteins; C482578:Map3k1 protein, mouse