Direct stimulation of receptor-controlled phospholipase D1 by phospho-cofilin.
The activity state of cofilin, which controls actin dynamics, is driven by a phosphorylation-dephosphorylation cycle. Phosphorylation of cofilin by LIM-kinases results in its inactivation, a process supported by 14-3-3zeta and reversed by dephosphorylation by slingshot phosphatases. Here we report on a novel cellular function for the phosphorylation-dephosphorylation cycle of cofilin. We demonstrate that muscarinic receptor-mediated stimulation of phospholipase D1 (PLD1) is controlled by LIM-kinase, slingshot phosphatase as well as 14-3-3zeta, and requires phosphorylatable cofilin. Cofilin directly and specifically interacts with PLD1 and upon phosphorylation by LIM-kinase1, stimulates PLD1 activity, an effect mimicked by phosphorylation-mimic cofilin mutants. The interaction of cofilin with PLD1 is under receptor control and encompasses a PLD1-specific fragment (aa 585-712). Expression of this fragment suppresses receptor-induced cofilin-PLD1 interaction as well as PLD stimulation and actin stress fiber formation. These data indicate that till now designated inactive phospho-cofilin exhibits an active cellular function, and suggest that phospho-cofilin by its stimulatory effect on PLD1 may control a large variety of cellular functions.
Han
Li
L
Institut für Pharmakologie, Universitätsklinikum Essen, Essen, Germany.
Stope
Matthias B
MB
de Jesús
Maider López
ML
Oude Weernink
Paschal A
PA
Urban
Martina
M
Wieland
Thomas
T
Rosskopf
Dieter
D
Mizuno
Kensaku
K
Jakobs
Karl H
KH
Schmidt
Martina
M
D048948:14-3-3 Proteins; D000199:Actins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D015870:Gene Expression; D006801:Humans; D054461:Lim Kinases; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010739:Phospholipase D / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D011976:Receptors, Muscarinic / Q000235:genetics / Q000378:metabolism*
D048948:14-3-3 Proteins; D000199:Actins; D009687:Nuclear Proteins; D011976:Receptors, Muscarinic; C482983:YWHAE protein, human; C068921:p80-coilin; D011494:Protein Kinases; C515892:LIMK1 protein, human; D054461:Lim Kinases; D010739:Phospholipase D; C106801:phospholipase D1