Abstract
The MAPK-activated protein kinases belong to the Ca2+/calmodulin-dependent protein kinases. Within this group, MK2, MK3, and MK5 constitute three structurally related enzymes with distinct functions. Few genuine substrates for MK5 have been identified, and the only known biological role is in ras-induced senescence and in tumor suppression. Here we demonstrate that activation of cAMP-dependent protein kinase (PKA) or ectopic expression of the catalytic subunit Calpha in PC12 cells results in transient nuclear export of MK5, which requires the kinase activity of both Calpha and MK5 and the ability of Calpha to enter the nucleus. Calpha and MK5, but not MK2, interact in vivo, and Calpha increases the kinase activity of MK5. Moreover, Calpha augments MK5 phosphorylation, but not MK2, whereas MK5 does not seem to phosphorylate Calpha. Activation of PKA can induce actin filament accumulation at the plasma membrane and formation of actin-based filopodia. We demonstrate that small interfering RNA-triggered depletion of MK5 interferes with PKA-induced F-actin rearrangement. Moreover, cytoplasmic expression of an activated MK5 variant is sufficient to mimic PKA-provoked F-actin remodeling. Our results describe a novel interaction between the PKA pathway and MAPK signaling cascades and suggest that MK5, but not MK2, is implicated in PKA-induced microfilament rearrangement.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actin Cytoskeleton / genetics
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Actin Cytoskeleton / metabolism*
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Actins / genetics
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Actins / metabolism*
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Active Transport, Cell Nucleus / drug effects
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Active Transport, Cell Nucleus / physiology
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Animals
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Catalytic Domain / genetics
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Cell Nucleus / enzymology*
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Cell Nucleus / genetics
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Cyclic AMP / genetics
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Cyclic AMP / metabolism
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Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
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Cyclic AMP-Dependent Protein Kinases / genetics
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Cyclic AMP-Dependent Protein Kinases / metabolism*
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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PC12 Cells
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Phosphorylation / drug effects
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Pseudopodia / enzymology*
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RNA, Small Interfering
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Rats
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Tumor Suppressor Proteins / antagonists & inhibitors
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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ras Proteins / genetics
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ras Proteins / metabolism
Substances
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Actins
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Intracellular Signaling Peptides and Proteins
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RNA, Small Interfering
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Tumor Suppressor Proteins
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MAP-kinase-activated kinase 5
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Cyclic AMP
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Protein Serine-Threonine Kinases
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Cyclic AMP-Dependent Protein Kinases
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ras Proteins