Modulation of F-actin Rearrangement by the Cyclic AMP/cAMP-dependent Protein Kinase (PKA) Pathway Is Mediated by MAPK-activated Protein Kinase 5 and Requires PKA-induced Nuclear Export of MK5

Gerits, Nancy; Mikalsen, Theresa; Kostenko, Sergiy; Shiryaev, Alexey; Johannessen, Mona; Moens, Ugo

doi:10.1074/jbc.m704873200

Cited by 64 publications

(107 citation statements)

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“…Furthermore, MK5 may also be activated by PKA. In unstimulated cells, MK5 is located primarily in the nucleus whereas treatment of PC12 cells with the cAMP-elevating agent forskolin or overexpressing the catalytic subunit of PKA result in both a transient nuclear export and modest activation of MK5 [71]. Forskolin induces a similar nuclear export of MK5 in HeLa cells [71].…”

Section: Discussionmentioning

confidence: 86%

“…In HEK293 cells, forskolin-mediated hsp27 phosphorylation is suppressed by depletion of MK5, but not MK2 [73]. Forskolin also induces F-actin remodelling in PC12 cells and this remodelling is inhibited by siRNA-mediated MK5 knockdown [71] or overexpression of a nonphosphorylatable hsp27 mutant (S-15,78,82-A) [66]. In contrast, treatment of U251 MG human glioma cells with either forskolin or cholera toxin failed to induce dissociation of hsp27 aggregates whereas PMA induced a rapid redistribution of hsp27 from large aggregates into smaller complexes [9].…”

Section: Discussionmentioning

confidence: 88%

“…In unstimulated cells, MK5 is located primarily in the nucleus whereas treatment of PC12 cells with the cAMP-elevating agent forskolin or overexpressing the catalytic subunit of PKA result in both a transient nuclear export and modest activation of MK5 [71]. Forskolin induces a similar nuclear export of MK5 in HeLa cells [71]. This translocation requires catalytically active forms of both MK5 and PKA and the PKA-mediated phosphorylation of MK5 at Ser-115 [72].…”

Section: Discussionmentioning

confidence: 91%

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Characterization of hsp27 kinases activated by elevated aortic pressure in heart

et al. 2012

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Chronic hemodynamic overload results in left ventricular hypertrophy, fibroblast proliferation, and interstitial fibrosis. The small heat shock protein hsp27 has been shown to be cardioprotective and this requires a phosphorylatable form of this protein. To further understand the regulation of hsp27 in heart in response to stress, we investigated the ability of elevated aortic pressure to activate hsp27-kinase activities. Isolated hearts were subjected to retrograde perfusion and then snapfrozen. Hsp27-kinase activity was measured in vitro as hsp27 phosphorylation. Immune complex assays revealed that MK2 activity was low in non-perfused hearts and increased following crystalline perfusion at 60 or 120 mmHg. Hsp27-kinase activities were further studied following ion-exchange chromatography. Anion exchange chromatography on Mono Q revealed 2 peaks ('b' and 'c') of hsp27-kinase activity. A third peak 'a' was detected upon chromatography of the Mono Q flow-through fractions on the cation exchange resin, Mono S. The hsp27-kinase activity underlying peaks 'a' and 'c' increased as perfusion pressure was increased from 40 to 120 mmHg. In contrast, peak 'b' increased over pressures 60-100 mmHg but was decreased at 120 mmHg. Peaks 'a', 'b', and 'c' contained MK2 immunoreactivity, whereas MK3 and MK5 immunoreactivity was detected in peak 'a'. p38 MAPK and phospho-p38 MAPK were also detected in peaks 'b' and 'c' but absent from peak 'a'. Hsp27-kinase activity in peaks 'b' and 'c' (120 mmHg) eluted from a Superose 12 gel filtration column with an apparent molecular mass of 50-kDa. Hence, peaks 'b' and 'c' were not a result of MK2 forming complexes. In-gel hsp27-kinase assays revealed a single 49-kDa renaturable hsp27-kinase activity in peaks 'b' and 'c' at 60 mmHg, whereas several hsp27-kinases (p43, p49, p54, p66) were detected in peaks 'b' and 'c' from hearts perfused at 120 mmHg. Thus, multiple hsp27-kinases were activated in response to elevated aortic pressure in isolated, perfused rat hearts and hence may be implicated in regulating the cardioprotective effects of hsp27 and thus may represent targets for cardioprotective therapy.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 91%

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Characterization of hsp27 kinases activated by elevated aortic pressure in heart

et al. 2012

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“…Biological functions of MK5 are poorly understood despite the high similarity in structure with other widely studied members of the subgroup [3] . Recent studies have highlighted the importance of MK5 in ras-induced senescence, antiproliferation, tumor suppression, anxiety-related behavior, energy-depletioninduced suppression of mammalian target of rapamycin C1, rearrangements of the cytoskeleton, endothelial cell migration, and tumor angiogenesis [4][5][6][7][8][9] . Several bona fide substrates have been identified, including extracellular signal-regulated kinase (ERK)3, ERK4, 14-3-3ε, p53, Ras homolog enriched in brain (Rheb) and heat shock protein (Hsp)27 [6,8,[10][11][12][13][14][15] .…”

Section: Introductionmentioning

confidence: 99%

“…These GTP-binding proteins are involved in diverse processes such as cytokinesis, membrane remodeling and compartmentalization, cytoskeleton rearrangement, vesicle trafficking, and apoptosis [18,20,21] . Knockout mice have been generated for SEPT3, 4,5,6, 7 and 9 genes [22] .…”

Section: Introductionmentioning

confidence: 99%

Septin 8 is an interaction partner and in vitro substrate of MK5

Shiryaev

Kostenko²,

Dumitriu³

et al. 2012

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AIM:To identify novel substrates for the mitogen-activated protein kinase-activated protein kinase 5 (MK5). METHODS:Yeast two-hybrid screening with MK5 as bait was used to identify novel possible interaction partners. The binding of putative partner was further examined by glutathione S-transferase (GST) pull-down, co-immunoprecipitation and fluorescence resonance energy transfer (FRET) analysis. In vitro kinase and peptide array assays were used to map MK5 phosphoacceptor sites on the new partner. Confocal microscopy was performed to study the subcellular localization of MK5 and its partners. RESULTS:Septin 8 was identified as a novel interaction partner for MK5 by yeast two-hybrid screening. This interaction was confirmed by GST pull-down, coimmunoprecipitation and FRET analysis. Septin 5, which can form a complex with septin 8, did not interact with MK5. Serine residues 242 and 271 on septin 8 were identified as in vitro MK5 phosphorylation sites. MK5and septin 8 co-localized in the perinuclear area and in cell protrusions. Moreover, both proteins co-localized with vesicle marker synaptophysin. CONCLUSION:Septin 8 is a bona fide interaction partner and in vitro substrate for MK5. This interaction may be implicated in vesicle trafficking.

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TLK1‐mediated MK5‐S354 phosphorylation drives prostate cancer cell motility and may signify distinct pathologies

et al. 2022

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Metastases account for the majority of prostate cancer (PCa) deaths, and targeting them is a major goal of systemic therapy. We identified a novel interaction between two kinases: tousled-like kinase 1 (TLK1) and MAP kinase-activated protein kinase 5 (MK5) that promotes PCa spread. In PCa progression, TLK1-MK5 signalling appears to increase following antiandrogen treatment and in metastatic castration-resistant prostate cancer (mCRPC) patients. Determinations of motility rates (2D and 3D) of different TLK1-and MK5-perturbed cells, including knockout (KO) and knockdown (KD), as well as the use of specific inhibitors, showed the importance of these two proteins for in vitro dissemination. We established that TLK1 phosphorylates MK5 on three residues (S160, S354 and S386), resulting in MK5 activation, and additionally, mobility shifts of MK5 also supported its phosphorylation by TLK1 in transfected HEK 293 cells. Expression of MK5-S354A or kinase-dead MK5 in MK5-depleted mouse embryonic fibroblast (MEF) cells failed to restore their motility compared with that of wild-type (WT) MK5-rescued MK5 À/À MEF cells. A pMK5-S354 antiserum was used to establish this site as an authentic TLK1 target in androgen-sensitive human prostate adenocarcinoma (LNCaP) cells, and was used in immunohistochemistry (IHC) studies of age-related PCa sections from TRAMP (transgenic adenocarcinoma of the mouse prostate) mice and to probe a human tissue microarray (TMA), which revealed pMK5-S354 level is correlated with disease progression (Gleason score and nodal metastases). In addition, The Cancer Genome Atlas (TCGA) analyses of PCa expression and genome-wide association study (GWAS) relations identify TLK1 and MK5 as potential drivers of advanced PCa and as markers of mCRPC. Our work suggests that TLK1-MK5 signalling is functionally involved in driving PCa cell motility and clinical features of aggressiveness; hence, disruption of this axis may inhibit the metastatic spread of PCa.

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Modulation of F-actin Rearrangement by the Cyclic AMP/cAMP-dependent Protein Kinase (PKA) Pathway Is Mediated by MAPK-activated Protein Kinase 5 and Requires PKA-induced Nuclear Export of MK5

Cited by 64 publications

References 63 publications

Characterization of hsp27 kinases activated by elevated aortic pressure in heart

Characterization of hsp27 kinases activated by elevated aortic pressure in heart

Septin 8 is an interaction partner and in vitro substrate of MK5

TLK1‐mediated MK5‐S354 phosphorylation drives prostate cancer cell motility and may signify distinct pathologies

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