Serine residue 115 of MAPK-activated protein kinase MK5 is crucial for its PKA-regulated nuclear export and biological function

Kostenko, Sergiy; Shiryaev, Alexey; Gerits, Nancy; Dumitriu, Gianina; Klenow, Helle Bagterp; Johannessen, Mona; Moens, Ugo

doi:10.1007/s00018-010-0496-2

Cited by 16 publications

(28 citation statements)

References 47 publications

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“…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]. In HEK293 cells, forskolin-mediated hsp27 phosphorylation is suppressed by depletion of MK5, but not MK2 [73].…”

Section: Discussionmentioning

confidence: 95%

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: 95%

Characterization of hsp27 kinases activated by elevated aortic pressure in heart

et al. 2012

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“…MK5 phosphorylations at have been reported (New et al , 1998 ;Marasa et al , 2009 ;Mayya et al , 2009 ;Kostenko et al , 2011b ;Weber et al , 2012 ;Shiromizu et al , 2013 ). Phosphorylation of Ser-115 and Thr-182 stimulates the activity of MK5 (see further), while the functional implications of the other phosphorylations are not known.…”

Section: The Mk5 Proteinmentioning

confidence: 92%

“…PKA-phosphorylated MK5 displayed a higher catalytic activity toward ERK3 and the synthetic Praktide substrate than the nonphosphorylated form (Gerits et al , 2007a ). A phosphomimicking MK5 S115D mutant, but not wild-type MK5, is able to stimulate the transcriptional activity of p53 and trigger HSP27 phosphorylation in cells (Kostenko et al , 2011b ). We have not investigated whether phosphorylation of Ser-115 stimulates phosphorylation of Thr-182.…”

Section: Regulation Of Activitymentioning

confidence: 96%

“…Indeed, several groups showed that endogenous as well as fusion proteins of MK5 and green fluorescence protein (GFP) or small tags were predominantly nuclear, but the protein can shuttle between the nucleus and the cytoplasm (Seternes et al , 2002 ;New et al , 2003 ;Schumacher et al , 2004 ;Seternes et al , 2004 ;Kant et al , 2006 ;Gerits et al , 2007a ;D é l é ris et al, 2008 ;Hansen et al , 2008 ;Gong et al , 2010 ;Kostenko et al , 2011b ). The conformation of MK5 and the interaction with other proteins probably determine which of the subcellular localization signals is exposed and, therefore, regulates the location of MK5.…”

Section: Subcellular Localizationmentioning

confidence: 98%

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Structure and function of MK5/PRAK: the loner among the mitogen-activated protein kinase-activated protein kinases

Moens

Kostenko²

2013

Biological Chemistry

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Mitogen-activated protein kinase (MAPK) pathways are important signal transduction pathways that control pivotal cellular processes including proliferation, differentiation, survival, apoptosis, gene regulation, and motility. MAPK pathways consist of a relay of consecutive phosphorylation events exerted by MAPK kinase kinases, MAPK kinases, and MAPKs. Conventional MAPKs are characterized by a conserved Thr-X-Tyr motif in the activation loop of the kinase domain, while atypical MAPKs lack this motif and do not seem to be organized into the classical three-tiered kinase cascade. One functional group of conventional and atypical MAPK substrates consists of protein kinases known as MAPK-activated protein kinases. Eleven mammalian MAPK-activated protein kinases have been identified, and they are divided into five subgroups: the ribosomal-S6-kinases RSK1-4, the MAPK-interacting kinases MNK1 and 2, the mitogen- and stress-activated kinases MSK1 and 2, the MAPK-activated protein kinases MK2 and 3, and the MAPK-activated protein kinase MK5 (also referred to as PRAK). MK5/PRAK is the only MAPK-activated protein kinase that is a substrate for both conventional and atypical MAPK, while all other MAPKAPKs are exclusively phosphorylated by conventional MAPKs. This review focuses on the structure, activation, substrates, functions, and possible implications of MK5/PRAK in malignant and nonmalignant diseases.

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“…MAPK pathways mediate cellular responses to many different extracellular signaling molecules such as the ones involved in differentiation, gene expression, regulation of proliferation, apoptosis, development, motility or metabolism. The typical MAPK pathways, characterized by the ERK1/2, ERK5, JNK, and p38 MAPK components, comprise a cascade of three successive phosphorylation events exerted by a MAPK kinase kinase (MAPKKK), a MAPK kinase (MAPKK), and a MAPK (Kostenko et al, 2011).…”

mentioning

confidence: 99%

Biological Effects Induced by Ultraviolet Radiation in Human Fibroblasts

Gaiba¹,

Tucci-Viegas²,

França³

et al. 2012

Flow Cytometry - Recent Perspectives

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Serine residue 115 of MAPK-activated protein kinase MK5 is crucial for its PKA-regulated nuclear export and biological function

Cited by 16 publications

References 47 publications

Characterization of hsp27 kinases activated by elevated aortic pressure in heart

Characterization of hsp27 kinases activated by elevated aortic pressure in heart

Structure and function of MK5/PRAK: the loner among the mitogen-activated protein kinase-activated protein kinases

Biological Effects Induced by Ultraviolet Radiation in Human Fibroblasts

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