Characterization of an Autoinhibitory Domain in Human Mitogen-activated Protein Kinase-activated Protein Kinase 2

Zu, Youli; Ai, Youxi; Huang, Chi‐Kuang

doi:10.1074/jbc.270.1.202

Cited by 45 publications

(33 citation statements)

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“…Thr 317 of the p54 isoform of MK2 (Thr 334 of the p46; Ref. 60) has been shown as the major phosphorylation site of p38 MAPK, and its phosphorylation is required for activation and nuclear export of MK2 (29,34). We have previously prepared anti-phosphopeptide Abs that recognize the Thr 317 -phosphorylated form of MK2 in neutrophils stimulated by fMLP (56,60).…”

Section: Intracellular Staining Pattern Of Phospho-mk2mentioning

confidence: 99%

Abnormal Migration Phenotype of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2−/− Neutrophils in Zigmond Chambers Containing Formyl-Methionyl-Leucyl-Phenylalanine Gradients

Hannigan

Zhan

et al. 2001

The Journal of Immunology

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Time-lapsed video microscopy and confocal imaging were used to study the migration of wild-type (WT) and mitogen-activated protein kinase-activated protein kinase 2 (MK2)−/− mouse neutrophils in Zigmond chambers containing fMLP gradients. Confocal images of polarized WT neutrophils showed an intracellular gradient of phospho-MK2 from the anterior to the posterior region of the neutrophils. Compared with WT neutrophils, MK2−/− neutrophils showed a partial loss of directionality but higher migration speed. Immunoblotting experiments showed a lower protein level of p38 mitogen-activated protein kinase and a loss of fMLP-induced extracellular signal-related kinase phosphorylation in MK2−/− neutrophils. These results suggest that MK2 plays an important role in the regulation of neutrophil migration and may also affect other signaling molecules.

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Section: Intracellular Staining Pattern Of Phospho-mk2mentioning

confidence: 99%

Abnormal Migration Phenotype of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2−/− Neutrophils in Zigmond Chambers Containing Formyl-Methionyl-Leucyl-Phenylalanine Gradients

Hannigan

Zhan

et al. 2001

The Journal of Immunology

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“…In in vitro studies, both Erk and p38 MAP kinases can phosphorylate and activate MAPKAP kinase 2 [17,22]. To detect tissue/cellular MAPKAP kinase 2 activity, a synthetic peptide derived from the N-terminus of glycogen synthase [22] is widely used as a specific substrate in in vitro kinase assays.…”

Section: Controlmentioning

confidence: 99%

“…To examine MAPKAP kinase 2, a synthetic peptide substrate derived from the glycogen synthase N-terminus (KKPLNRT-LSVASLPG-amide) was used [17]. The kinase assay was initiated by adding 15 /ag of supernatant protein to a 40/al reaction mixture con- The reaction was allowed to proceed for 10 min at 30°C.…”

Section: Enzymatic Assay Of Protein Kinase C Map Kinases and Mapkapmentioning

confidence: 99%

Ischemic preconditioning triggers the activation of MAP kinases and MAPKAP kinase 2 in rat hearts

et al. 1996

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While much is known about the beneficial effects of myocardial stress adaptation, relatively less information is available about the adaptive mechanisms. To explore the signaling pathways of stress adaptation, isolated working rat hearts were divided into three groups. Group I was adapted to stress by conventional technique of repeated ischemia and reperfusion consisting of 5 min of isehemia followed by 10 rain of reperfusion, repeated four times. Group II was treated with 100 pM of genistein, a tyrosine kinase inhibitor, followed by preconditioning as described for group I. The third group, perfosed with buffer only for 60 rain, served as control. All hearts were subjected to 30 min of ischemia followed by 30 min of reperfusion. The results of our study demonstrated better postiscbemic myocardial functions in the preconditioned hearts as evidenced by increased aortic flow, coronary flow, developed pressure and lesser amount of tissue injury as evidenced by the decreased creatine kinase release. The preconditioning effects were associated with enhancement of phospholipase D activity in the heart. The preconditioning effect was almost abolished by the genistein treatment which also prevented the enhancement of phospholipase D activities. Additionally, preconditioning of the rat hearts stimulated protein kinase C, MAP kinase, and MAPKAP kinase 2 activities which were inhibited by genistein. The results identifies for the first time tyrosine kinasephospholipase D as potential signaling pathway for isehemic preconditioning, and implicates the involvement of multiple protein kinases in myocardial adaptation to ischemia.

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“…Two splice variants of MK2 have been identified. MK2a contains the nuclear localization signal (NLS) and the p38 docking domain, whereas MK2b is a truncated variant of MK2 that lacks the NLS and p38 docking domain (13,14). MK2b is still phosphorylated by p38␣ but the signal transduction is less efficient (15).…”

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Crystal Structure of the P38α-MAPKAP Kinase 2 Heterodimer

Haar

Prabakhar

Liu

et al. 2007

Journal of Biological Chemistry

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The p38 signaling pathway is activated in response to cell stress and induces production of proinflammatory cytokines. P38␣ is phosphorylated and activated in response to cell stress by MKK3 and MKK6 and in turn phosphorylates a number of substrates, including MAPKAP kinase 2 (MK2). We have determined the crystal structure of the unphosphorylated p38␣-MK2 heterodimer. The C-terminal regulatory domain of MK2 binds in the docking groove of p38␣, and the ATP-binding sites of both kinases are at the heterodimer interface. The conformation suggests an extra mechanism in addition to the regulation of the p38␣ and MK2 phosphorylation states that prevents phosphorylation of substrates in the absence of cell stress. Addition of constitutively active MKK6-DD results in rapid phosphorylation of the p38␣-MK2 heterodimer.The p38 signal transduction pathway regulates cellular inflammatory responses. The pathway is activated by proinflammatory cytokines, tumor necrosis factor ␣, bacterial lipopolysaccharides, or osmotic stress (1) and results in increased levels of tumor necrosis factor ␣, interleukin 1␤, interleukin 6, interleukin 10 interferon-␥, and COX-2 (2, 3). Inhibitors of this pathway have been demonstrated to reduce inflammation (4). The p38 kinase family has four members: P38␣, ␤, ␥, and ␦ (5). P38␣ and ␤ are the main transponders of the inflammatory response (6) and have been targets for anti-inflammatory therapy. Several p38␣ and ␤ inhibitors are in clinical trials for the treatment of chronic obstructive pulmonary disease, psoriasis, and rheumatoid arthritis (7). Activated p38␣ phosphorylates transcription factors such as ATF2, Elk-1, and MEF2A and downstream kinases such as MAPKAP kinase 2 (MK2), 2 MK3, PRAK, MNK1/2, and MSK1 (8, 9). Several p38␣ substrates are phosphorylated in the nucleus, others in the cytoplasm. MK2 also phosphorylates proteins found in both the nucleus (cAMP-response elementbinding protein, or CREB) (10) and cytoplasm (HSP25/27 and LSP-1) (11,12). Two splice variants of MK2 have been identified. MK2a contains the nuclear localization signal (NLS) and the p38 docking domain, whereas MK2b is a truncated variant of MK2 that lacks the NLS and p38 docking domain (13,14). MK2b is still phosphorylated by p38␣ but the signal transduction is less efficient (15). P38␣ forms a complex with MK2a even when the signaling pathway is not activated (16). This heterodimer is found mainly in the nucleus. Upon activation of the p38␣ signaling cascade, p38␣ and MK2a phosphorylate their nuclear substrates before translocating to the cytoplasm. P38␣ does not have a nuclear export signal (NES) and cannot leave the nucleus by itself but rather needs to be associated with MK2a. The NES of MK2a facilitates the transfer of both kinases from the nucleus to the cytoplasm but only after MK2 has been phosphorylated by p38␣ (17,18 has been demonstrated to be critical for the nuclear export of the p38␣-MK2 complex, whereas the kinase activity of MK2 is not (18). Phosphorylation of Thr 334 is believed to induce a conformation...

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Characterization of an Autoinhibitory Domain in Human Mitogen-activated Protein Kinase-activated Protein Kinase 2

Cited by 45 publications

References 44 publications

Abnormal Migration Phenotype of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2−/− Neutrophils in Zigmond Chambers Containing Formyl-Methionyl-Leucyl-Phenylalanine Gradients

Abnormal Migration Phenotype of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2−/− Neutrophils in Zigmond Chambers Containing Formyl-Methionyl-Leucyl-Phenylalanine Gradients

Ischemic preconditioning triggers the activation of MAP kinases and MAPKAP kinase 2 in rat hearts

Crystal Structure of the P38α-MAPKAP Kinase 2 Heterodimer

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