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

Hannigan, Michael; Zhan, Lijun; Ai, Youxi; Kotlyarov, Alexey; Gaestel, Matthias; Huang, Chi‐Kuang

doi:10.4049/jimmunol.167.7.3953

Cited by 70 publications

(51 citation statements)

References 73 publications

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“…Remodeling of the actin cytoskeleton is a prerequisite for cell migration, and phosphorylation of Hsp27 by MK2/3 was shown to contribute to cell motility (237). Consistent with this, MK2-deficient neutrophils have defects in chemotaxis and altered chemokinesis (146). The exact contribution of other MK2/3 substrates involved in actin remodeling remains elusive.…”

Section: Mk2/3mentioning

confidence: 73%

Activation and Function of the MAPKs and Their Substrates, the MAPK-Activated Protein Kinases

Cargnello

Roux

2011

Microbiol Mol Biol Rev

2,599

1,619

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SUMMARY The mitogen-activated protein kinases (MAPKs) regulate diverse cellular programs by relaying extracellular signals to intracellular responses. In mammals, there are more than a dozen MAPK enzymes that coordinately regulate cell proliferation, differentiation, motility, and survival. The best known are the conventional MAPKs, which include the extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun amino-terminal kinases 1 to 3 (JNK1 to -3), p38 (α, β, γ, and δ), and ERK5 families. There are additional, atypical MAPK enzymes, including ERK3/4, ERK7/8, and Nemo-like kinase (NLK), which have distinct regulation and functions. Together, the MAPKs regulate a large number of substrates, including members of a family of protein Ser/Thr kinases termed MAPK-activated protein kinases (MAPKAPKs). The MAPKAPKs are related enzymes that respond to extracellular stimulation through direct MAPK-dependent activation loop phosphorylation and kinase activation. There are five MAPKAPK subfamilies: the p90 ribosomal S6 kinase (RSK), the mitogen- and stress-activated kinase (MSK), the MAPK-interacting kinase (MNK), the MAPK-activated protein kinase 2/3 (MK2/3), and MK5 (also known as p38-regulated/activated protein kinase [PRAK]). These enzymes have diverse biological functions, including regulation of nucleosome and gene expression, mRNA stability and translation, and cell proliferation and survival. Here we review the mechanisms of MAPKAPK activation by the different MAPKs and discuss their physiological roles based on established substrates and recent discoveries.

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Section: Mk2/3mentioning

confidence: 73%

Activation and Function of the MAPKs and Their Substrates, the MAPK-Activated Protein Kinases

Cargnello

Roux

2011

Microbiol Mol Biol Rev

2,599

1,619

View full text Add to dashboard Cite

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“…The targeted deletion of the mk2 gene in mice provided the unexpected result that, although p38 mediates the activation of many similar kinases, MK2 seems to be the key kinase responsible for these p38-dependent biological processes (101,102). Loss of MK2 leads to a defect in lipopolysaccharideinduced synthesis of cytokines such as tumor necrosis factor alpha, interleukin-6, and gamma interferon (101) and also to changes in the migration of mouse embryonic fibroblasts, smooth muscle cells, and neutrophils (75,102,132). Consistent with a role for MK2 in inflammatory responses, MK2-deficient mice show increased susceptibility to Listeria monocytogenes infection (109) and reduced inflammation-mediated neuronal death following focal ischemia (218).…”

Section: Mk2 and -3 Subfamilymentioning

confidence: 99%

ERK and p38 MAPK-Activated Protein Kinases: a Family of Protein Kinases with Diverse Biological Functions

Roux

Blenis

2004

Microbiol Mol Biol Rev

2,171

1,861

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Conserved signaling pathways that activate the mitogen-activated protein kinases (MAPKs) are involved in relaying extracellular stimulations to intracellular responses. The MAPKs coordinately regulate cell proliferation, differentiation, motility, and survival, which are functions also known to be mediated by members of a growing family of MAPK-activated protein kinases (MKs; formerly known as MAPKAP kinases). The MKs are related serine/threonine kinases that respond to mitogenic and stress stimuli through proline-directed phosphorylation and activation of the kinase domain by extracellular signal-regulated kinases 1 and 2 and p38 MAPKs. There are currently 11 vertebrate MKs in five subfamilies based on primary sequence homology: the ribosomal S6 kinases, the mitogen- and stress-activated kinases, the MAPK-interacting kinases, MAPK-activated protein kinases 2 and 3, and MK5. In the last 5 years, several MK substrates have been identified, which has helped tremendously to identify the biological role of the members of this family. Together with data from the study of MK-knockout mice, the identities of the MK substrates indicate that they play important roles in diverse biological processes, including mRNA translation, cell proliferation and survival, and the nuclear genomic response to mitogens and cellular stresses. In this article, we review the existing data on the MKs and discuss their physiological functions based on recent discoveries

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“…2/2 mouse embryonic fibroblasts (MEFs) and smooth muscle cells showed reduced migration (Kotlyarov et al, 2002), whereas MK2 2/2 neutrophils showed a partial loss of directionality but higher migration speed (Hannigan et al, 2001).…”

Section: Mk2-dependent Regulation Of Actin Remodeling and Cell Migrationmentioning

confidence: 99%

Mitogen-Activated Protein Kinase–Activated Protein Kinase 2 in Neuroinflammation, Heat Shock Protein 27 Phosphorylation, and Cell Cycle: Role and Targeting

2013

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Mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MAPKAPK-2 or MK2) is a downstream substrate of the p38 MAPK responsible for the signaling events influencing inflammation, cell division and differentiation, apoptosis, and cell motility in response to a wide range of extracellular stimuli. After the failure of p38 MAPK inhibitors in clinical trials, MK2 was unveiled as a potential target to regulate inflammatory cytokines' mRNA stability and translation. Recent work suggests that this mechanism may underlie the pathophysiology of brain disorders associated with inflammation. In addition, MK2 is a prominent kinase that phosphorylates heat shock protein 27 (Hsp27), an intensively investigated biomarker of cancer progression. This phosphorylation decreases the chaperone properties of Hsp27, making MK2 an endogenous inhibitor of Hsp27. MK2 is also one of the major players in the signal transduction pathways activated in response to DNA damage. Experimental evidence highlights the role of MK2 in G 2 /M and the mitotic spindle checkpoints, two mechanisms by which MK2 contributes to the maintenance of genomic stability. Thus, MK2 is considered a good molecular target to increase, in combination with chemotherapeutic agents, the sensitivity of treatment, especially in p53-mutated tumors. This review looks at the functions of MK2 in inflammation, Hsp27 regulation, and cell cycle checkpoint control with a focus on brain pathologies. Analysis of MK2 signaling in various disease models and a summary of the data on MK2 inhibitors suggest novel indications for MK2 inhibitors in addition to their mainstream use against peripheral inflammatory disorders.

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

Cited by 70 publications

References 73 publications

Activation and Function of the MAPKs and Their Substrates, the MAPK-Activated Protein Kinases

Activation and Function of the MAPKs and Their Substrates, the MAPK-Activated Protein Kinases

ERK and p38 MAPK-Activated Protein Kinases: a Family of Protein Kinases with Diverse Biological Functions

Mitogen-Activated Protein Kinase–Activated Protein Kinase 2 in Neuroinflammation, Heat Shock Protein 27 Phosphorylation, and Cell Cycle: Role and Targeting

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