Structure of Mitogen-activated Protein Kinase-activated Protein (MAPKAP) Kinase 2 Suggests a Bifunctional Switch That Couples Kinase Activation with Nuclear Export

Meng, Wuyi; Swenson, Lora; Fitzgibbon, Matthew J.; Hayakawa, Koto; Haar, Ernst ter; Behrens, Anne E.; Fulghum, John R.; Lippke, Judith A.

doi:10.1074/jbc.c200418200

Cited by 117 publications

(117 citation statements)

References 30 publications

(27 reference statements)

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“…Mutation of both Thr 344 and the T-loop phosphorylation site in MAPKAPK2 to acidic residues resulted in a kinase that is constitutively active [34,35]. In combination with structural information from crystallographic studies [36,37] this has suggested a model for MAPKAPK2 activation in which phosphorylation of Thr 334 promotes the dissociation of an autoinhibitory C-terminal helix from the substrate-binding groove of the kinase domain, while phosphorylation of the activation loop on Thr 222 stabilizes its structure and promotes substrate binding [35,37].…”

Section: Discussionmentioning

confidence: 99%

Identification of novel phosphorylation sites in MSK1 by precursor ion scanning MS

McCoy

Macdonald

Morrice

et al. 2007

Biochemical Journal

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MSK1 (mitogen-and stress-activated kinase 1) is a dual kinase domain protein that acts downstream of the ERK1/2 (extracellular-signal-regulated kinase 1/2) and p38 MAPK (mitogenactivated protein kinase) signalling pathways in cells. MSK1, and its related isoform MSK2, phosphorylate the transcription factors CREB (cAMP-response-element-binding protein) and ATF1 (activating transcription factor 1), and the chromatin proteins histone H3 and HMGN1 (high-mobility-group nucleosomalbinding protein 1) in response to either mitogenic stimulation or cellular stress. MSK1 activity is tightly regulated in cells, and activation requires the phosphorylation of MSK1 by either ERK1/2 or p38α. This results in activation of the C-terminal kinase domain, which then phosphorylates further sites in MSK1, leading to the activation of the N-terminal kinase domain and phosphorylation of substrates. Here, we use precursor ion scanning MS to identify five previously unknown sites in MSK1: Thr 630 , Ser 647 , Ser 657 , Ser 695 and Thr 700 . One of these sites, Thr 700 , was found to be a third site in MSK1 phosphorylated by the upstream kinases ERK1/2 and p38α. Mutation of Thr 700 resulted in an increased basal activity of MSK1, but this could be further increased by stimulation with PMA or UV-C radiation. Surprisingly, however, mutation of Thr 700 resulted in a dramatic loss of Thr 581 phosphorylation, a site essential for activity. Mutation of Thr 700 and Thr 581 to an alanine residue resulted in an inactive kinase, while mutation of both sites to an aspartic acid residue resulted in a kinase with a significant basal activity that could not be further stimulated. Together these results are consistent with a mechanism by which Thr 700 phosphorylation relieves the inhibition of MSK1 by a C-terminal autoinhibitory helix and helps induce a conformational shift that protects Thr 581 from dephosphorylation.

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Section: Discussionmentioning

confidence: 99%

Identification of novel phosphorylation sites in MSK1 by precursor ion scanning MS

McCoy

Macdonald

Morrice

et al. 2007

Biochemical Journal

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“…Other hydrophobic residues and, in particular, isoleucine, may replace the leucines. Some NESs have been recognized to have a specific secondary structure, with a portion of the NES residing on an ␣-helix and a portion extending onto an adjacent random coil (39,40). This structure is found in NESs from p53, IB␣, MAPK-activated protein kinase (MK)-2 and 14 -3-3.…”

mentioning

confidence: 99%

Phosphorylation of Serine 271 on 5-Lipoxygenase and Its Role in Nuclear Export

Flamand

Luo

Peters‐Golden

et al. 2009

Journal of Biological Chemistry

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The enzyme 5-lipoxygenase (5-LO) initiates the biosynthesis of leukotrienes, inflammatory mediators involved in immune diseases and defense. The subcellular localization of 5-LO is regulated, with nuclear import commonly leading to increased leukotriene production. We report here that 5-LO is constitutively phosphorylated on Ser-271 in transfected NIH 3T3 cells. This residue is nested in a classical nuclear export sequence, and phosphorylated Ser-271 5-LO was exclusively found in the nucleus by immunofluorescence and by fractionation techniques. Mutation of Ser-271 to Ala allowed nuclear export of 5-LO that was blocked by the specific nuclear export inhibitor leptomycin b, suggesting that phosphorylation of Ser-271 serves to interfere with exportin-1-mediated nuclear export. Consistent with previous reports that purified 5-LO can be phosphorylated on Ser-271 in vitro by MAPK-activated protein kinase 2, the nuclear export of 5-LO was increased by either treatment with the p38 inhibitor SB 203,580 or co-expression of a kinasedeficient p38 MAPK. Nuclear export of 5-LO can also be induced by KN-93, an inhibitor of Ca 2؉ /calmodulin-dependent kinase II, and the effects of SB 203,580 plus KN-93 are additive. Finally, HeLa cells, which lack nuclear 5-LO, also lack constitutive phosphorylation of Ser-271. Taken together, these results indicate that the phosphorylation of Ser-271 serves to inhibit the nuclear export of 5-LO. This action works in concert with nuclear import, which is regulated by phosphorylation on Ser-523, to determine the subcellular distribution of 5-LO, which in turn regulates leukotriene biosynthesis. Leukotrienes (LTs)2 are intercellular messengers that play critical roles in inflammatory and allergic diseases (for review, see Ref. 1). In particular, LTB 4 promotes the recruitment and activation of leukocytes, stimulates phagocytosis and killing of pathogens, and promotes the synthesis of proteins involved in the inflammatory process. Through these effects and others, the overproduction of LTB 4 helps drive the chronic inflammation that characterizes asthma (2-4), bronchitis (5-7), and rhinitis (8). On the other hand, the underproduction of LTB 4 represents a form of immune suppression, resulting in impaired host defense against infectious pathogens. Thus, LTB 4 promotes immune defense against pathogenic bacteria (9 -11), fungi (12), viruses (13), and parasites (14 -16). Significantly, reduced LT biosynthesis correlates with increased susceptibility to infectious disease in numerous conditions, including cigarette smoking (17, 18), malnutrition (19 -22), vitamin D deficiency (23), human immunodeficiency virus infection (24, 25), and type II diabetes (26).The enzyme 5-lipoxygenase (5-LO) initiates the biosynthesis of LTs from the polyunsaturated fatty acid arachidonic acid and represents a key point of regulation. In its resting state 5-LO is a soluble enzyme that can reside in either the cytoplasm or the nucleus (27-29). The 5-LO protein has three nuclear import sequences that can be regulated and f...

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“…Among the targets of p38 is MAPK-kinase 2 (MKK2). Its phosphorylation at T317 allows MKK2 nuclear export in a complex containing p38 itself (Meng et al, 2002). Phosphorylation of heat shock protein 27 (HSP27), a substrate of MKK2, is increased in skeletal muscle hypertrophy and decreased during atrophy (Huey, 2006;Kawano et al, 2007), while HSP27…”

Section: Strategies To Correct Metabolic Alterationsmentioning

confidence: 99%

Mechanism-Based Therapeutic Approaches to Cachexia

et al. 2013

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Cachexia is a multifactorial syndrome characterized by body weight loss, depletion of adipose tissue and skeletal muscle mass, and marked alterations of the metabolic homeostasis.The occurrence of cachexia significantly impinges on patient's morbidity and mortality, and on quality of life. Inflammation, anorexia/malnutrition, alterations of protein and lipid metabolism are among the main mechanisms involved in the development of cachexia. While anorexia and malnutrition are long known contributing factors, the mechanisms leading to inflammation and metabolic alterations were clarified later on. On these premises, several therapeutic approaches were proposed. Most of them are in the pre-clinical phase, but some already reached the clinical experimentation. The present review will focus on treatment options proposed on the basis of mechanistic alterations. In this regard, in addition to nutritional and anti-inflammatory strategies, also approaches based on perturbation of specific signal transduction pathways are taken into consideration.

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Structure of Mitogen-activated Protein Kinase-activated Protein (MAPKAP) Kinase 2 Suggests a Bifunctional Switch That Couples Kinase Activation with Nuclear Export

Cited by 117 publications

References 30 publications

Identification of novel phosphorylation sites in MSK1 by precursor ion scanning MS

Identification of novel phosphorylation sites in MSK1 by precursor ion scanning MS

Phosphorylation of Serine 271 on 5-Lipoxygenase and Its Role in Nuclear Export

Mechanism-Based Therapeutic Approaches to Cachexia

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