Cloning and Characterization of RLPK, a Novel RSK-related Protein Kinase

New, Liguo; Zhao, Ming; Li, Yingqiu; Bassett, William W.; Feng, Yue; Ludwig, Stephan; Padova, Franco Di; Gram, Hermann; Han, Jiahuai

doi:10.1074/jbc.274.2.1026

Cited by 45 publications

(54 citation statements)

References 44 publications

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“…p38 regulated/activated kinase (PRAK) is a p38α and/or p38β activated kinase that shares 20-30% sequence identity to MK2 and is thought to regulate heat shock protein 27 (HSP27) [61]. Mitogen-and stress-activated protein kinase-1 (MSK1) can be directly activated by p38 and ERK, and may mediate activation of CREB [62][63][64]. p38 is also thought to regulate S phase activation of histone 2B (H2B) promoter through OCA-S, a component of p38 [65].…”

Section: Downstream Substrates Of P38 Group Map Kinases Protein Kinasmentioning

confidence: 99%

Activation and signaling of the p38 MAP kinase pathway

2005

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The family members of the mitogen-activated protein (MAP) kinases mediate a wide variety of cellular behaviors in response to extracellular stimuli. One of the four main sub-groups, the p38 group of MAP kinases, serve as a nexus for signal transduction and play a vital role in numerous biological processes. In this review, we highlight the known characteristics and components of the p38 pathway along with the mechanism and consequences of p38 activation. We focus on the role of p38 as a signal transduction mediator and examine the evidence linking p38 to inflammation, cell cycle, cell death, development, cell differentiation, senescence and tumorigenesis in specific cell types. Upstream and downstream components of p38 are described and questions remaining to be answered are posed. Finally, we propose several directions for future research on p38.

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Section: Downstream Substrates Of P38 Group Map Kinases Protein Kinasmentioning

confidence: 99%

Activation and signaling of the p38 MAP kinase pathway

2005

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“…The family of downstream kinases of MAP kinases can be divided into several groups (Stokoe et al, 1992;Ludwig et al, 1996;Fukunaga and Hunter, 1997;Waskiewicz et al, 1997;Deak et al, 1998;New et al, 1999). It was proposed that PRAK represents a subgroup of this family because it only has 20 -30% sequence identity with kinases in the family (New et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…There are at least six protein kinases that can be regulated by p38␣ and/or p38␤. These downstream kinases of p38s include MAPK-activated protein kinase 2 (MAPKAPK2 or MK2; Stokoe et al, 1992), MAPKAPK3 (Ludwig et al, 1996), MAPK-interacting kinase 1 (MNK1; Fukunaga and Hunter, 1997), MNK2 (Waskiewicz et al, 1997), p38-activated/regulated protein kinase (PRAK or MAPKAPK5; New et al, 1998;Ni et al, 1998), and mitogen-and stress-activated protein kinase (MSK; Deak et al, 1998;New et al, 1999). Several downstream targets of this family of kinases have been discovered, which include small heat shock protein, cAMP response element binding protein (CREB; Iordanov et al, 1997), serum response factor (SRF; Heidenreich et al, 1999), and the basic helix-loop-helix (HLH) protein E47 (Neufeld et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Regulation of PRAK Subcellular Location by p38 MAP Kinases

New

Jiang

Han

2003

MBoC

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The p38 mitogen-activated protein kinase (MAPK) pathway plays an important role in cellular responses to inflammatory stimuli and environmental stress. p38 regulated/activated protein kinase (PRAK, also known as mitogen-activated protein kinase activated protein kinase 5 [MAP-KAPK5]) functions downstream of p38␣ and p38␤ in mediating the signaling of the p38 pathway. Immunostaining revealed that endogenous PRAK was predominantly localized in the cytoplasm. Interestingly, ectopically expressed PRAK was localized in the nucleus and can be redistributed by coexpression of p38␣ or p38␤ to the locations of p38␣ and p38␤. Mutations in the docking groove on p38␣/p38␤, or the p38-docking site in PRAK, disrupted the PRAK-p38 interaction and impaired the ability of p38␣ and p38␤ to redistribute ectopically expressed PRAK, indicating that the location of PRAK could be controlled by its docking interaction with p38␣ and p38␤. Although the majority of PRAK molecules were detected in the cytoplasm, PRAK is consistently shuttling between the cytoplasm and the nucleus. A sequence analysis of PRAK shows that PRAK contains both a putative nuclear export sequence (NES) and a nuclear localization sequence (NLS). The shuttling of PRAK requires NES and NLS motifs in PRAK and can be regulated through cellular activation induced by stress stimuli. The nuclear content of PRAK was reduced after stimulation, which resulted from a decrease in the nuclear import of PRAK and an increase in the nuclear export of PRAK. The nuclear import of PRAK is independent from p38 activation, but the nuclear export requires p38-mediated phosphorylation of PRAK. Thus, the subcellular distribution of PRAK is determined by multiple factors including its own NES and NLS, docking interactions between PRAK and docking proteins, phosphorylation of PRAK, and cellular activation status. The p38 MAPKs not only regulate PRAK activity and PRAK activation-related translocation, but also dock PRAK to selected subcellular locations in resting cells.

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“…MSKs are most closely related to the RSK (p90 ribosomal S6 kinase) family of kinases and, like RSK, MSKs contain two distinct kinase domains within a single polypeptide [14][15][16]. The N-terminal domain, which is thought to phosphorylate MSK substrates, is a member of the AGC-type kinases (protein kinase A/protein kinase G/protein kinase C-family kinases), while the C-terminal kinase domain is related to the calmodulin-dependent protein kinase family [17].…”

Section: Introductionmentioning

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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Cloning and Characterization of RLPK, a Novel RSK-related Protein Kinase

Cited by 45 publications

References 44 publications

Activation and signaling of the p38 MAP kinase pathway

Activation and signaling of the p38 MAP kinase pathway

Regulation of PRAK Subcellular Location by p38 MAP Kinases

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

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