Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel pp90rsk Ser/Thr kinase (referred to as RSK3) was cloned from a human cDNA library. The RSK3 cDNA encodes a predicted 733-amino-acid protein with a unique N-terminal region containing a putative nuclear localization signal. RSK3 mRNA was widely expressed (but was predominant in lung and skeletal muscle). By using fluorescence in situ hybridization, the human RSK3 gene was localized to band q27 of chromosome 6. Hemagglutinin epitope-tagged RSK3 was expressed in transiently transfected COS cells. Growth factors, serum, and phorbol ester stimulated autophosphorylation of recombinant RSK3 and its kinase activity toward several protein substrates known to be phosphorylated by RSKs. However, the relative substrate specificity of RSK3 differed from that reported for other isoforms. RSK3 also phosphorylated potential nuclear target proteins including c-Fos and histones. Furthermore, although RSK3 was inactivated by protein phosphatase 2A in vitro, the enzyme was not activated by ERK2/mitogen-activated protein (MAP) kinase. In contrast, the kinase activity of another epitope-tagged RSK isoform (RSK-1) was significantly increased by in vitro incubation with ERK2/MAP kinase. Finally, we used affinity-purified RSK3 antibodies to demonstrate by immunofluorescence that endogenous RSK3 undergoes serum-stimulated nuclear translocation in cultured HeLa cells. These results provide evidence that RSK3 is a third distinct isoform of pp90rsk which translocates to the cell nucleus, phosphorylates potential nuclear targets, and may have a unique upstream activator. RSK3 may therefore subserve a discrete physiologic role(s) that differs from those of the other two known mammalian RSK isoforms.
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PMID:RSK3 encodes a novel pp90rsk isoform with a unique N-terminal sequence: growth factor-stimulated kinase function and nuclear translocation. 762 30

Each of the three known mammalian 90-kDa S6 kinase (pp90(rsk)) isoforms (RSK1, RSK2, and RSK3) was expressed in transfected cells and further characterized. The kinase activity (immunocomplex toward S6 peptide) of each isoform was activated by in vivo growth factor (epidermal growth factor (EGF)) stimulation; RSK1 was more responsive (10-15-fold) versus RSK2 and RSK3 (2-4-fold). Pretreatment with PD98059 (MEK1 inhibitor) partially (80%) blocked EGF-mediated ERK1 activation and had similar effects on EGF stimulation of each ribosomal S6 kinase (RSK). Cotransfection with dominant-negative MEK1 inhibited activation of each RSK; furthermore, the kinase activity of RSK1, RSK2, and RSK3 was markedly increased by cotransfection with constitutively active MEK1. A specific association between mitogen-activated protein kinases (MAPKs) (ERK1 and ERK2) and RSK isoforms was tested by MAPK immunoblotting after immunoprecipitation of RSKs. ERK1 and ERK2 were present in RSK3 (and to a lesser extent, RSK2) immunoprecipitates, but were absent in RSK1 immunoprecipitates. Both dephosphorylated (from quiescent cells) and phosphorylated (from stimulated cells) MAPKs were associated with RSK2 and RSK3. Deletion mutants of RSK3 were characterized: the C terminus (33 residues) was shown to be required for association with MAPKs. The kinase activity of RSK1 or RSK2 was enhanced by in vitro incubation with ERK1. In contrast, RSK3 activity was not affected by exposure to ERK1. Furthermore, MAPKs in RSK3 immunoprecipitates were phosphorylated by purified MEK1; however, RSK3 kinase activity was unaffected. We conclude that 1) the MEK1-MAPK signaling pathway is both necessary and sufficient for in vivo growth factor-mediated activation of all three RSK isoforms; 2) RSK isoforms differ with respect to growth factor responsiveness and their physical association with MAPK; and 3) formation of the MAPK.RSK complex is mediated by the RSK C terminus.
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PMID:Regulation and interaction of pp90(rsk) isoforms with mitogen-activated protein kinases. 893 14

The 90-kDa ribosomal S6 kinases, the p90 Rsks, are a family of intracellular serine/threonine protein kinases distinguished by two distinct kinase domains. Rsks are activated downstream of the ERK1 (p44) and ERK2 (p42) mitogen-activated protein (MAP) kinases in diverse biological contexts, including progression through meiotic and mitotic M phases in Xenopus oocytes and cycling Xenopus egg extracts, and are critical for the M phase functions of Xenopus p42 MAPK. Here we report the cloning and biochemical characterization of Xenopus Rsk2. Xenopus Rsk1 and Rsk2 are specifically recognized by commercially available RSK1 and RSK2 antisera on immunoblots, but both Rsk1 and Rsk2 are immunoprecipitated by RSK1, RSK2, and RSK3 sera. Rsk2 is about 20-fold more abundant than the previously described Xenopus Rsk1 protein; their concentrations are approximately 120 and 5 nm, respectively. Rsk2, like Rsk1, forms a heteromeric complex with p42 MAP kinase. This interaction depends on sequences at the extreme C terminus of Rsk2 and can be disrupted by a synthetic peptide derived from the C-terminal 20 amino acids of Rsk2. Finally, we demonstrate that p42 MAP kinase can activate recombinant Rsk2 in vitro to a specific activity comparable to that found in Rsk2 that has been activated maximally in vivo. These findings underscore the importance of the Rsk2 isozyme in the M phase functions of p42 MAP kinase and provide tools for further examining Rsk2 function.
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PMID:Cloning and characterization of Xenopus Rsk2, the predominant p90 Rsk isozyme in oocytes and eggs. 1093 12

The mitogen-activated protein (MAP) kinase pathway has been implicated in cell cycle control for some time. Several reports have suggested a role for this pathway in growth factor stimulation of DNA synthesis, while other reports have proposed a role in the transition of cells through mitosis. Here, we have examined the potential involvement of the extracellular signal-related kinase (ERK)1/2 MAP kinases, their upstream regulators, and downstream effectors in the regulation of mitosis. Inhibition of MAP kinase/ERK kinase (MEK) activity reduced the serum-stimulated DNA synthesis and proliferation of Swiss 3T3 cells. To study the potential mechanisms of this effect, we examined the subcellular localization of members of the MAP kinase pathway including regulators (MEK1/2), substrates (90-kDa ribosomal S6 kinases (RSKs): RSK1, RSK2 and RSK3), and ERK itself. We show that there is enrichment of ERK, MEK, and the RSK enzymes on both the spindle and midbody tubulin of dividing cells. Inhibition of MEK1/2 activity in cells released from mitotic arrest results in an inability of cells to complete mitosis. This failure to exit mitosis correlated with altered cyclin-dependent kinase (cdk) activities. Thus, the MAP kinase pathway may act to coordinate passage through mitosis in Swiss 3T3 fibroblasts by regulation of cdk activity.
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PMID:MEK, ERK, and p90RSK are present on mitotic tubulin in Swiss 3T3 cells: a role for the MAP kinase pathway in regulating mitotic exit. 1149 23

Noonan syndrome (NS) is a congenital disorder resulting from mutations of the Ras-Raf signaling pathway. Hypertrophic cardiomyopathy associated with RAF1 "RASopathy" mutations is a major risk factor for heart failure and death in NS and has been attributed to activation of MEK1/2-ERK1/2 mitogen-activated protein kinases. We recently discovered that type 3 p90 ribosomal S6 kinase (RSK3) is an ERK effector that is required, like ERK1/2, for concentric myocyte hypertrophy in response to pathological stress such as pressure overload. In order to test whether RSK3 also contributes to NS-associated hypertrophic cardiomyopathy, RSK3 knock-out mice were crossed with mice bearing the Raf1(L613V) human NS mutation. We confirmed that Raf1(L613V) knock-in confers a NS-like phenotype, including cardiac hypertrophy. Active RSK3 was increased in Raf1(L613V) mice. Constitutive RSK3 gene deletion prevented the Raf1(L613V)-dependent concentric growth in width of the cardiac myocyte and attenuated cardiac hypertrophy in female mice. These results are consistent with RSK3 being an important mediator of ERK1/2-dependent growth in RASopathy. In conjunction with previously published data showing that RSK3 is important for pathological remodeling of the heart, these data suggest that targeting of this downstream MAP-kinase pathway effector should be considered in the treatment of RASopathy-associated hypertrophic cardiomyopathy.
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PMID:RSK3 is required for concentric myocyte hypertrophy in an activated Raf1 model for Noonan syndrome. 2694 Sep 93