ribosomal protein S6 kinase alpha-5; S6K-alpha-5; 90 kD ribosomal protein S6 kinase 5; nuclear mitogen- & stress-activated protein kinase 1; RSK-like protein kinase; RSKL (RPS6KA5, MSK1)

Function: - serine/threonine protein kinase with functions similar to RPS6KA4 - required for mitogen or stress-induced phosphorylation of transcription factors CREB1 & ATF1 - role in regulation of transcription factors RELA, STAT3 & ETV1/ER81 - contributes to gene activation by histone phosphorylation - role in regulation of inflammatory genes - phosphorylates CREB1 & ATF1 in response to mitogenic or stress stimuli such as UV-C irradiation, EGF & anisomycin - role in control of RELA transcriptional activity in response to TNF & upon glucocorticoid, associates in the cytoplasm with the glucocorticoid receptor NR3C1 & contributes to RELA inhibition & repression of inflammatory gene expression - in skeletal myoblasts required for phosphorylation of RELA at Ser-276 during oxidative stress - in erythropoietin-stimulated cells, is necessary for the Ser-727 phosphorylation of STAT3 & regulation of its transcriptional activity - phosphorylates ETV1/ER81 at Ser-191 & Ser-216, & thus regulates its ability to stimulate transcription, which may be important during development & breast tumor formation - directly represses transcription via phosphorylation of Ser-1 of histone H2A - phosphorylates Ser-10 of histone H3 in response to mitogens, stress stimuli & EGF, which results in the transcriptional activation of several immediate early genes, including proto-oncogenes c-fos/FOS & c-jun/JUN - may also phosphorylate Ser-28 of histone H3 - mediates mitogen- & stress-induced phosphorylation of high mobility group protein 1 (HMGN1/HMG14) - in lipopolysaccharide-stimulated primary macrophages, acts downstream of the Toll-like receptor TLR4 to limit production of pro- inflammatory cytokines - probably induces transcription of the MAP kinase phosphatase DUSP1 & the anti-inflammatory cytokine interleukin 10 (IL10), via CREB1 & ATF1 transcription factors - role in neuronal cell death by mediating the downstream effects of excitotoxic injury - activated by phosphorylation at Ser-360, Thr- 581 & Thr-700 by MAPK1/ERK2, MAPK3/ERK1 & MAPK14/p38-alpha, & by further autophosphorylation of Ser-212, Ser-376 & Ser-381 by the activated C-terminal kinase domain - the active N-terminal kinase domain phosphorylates downstream substrates, as well as Ser-750, Ser-752 & Ser-758 in its own C-terminal region - Ser-376 & Thr-581 phosphorylation is required for kinase activity - Ser-376 & Ser-212 are autophosphorylated by the C-terminal kinase domain, & their phosphorylation is essential for catalytic activity of the N-terminal kinase domain - phosphorylated at Ser-360, Thr-581 & Thr-700 by MAPK1/ERK2, MAPK3/ERK1 & MAPK14/p38-alpha - autophosphorylated at Ser-750, Ser-752 & Ser-758 by the N-terminal kinase domain - forms a complex with either MAPK1/ERK2 or MAPK3/ERK1 in quiescent cells which transiently dissociates following mitogenic stimulation - associates with MAPK14/p38-alpha - activated RPS6KA5 associates with & phosphorylates the NF-kappa-B p65 subunit RELA - interacts with CREBBP & EP300 Cofactor: Mg⁺² Structure: - belongs to the protein kinase superfamily, AGC Ser/Thr protein kinase family, S6 kinase subfamily - contains 1 AGC-kinase C-terminal domain - contains 2 protein kinase domains - both kinase domains required for enzyme activity Compartment: - nucleus, cytoplasm - predominantly nuclear - exported into cytoplasm in response to glucocorticoids Alternative splicing: named isoforms=2 Expression: - widely expressed - high expression in heart, brain & placenta - less abundant in lung, kidney & liver

General

nuclear protein ribosomal protein S6 kinase

Properties

SIZE: entity length = 802 aa MW = 90 kD COMPARTMENT: cytoplasm cell nucleus MOTIF: kinase domain SITE: 49-318 MOTIF: ATP-binding site NAME: ATP-binding site SITE: 55-63 ATP-binding site NAME: ATP-binding site SITE: 81-81 aspartate residue {D177} Ser phosphorylation site {S212} AGC-kinase C-terminal {319-387} MOTIF: Ser phosphorylation site {S360} Ser phosphorylation site {S376} Ser phosphorylation site {S381} kinase domain SITE: 426-687 MOTIF: ATP-binding site NAME: ATP-binding site SITE: 432-440 ATP-binding site NAME: ATP-binding site SITE: 455-455 aspartate residue {D544} Thr phosphorylation site {T581} Ser phosphorylation site {S647} Ser phosphorylation site {S657} Ser phosphorylation site {S695} Thr phosphorylation site {T700} Ser phosphorylation site {S750} Ser phosphorylation site {S752} Ser phosphorylation site {S758} STATE: active state

Database Correlations

OMIM 603607 UniProt O75582 PFAM correlations Entrez Gene 9252 Kegg hsa:9252 ENZYME 2.7.11.1

References

UniProt :accession O75582