ribosomal protein S6 kinase alpha-4; S6K-alpha-4; 90 kD ribosomal protein S6 kinase 4; nuclear mitogen- & stress-activated protein kinase 2; ribosomal protein kinase B; RSKB (RPS6KA4, MSK2)

Function: - serine/threonine protein kinase with functions similar to RPS6KA5 - required for mitogen or stress-induced phosphorylation of transcription factors CREB1 & ATF1 - role in regulation of transcription factor RELA - contributes to gene activation by histone phosphorylation - functions in the 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 - 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 the 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 - activated by phosphorylation at Ser-343, Thr- 568 & Thr-687 by MAPK1/ERK2, MAPK3/ERK1 & MAPK14/p38-alpha, & by further autophosphorylation of Ser-196, Ser-360 & Ser-365 by the activated C-terminal kinase domain (putative) - Ser-343 & Thr-568 phosphorylation is required for kinase activity - Ser-343 & Ser-196 are autophosphorylated by the C-terminal kinase domain, & their phosphorylation is essential for catalytic activity of the N-terminal kinase domain - phosphorylated at Ser-343, Thr-568 & Thr-687 by MAPK1/ERK2, MAPK3/ERK1 & MAPK14/p38-alpha - autophosphorylated at Ser-737 & Ser-745 by the N-terminal kinase domain (putative) - forms a complex with either MAPK1/ERK2 or MAPK3/ERK1 in quiescent cells which transiently dissociates following mitogenic stimulation - also associates with MAPK14/p38-alpha - activated RPS6KA4 associates with & phosphorylates the NF-kappa-B p65 subunit RELA 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 - enzyme activity requires the presence of both kinase domains (putative) Compartment: nucleus Alternative splicing: named isoforms=2

General

nuclear protein ribosomal protein S6 kinase

Properties

SIZE: entity length = 772 aa MW = 86 kD COMPARTMENT: cell nucleus MOTIF: kinase domain SITE: 33-301 MOTIF: ATP-binding site NAME: ATP-binding site SITE: 39-47 ATP-binding site NAME: ATP-binding site SITE: 65-65 aspartate residue {D161} Ser phosphorylation site {S196} AGC-kinase C-terminal {302-371} MOTIF: Tyr phosphorylation site {Y342} Ser phosphorylation site {S343} Ser phosphorylation site {S347} Ser phosphorylation site {S360} Ser phosphorylation site {S365} kinase domain SITE: 411-674 MOTIF: ATP-binding site NAME: ATP-binding site SITE: 417-425 ATP-binding site NAME: ATP-binding site SITE: 440-440 aspartate residue {D530} Thr phosphorylation site {T542} Thr phosphorylation site {T568} Ser phosphorylation site {S634} Ser phosphorylation site {S678} Ser phosphorylation site {S681} Ser phosphorylation site {S682} Thr phosphorylation site {T687} nuclear targeting {725-772} MOTIF: Ser phosphorylation site {S737} Ser phosphorylation site {S745} STATE: active state

Database Correlations

OMIM 603606 UniProt O75676 PFAM correlations Entrez Gene 8986 Kegg hsa:8986 ENZYME 2.7.11.1

References

UniProt :accession O75676