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)
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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
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
Compartment
Alternative splicing
named isoforms=2