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)
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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
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