RSK activation

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R-HSA-444257
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Homo sapiens
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Ribosomal S6 kinase (RSK) has four isoforms in humans, RPS6KA1 (RSK1), RPS6KA2 (RSK3), RPS6KA3 (RSK2) and RPS6KA6 (RSK4), and each of the isoforms have six conserved phosphorylation sites (in RPS6KA1, these are serine residues S221, S363 and S380 and threonine residues T359, T573 and T732). Phosphorylation at four of these residues appears to be critically important for the catalytic activity of RSKs: S221, S363, S380 and T573 (in RPS6KA1).
Phosphorylation and activation of RSKs primarily occurs at the plasma membrane, but can occur in the cytoplasm and in the nucleus. ERKs (MAPK1 and MAPK3), activated downstream of RAS signaling, phosphorylate RSKs on threonine and serine residues T359, S363 and T573 (in RPS6KA1). Phosphorylation by ERKs enables autophosphorylation of RSKs on serine residue S380 and threonine residue T732 (in RPS6KA1). Phosphorylation of RSKs by PDPK1 (PDK1) at serine residue S221 (in RPS6KA1) is necessary for the full activation of RSKs and phosphorylation of RSK substrates (reviewed by Anjum and Blenis 2012). RSK4 differs from other RSKs because it shows high level of constitutive phosphorylation and activity in the absence of growth factors, although it is still responsive to growth factors and ERK activity (Dummler et al. 2005).
RSKs, especially RSK2, are highly expressed in brain regions with high synaptic activity. RSK2 mutations are the underlying cause of Coffin-Lowry syndrome (CLS), which is characterized by cognitive impairment and skeletal anomalies (Zeniou et al. 2002).

Literature References
PubMed ID Title Journal Year
12393804 Expression analysis of RSK gene family members: the RSK2 gene, mutated in Coffin-Lowry syndrome, is prominently expressed in brain structures essential for cognitive function and learning

Zeniou, M, Ding, T, Trivier, E, Hanauer, A

Hum Mol Genet 2002
18813292 The RSK family of kinases: emerging roles in cellular signalling

Anjum, R, Blenis, J

Nat Rev Mol Cell Biol 2008
15632195 Functional characterization of human RSK4, a new 90-kDa ribosomal S6 kinase, reveals constitutive activation in most cell types

Dümmler, BA, Hauge, C, Silber, J, Yntema, HG, Kruse, LS, Kofoed, B, Hemmings, BA, Alessi, DR, Frödin, M

J. Biol. Chem. 2005
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