MSK activation and physiological roles

Front Biosci. 2008 May 1;13:5866-79. doi: 10.2741/3122.


Mitogen and stress activated protein kinase (MSK) 1 and 2 are nuclear serine/threonine protein kinases that are activated in vivo downstream of either the ERK1/2 or p38 mitogen activated protein kinase (MAPK) cascades. MSKs contain two kinase domains, an N-terminal kinase domain related to the AGC kinase family, and a C-terminal kinase domain related to the CaMK family. The upstream MAPK phosphorylates the C-terminal domain, which then phosphorylates and activates the N-terminal domain. Once activated, the N-terminal domain phosphorylates substrates. MSKs do not have a precisely defined substrate consensus sequence, however the do have a preference for a basic cluster prior to the phosphorylated residue. In cells MSKs phosphorylate several substrates including CREB, NFkB, HMGN1 and histone H3. The major role of MSKs appear to be in the regulation of immediate early (IE) genes, and consistent with this the transcription of several CRE dependent IE genes is compromised in MSK knockouts. The physiological roles of MSKs still remain to be completely determined, however recent work has suggested a role for MSKs in neuronal synaptic plasticity and in regulating cytokine production in the innate immune system.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Enzyme Activation
  • Humans
  • Isoquinolines / pharmacology
  • Kinetics
  • MAP Kinase Signaling System / physiology*
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Ribosomal Protein S6 Kinases, 90-kDa / antagonists & inhibitors
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
  • Signal Transduction
  • Substrate Specificity
  • Sulfonamides / pharmacology
  • Toll-Like Receptors / physiology


  • Isoquinolines
  • Protein Kinase Inhibitors
  • Sulfonamides
  • Toll-Like Receptors
  • RPS6KA4 protein, human
  • Ribosomal Protein S6 Kinases, 90-kDa
  • mitogen and stress-activated protein kinase 1
  • Mitogen-Activated Protein Kinase 3
  • N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide