Abstract

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.