MSK1

MSK1, short for mitogen- and stress-activated protein kinase 1, is a member of the MAP kinase-activated protein kinase family and a dual-specificity serine/threonine kinase. It plays a role downstream of mitogen-activated protein kinases and is activated by the ERK1/2 and p38 pathways. MSK1 contains two catalytic kinase domains, an N-terminal and a C-terminal domain, and activation involves phosphorylation events that coordinate the activity of both domains.

Activation and mechanism: Upstream MAPKs phosphorylate MSK1, with the C-terminal kinase domain capable of autophosphorylation that contributes to full activation of the protein. Once active, MSK1 phosphorylates a variety of substrates that influence transcription and chromatin structure.

Substrates and effects: A key target of MSK1 is the transcription factor CREB (cyclic AMP response element-binding protein), along with ATF1 and components of AP-1. Phosphorylation of NF-κB p65 subunit at Ser276 is also attributed to MSK1 activity, promoting transcription of inflammatory genes. MSK1 can phosphorylate histone H3 at Ser10, linking MAPK signaling to chromatin remodeling and transcriptional regulation.

Biological roles: Through its substrates, MSK1 regulates immediate-early gene expression in response to mitogenic and stress stimuli. It contributes to inflammatory responses, immune cell activation, and neuronal signaling processes, including aspects of synaptic plasticity and memory formation in the nervous system.

Regulation and localization: MSK1 functions in both the cytoplasm and nucleus and is regulated by upstream kinases and phosphatases that control its phosphorylation state. Signals such as growth factors, stress, and cytokines can modulate its activity.

Clinical relevance: Altered MSK1 signaling has been associated with inflammatory diseases and cancer. Research continues into its potential as a target for therapies that modulate inflammatory gene expression and neural signaling pathways.