Mitogen-activated protein kinase-activated protein kinase 1 (MAPKAP-K1) (MAPKAP-K1)

Mitogen-activated protein kinase-activated protein kinase 1 (MAPKAP-K1), also known as the p90 ribosomal S6 kinase (RSK) family, is a group of serine/threonine kinases that act as key downstream effectors of the Ras-ERK signaling pathway (UniProt, PubMed: 22560206). The family comprises four human isoforms (RSK1-4), which are unique for containing two distinct, non-identical kinase domains in a single polypeptide chain (NCBI Gene). MAPKAP-K1 regulates a variety of essential cellular processes, including cell growth, proliferation, survival, and motility, by phosphorylating numerous cytosolic and nuclear substrates such as transcription factors and translational regulators (PubMed: 16446357). In many human cancers, including breast, prostate, and lung carcinomas, MAPKAP-K1 is frequently overexpressed or hyperactivated, contributing to tumor growth and therapeutic resistance (PubMed: 30655417). Consequently, it has become a significant target for drug development, with small-molecule inhibitors like PMD-026 entering clinical trials for oncology indications (ClinicalTrials.gov). Additionally, mutations in the RSK2 isoform are linked to Coffin-Lowry syndrome, a genetic disorder characterized by intellectual disability and skeletal abnormalities, highlighting the kinase's vital role in normal development (OMIM: 303600).

Other names

RSKp90RSKRibosomal S6 kinaseRPS6KAMAPKAPK1p90 ribosomal S6 kinase

MAPKAP-K1 inhibitors primarily function by binding to the ATP-binding site of the N-terminal kinase domain (NTKD) to block substrate phosphorylation or the C-terminal kinase domain (CTKD) to prevent auto-activation (PubMed: 22560206). Some inhibitors, such as PMD-026, are highly selective for the NTKD, while others may act as irreversible inhibitors or allosteric modulators (PubMed: 17202133).