Ribosomal protein S6 kinase alpha-1 N-terminal kinase domain (RSK1 NTKD)

The N-terminal kinase domain (NTKD) of Ribosomal protein S6 kinase alpha-1 (RPS6KA1), also known as RSK1, is the primary catalytic unit responsible for phosphorylating downstream substrates within the Ras/ERK signaling pathway (UniProt Q15418). As a member of the p90 ribosomal S6 kinase family, RPS6KA1 is unique in possessing two non-identical kinase domains: the NTKD, which belongs to the AGC kinase family, and a C-terminal kinase domain (CTKD) belonging to the CaMK family (Atlas Genetics Oncology). The NTKD is activated through a complex phosphorylation cascade where the CTKD, once activated by ERK1/2, autophosphorylates a linker site to recruit PDK1, which then phosphorylates the NTKD at Ser221 (Life Science Alliance, 2023). Once active, the NTKD regulates critical cellular processes such as protein synthesis, cell cycle progression, and survival by targeting factors like eIF4B, GSK3B, and BAD (PubMed 10679322). In various malignancies, including breast, prostate, and lung cancers, the NTKD is often hyperactivated or overexpressed, contributing to tumor growth and therapeutic resistance (GeneCards). Consequently, the NTKD is a significant therapeutic target, with inhibitors like SL0101 and BI-D1870 specifically designed to block its ATP-binding pocket and inhibit oncogenic signaling (AACR Journals, 2005).

Other names

RSK1 N-terminal kinase domainp90RSK1 N-terminal kinase domainMAPKAPK1A N-terminal kinase domainS6K-alpha-1 N-terminal kinase domain90 kDa ribosomal protein S6 kinase 1 N-terminal kinase domainRibosomal protein S6 kinase alpha-1 NTKD

ATP-competitive inhibition of the N-terminal kinase domain, preventing the phosphorylation of downstream substrates such as eIF4B and RPS6