Ribosomal protein S6 kinase alpha-3 (RSK2) (N-terminal kinase domain) (RSK2 NTKD)

Ribosomal protein S6 kinase alpha-3 (RPS6KA3), also known as RSK2, is a highly conserved serine/threonine kinase that functions as a downstream effector of the Ras-MAPK signaling pathway [1, 3]. It is structurally unique, possessing two non-identical kinase domains: the N-terminal kinase domain (NTKD) and the C-terminal kinase domain (CTKD) [1, 4]. The NTKD is the primary effector domain responsible for phosphorylating a wide array of substrates, including transcription factors like CREB and histone H3, which collectively regulate cell proliferation, survival, and differentiation [3, 4]. Activation of the NTKD requires a complex sequential phosphorylation cascade involving the CTKD and upstream kinases like ERK1/2 and PDK1 [1, 3]. Mutations in the RPS6KA3 gene lead to Coffin-Lowry syndrome, a rare X-linked disorder characterized by severe intellectual disability and dysmorphic features [5]. In many human cancers, including breast, lung, and prostate cancer, RSK2 is frequently overexpressed or hyperactivated, promoting tumor growth, motility, and metastasis [4]. Consequently, the NTKD has emerged as a critical target for drug development, as it contains the catalytic activity required for most RSK2-mediated biological effects [3, 4]. Small-molecule inhibitors such as SL0101 and BI-D1870 have been developed to competitively bind the NTKD's ATP-binding pocket, effectively blocking oncogenic signaling [3, 4]. Therapeutic challenges include achieving selectivity over other AGC kinases and managing potential neurological side effects given the protein's role in cognitive function [4, 5].

Other names

RSK2p90RSK2MAPKAPK1BRibosomal S6 kinase 2pp90RSK2S6K-alpha-390 kDa ribosomal protein S6 kinase 3

ATP-competitive inhibition of the N-terminal kinase domain to prevent phosphorylation of downstream substrates