Ribosomal S6 kinase and Mitogen- and stress-activated protein kinase (RSK/MSK)

The Ribosomal S6 Kinase (RSK) and Mitogen- and Stress-activated protein Kinase (MSK) families are groups of serine/threonine protein kinases that serve as critical downstream effectors of the mitogen-activated protein kinase (MAPK) signaling pathway [1, 11]. The RSK family (RSK1-4) is primarily activated by the ERK1/2 cascade, whereas the MSK family (MSK1-2) is activated by both the ERK1/2 and p38 MAPK pathways [14, 24]. These kinases are structurally unique, possessing two distinct catalytic domains—an N-terminal kinase domain (NTKD) and a C-terminal kinase domain (CTKD)—within a single polypeptide chain [2, 8]. They regulate diverse cellular processes, including gene transcription, protein translation, cell proliferation, survival, and the inflammatory response by phosphorylating various substrates such as CREB, YB-1, and histone H3 [5, 28, 31]. Dysregulation of RSK/MSK signaling is frequently observed in multiple cancers, where it promotes tumor growth, metastasis, and drug resistance, as well as in inflammatory and neurodegenerative disorders [4, 9, 17]. Consequently, they are considered promising therapeutic targets, with several small-molecule inhibitors like PMD-026 currently undergoing clinical and preclinical evaluation for the treatment of advanced malignancies [22, 26].

Other names

p90RSKMAPKAP-K1RPS6KAMSK90 kDa ribosomal S6 kinaseMitogen- and stress-activated protein kinaseMAPK-activated protein kinase

Inhibition of kinase activity through ATP-competitive binding to the N-terminal or C-terminal kinase domains, or via allosteric modulation to prevent activation and substrate phosphorylation.