| Phospho-RSK1 p90 (Thr573) designates the activated form of the ribosomal S6 kinase RSK1 in which a threonine residue within the C‑terminal kinase domain is phosphorylated as part of the canonical ERK/MAPK cascade, and this modification is required for full catalytic competence toward downstream substrates that control transcription, translation, and cell survival. RSK1 belongs to the RSK family of growth factor–regulated serine/threonine kinases and is characterized by two nonidentical functional kinase domains arranged in tandem, with the C‑terminal kinase domain acting as a regulatory module that, once phosphorylated at sites including Thr573, activates the N‑terminal kinase domain responsible for substrate phosphorylation in the cytoplasm and nucleus. Upstream engagement of ERK1/2 by mitogens, polypeptide hormones, or neurotransmitters leads to docking of ERK on the RSK1 C‑terminal tail and sequential phosphorylation of multiple residues within and outside the catalytic domains; phosphorylation of Thr573 in the C‑terminal kinase domain stabilizes its active conformation and completes the intramolecular activation relay that allows the N‑terminal domain to phosphorylate effector proteins. Activated, Thr573‑phosphorylated RSK1 transmits mitogenic and stress-induced signals to nuclear transcription factors such as CREB1, ETV1, and NR4A1 and to translational regulators including ribosomal protein S6 and eIF4B, and it also acts on pro‑apoptotic molecules such as BAD and DAPK1, thereby promoting cell-cycle progression, anabolic metabolism, and survival in response to ERK pathway input. This phosphorylation event integrates RSK1 into broader MAPK and PI3K‑responsive signaling networks, since RSK1 activation depends on coordinated ERK docking, autophosphorylation, and PDK1-mediated N‑terminal domain phosphorylation, with phospho‑Thr573 marking the state at which the C‑terminal kinase domain has been engaged and the kinase is competent to execute its effector functions. Elevated ERK–RSK signaling and increased levels of activated RSK1, including its Thr573‑phosphorylated form, are described in diverse malignancies and associate with enhanced proliferation, resistance to apoptosis, and alterations in mTOR signaling. |
