p90 ribosomal S6 kinase 1 (RSK1) and the catalytic subunit of protein kinase A (PKA) compete for binding the pseudosubstrate region of PKAR1alpha: role in the regulation of PKA and RSK1 activities.

Previously we showed that the inactive form of p90 ribosomal S6 kinase 1 (RSK1) interacts with the regulatory subunit, of protein kinase A whereas the active RSK1 interacts with the catalytic subunit of Herein, we demonstrate that the N-terminal kinase domain (NTK) of RSK1 is necessary for interactions with Substitution of the activation loop phosphorylation site (Ser-221) in the NTK with the negatively charged Asp residue abrogated the association between RSK1 and duanyu1529RIalpha. This explains the lack of an interaction between active RSK1 and duanyu1529RIalpha. Full-length RSK1 bound to with an affinity of 0.8 nm. The NTK domain of RSK1 competed with for binding to the pseudosubstrate region (amino acids 93-99) of duanyu1529RIalpha. Overexpressed RSK1 dissociated duanyu1529c from duanyu1529RIalpha, increasing duanyu1529c activity, whereas silencing of RSK1 increased interactions and decreased duanyu1529c activity. Unlike which requires Arg-95 and -96 in the pseudosubstrate region of duanyu1529RIalpha for their interactions, association requires all four Arg residues (Arg-93-96) in the pseudosubstrate site of duanyu1529RIalpha. A peptide (Wt-PS) corresponding to residues 91-99 of duanyu1529RIalpha competed for binding of RSK1 with duanyu1529RIalpha both in vitro and in intact cells. Furthermore, peptide Wt-PS (but not control peptide Mut-PS), by dissociating RSK1 from duanyu1529RIalpha, activated RSK1 in the absence of any growth factors and protected cells from apoptosis. Thus, by competing for binding to the pseudosubstrate region of duanyu1529RIalpha, RSK1 regulates duanyu1529c activity in a cAMP-independent manner, and duanyu1529RIalpha by associating with RSK1 regulates its activation and its biological functions.

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