Ribosomal S6 kinase 2 interacts with and phosphorylates PDZ domain-containing proteins and regulates AMPA receptor transmission

Coffin-Lowry syndrome (CLS) is an X-linked syndromic form of mental retardation characterized by various skeletal dysmorphisms, moderate to severe mental retardation, and in some cases, psychosis. CLS is caused by loss-of-function mutations of the p90 ribosomal S6 kinase 2 (RPS6KA3) gene encoding a growth factor-regulated serine/threonine kinase, ribosomal S6 kinase 2 (RSK2). We previously identified RSK2 as a novel interacting protein that tonically inhibits 5-HT2A receptor signaling by phosphorylating Ser-314 within the third intracellular loop. To determine if RSK2 inhibits 5-HT2A receptor signaling in vivo and whether disruption of RSK2 could lead to schizophrenia-like behaviors - as is seen in some CLS patients - we genetically disrupted the function of RSK2 either globally or selectively in forebrain pyramidal neurons in mice. Both global and forebrain-selective RSK2 deletion augmented the locomotor responses to the psychotomimetic drugs phencyclidine (PCP) and amphetamine (AMPH). Significantly, forebrain-selective deletion of RSK2 augmented 5-HT2A receptor signaling as exemplified by enhanced 5-HT2A-mediated c-fos activation and head-twitch response without altering the levels or distribution of 5-HT2A receptor protein. Thus, RSK2 modulates 5HT2A receptor function in vivo, and disruption of RSK2 leads to augmented psychostimulant-induced responses reminiscent of those seen in many animal models of schizophrenia. These findings strengthen the association between 5-HT2A receptor dysfunction and psychosis, and provide a potential mechanism underlying the schizophrenia-like symptoms present in some CLS patients.

Download Full-text

Faculty Opinions recommendation of Regulation of ribosomal S6 kinase 2 by mammalian target of rapamycin.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718307095.793492161 ◽

2014 ◽

Author(s):

Troy Hornberger

Keyword(s):

Mammalian Target Of Rapamycin ◽

Target Of Rapamycin ◽

S6 Kinase ◽

Ribosomal S6 Kinase 2 ◽

Ribosomal S6 Kinase

Download Full-text

p90 ribosomal S6 kinase 2 is associated with and dephosphorylated by protein phosphatase 2Cδ

Biochemical Journal ◽

10.1042/bj20040948 ◽

2004 ◽

Vol 382 (2) ◽

pp. 425-431 ◽

Cited By ~ 19

Author(s):

Ulrik DOEHN ◽

Steen GAMMELTOFT ◽

Shi-Hsiang SHEN ◽

Claus J. JENSEN

Keyword(s):

Protein Phosphatase ◽

Kinase Activity ◽

Kinase Domain ◽

Protein Kinase Activity ◽

Dependent Manner ◽

S6 Kinase ◽

Ribosomal S6 Kinase 2 ◽

P90 Ribosomal S6 Kinase ◽

Ribosomal S6 Kinase

RSK2 (p90 ribosomal S6 kinase 2) is activated via the ERK (extracellular-signal-regulated kinase) pathway by phosphorylation on four sites: Ser227 in the activation loop of the N-terminal kinase domain, Ser369 in the linker, Ser386 in the hydrophobic motif and Thr577 in the C-terminal kinase domain of RSK2. In the present study, we demonstrate that RSK2 is associated in vivo with PP2Cδ (protein phosphatase 2Cδ). In epidermal growth factorstimulated cells, RSK2 is partially dephosphorylated on all four sites in an Mn2+-dependent manner, leading to reduced protein kinase activity. Furthermore, PP2Cδ is phosphorylated by ERK on Thr315 and Thr333 in the catalytic domain. Mutation of Thr315 and Thr333 to alanine in a catalytically inactive mutant PP2Cδ(H154D) (His154→Asp) increases the association with RSK2 significantly, whereas mutation to glutamate, mimicking phosphorylation, reduces the binding of RSK2. The domains of interaction are mapped to the N-terminal extension comprising residues 1–71 of PP2Cδ and the N-terminal kinase domain of RSK2. The interaction is specific, since PP2Cδ associates with RSK1–RSK4, MSK1 (mitogen- and stress-activated kinase 1) and MSK2, but not with p70 S6 kinase or phosphoinositide-dependent kinase 1. We conclude that RSK2 is associated with PP2Cδ in vivo and is partially dephosphorylated by it, leading to reduced kinase activity.

Download Full-text