Disease relevance of Rps6ka3

• RSK2 knockout mice may be a good animal model for the study of Coffin-Lowry syndrome [1].
• However, in the absence of RSK2, c-Fos-dependent osteosarcoma formation is impaired [2].
• Inactivation of the growth factor-regulated S6 kinase RSK2 causes Coffin-Lowry syndrome in humans, an X-linked mental retardation condition associated with progressive skeletal abnormalities [2].
• Here we show that mice lacking RSK2 develop a progressive skeletal disease, osteopenia due to impaired osteoblast function and normal osteoclast differentiation [2].
• Insulin resistance and lipodystrophy in mice lacking ribosomal S6 kinase 2 [3].

Psychiatry related information on Rps6ka3

• The loss of RSK2 activity in humans leads to Coffin-Lowry syndrome, which is manifested by mental retardation, growth deficits, skeletal deformations, and psychosis [4].

High impact information on Rps6ka3

• These findings identify ATF4 as a critical regulator of osteoblast differentiation and function, and indicate that lack of ATF4 phosphorylation by RSK2 may contribute to the skeletal phenotype of CLS [5].
• ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome [5].
• Here, we show that RSK2 is required for osteoblast differentiation and function [5].
• Additionally, RSK2 and ATF4 posttranscriptionally regulate the synthesis of Type I collagen, the main constituent of the bone matrix [5].
• Requirement of Rsk-2 for epidermal growth factor-activated phosphorylation of histone H3 [6].

Biological context of Rps6ka3

• However, cells deficient in p90 ribosomal S6 kinase 2 (Rsk2(-/-)) totally block this phosphorylation in a dose- and time-dependent manner [7].
• Moreover, this interaction leads to maintenance of the sustained activation of RSK2 in G1 phase of the cell cycle [8].
• We identify the transcription factor ATF4 as a critical substrate of RSK2 that is required for the timely onset of osteoblast differentiation, for terminal differentiation of osteoblasts, and for osteoblast-specific gene expression [5].
• The injection of constitutively active mutant forms of Rsk1 and Rsk2 does not induce a cell cycle arrest in two-cell mouse embryos [9].
• The lined deletion contains less than approximately 0.7 cM of genetic material and includes the growth factor-regulated protein kinase gene, Rsk2 [10].

Anatomical context of Rps6ka3

• In conclusion, RSK2 likely plays a major role in feedback inhibition of the ERK pathway in skeletal muscle [1].
• Here we describe the generation and characterization of immortalized embryonic fibroblast cell lines from mice in which the Rsk-2 gene was disrupted by homologous recombinant gene targeting [11].
• During midgestation we observed specifically enhanced expression of Rsk2 first in somites, later restricted to the dermatomyotome of the somites, then in the sensory ganglia of cranial nerves and in the dorsal root ganglia of the spinal nerves [12].
• In the brain of 2-day-old mice, Pdk1 is expressed in the cortical plate of the cerebral cortex and in the stratum pyramidale of the hippocampus, whereas Rsk2 expression is lower in these structures [12].
• Endogenous signaling by other GPCRs, including P2Y-purinergic, PAR-1-thrombinergic, beta1-adrenergic, and bradykinin-B receptors, was also potentiated in RSK2-deficient fibroblasts [4].

Associations of Rps6ka3 with chemical compounds

• By using purified proteins, FGF-2 is shown to directly interact through two separate domains with two RSK2 domains on both sides of the hydrophobic motif, namely the NH2-terminal kinase domain (residues 360-381) by amino acid Ser-117 and the COOH-terminal kinase domain (residues 388-400) by amino acids Leu-127 and Lys-128 [8].
• This defect is probably not mediated by RSK2-dependent phosphorylation of c-Fos on serine 362 in the C-terminus [2].
• Salicylic acid and aspirin inhibit the activity of RSK2 kinase and repress RSK2-dependent transcription of cyclic AMP response element binding protein- and NF-kappa B-responsive genes [13].
• 90-kDa ribosomal S6 kinase-2 (RSK2) belongs to a family of growth factor-activated serine/threonine kinases composed of two kinase domains connected by a regulatory linker region [14].
• RSK2-PDZ domain interactions are functionally important for synaptic transmission because neurons expressing kinase-dead RSK2 display a dramatic reduction in frequency of AMPA-type glutamate receptor-mediated miniature excitatory postsynaptic currents, an effect dependent on the PDZ ligand [15].

Enzymatic interactions of Rps6ka3

• Furthermore, assays with Rsk-2 showed that this kinase phosphorylates H2B but not H3 in vitro [16].

Regulatory relationships of Rps6ka3

• MIP-2-induced phosphorylation of RSK2 was inhibited by PD98059 but not by wortmannin [17].

Other interactions of Rps6ka3

• Furthermore, RSK2 is not required for activation of muscle glycogen synthase by insulin but may indirectly modulate muscle glycogen synthase activity and/or glycogen content by other mechanisms, possibly through regulation of Akt [1].
• In the present study, we show that VV infection provoked a sustained activation of both ERK1/2 and RSK2 (ribosomal S6 kinase 2) [18].
• Rsk-2-deficient (knockout or KO) cell lines have no detectable Rsk-2 protein, whereas Rsk-1 expression is unaltered as compared with cell lines derived from wild-type control mice [11].
• Phosphorylation of histone H3 at serine 10 was shown to be mediated by RSK2, mitogen- and stress-activated protein kinase-1 (MSK1), and mitogen-activated protein kinases depending on the specific stimulation or stress [19].
• Activation is classically brought about by signaling-dependent phosphorylation of a key acceptor site (Ser133 in CREB) by a number of possible kinases, including PKA, CamKIV, and Rsk-2 [20].

References