ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome.
Coffin-Lowry Syndrome (CLS) is an X-linked mental retardation condition associated with skeletal abnormalities. The gene mutated in CLS, RSK2, encodes a growth factor-regulated kinase. However, the cellular and molecular bases of the skeletal abnormalities associated with CLS remain unknown. Here, we show that RSK2 is required for osteoblast differentiation and function. 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. Additionally, RSK2 and ATF4 posttranscriptionally regulate the synthesis of Type I collagen, the main constituent of the bone matrix. Accordingly, Atf4-deficiency results in delayed bone formation during embryonic development and low bone mass throughout postnatal life. 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.
Yang
Xiangli
X
Department of Molecular and Human Genetics and Bone Disease Program of Texas, Baylor College of Medicine, Houston, TX 77030, USA.
Matsuda
Koichi
K
Bialek
Peter
P
Jacquot
Sylvie
S
Masuoka
Howard C
HC
Schinke
Thorsten
T
Li
Lingzhen
L
Brancorsini
Stefano
S
Sassone-Corsi
Paolo
P
Townes
Tim M
TM
Hanauer
Andre
A
Karsenty
Gerard
G
D000015:Abnormalities, Multiple / Q000201:enzymology / Q000235:genetics*; D051701:Activating Transcription Factor 4; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry; D024042:Collagen Type I / Q000096:biosynthesis; D005109:Extracellular Matrix / Q000737:chemistry; D015971:Gene Expression Regulation, Enzymologic; D005809:Genes, Regulator; D008607:Intellectual Disability / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D009024:Morphogenesis; D010006:Osteoblasts / Q000378:metabolism*; D015675:Osteocalcin / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics*; D013379:Substrate Specificity; D013577:Syndrome; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014960:X Chromosome
C081452:Atf4 protein, mouse; D024042:Collagen Type I; D011994:Recombinant Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D015675:Osteocalcin; D051701:Activating Transcription Factor 4; D019893:Ribosomal Protein S6 Kinases