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Phosphorylation of GSK-3beta by cGMP-dependent protein kinase II promotes hypertrophic differentiation of murine chondrocytes.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Kawasaki, Yosuke Kugimiya, Fumitaka Chikuda, Hirotaka Kamekura, Satoru Ikeda, Toshiyuki Kawamura, Naohiro Saito, Taku Shinoda, Yusuke Higashikawa, Akiro Yano, Fumiko Ogasawara, Takesi Ogata, Naoshi Hoshi, Kazuto Hofmann, Franz Joseph Woodgett, James R. Nakamura, Kozo Hitachiota-shi Chung, Ung-il Kawaguchi, Hiroyuki |
| Copyright Year | 2008 |
| Abstract | cGMP-dependent protein kinase II (cGKII; encoded by PRKG2) is a serine/threonine kinase that is critical for skeletal growth in mammals; in mice, cGKII deficiency results in dwarfism. Using radiographic analysis, we determined that this growth defect was a consequence of an elongated growth plate and impaired chondrocyte hypertrophy. To investigate the mechanism of cGKII-mediated chondrocyte hypertrophy, we performed a kinase substrate array and identified glycogen synthase kinase-3beta (GSK-3beta; encoded by Gsk3b) as a principal phosphorylation target of cGKII. In cultured mouse chondrocytes, phosphorylation-mediated inhibition of GSK-3beta was associated with enhanced hypertrophic differentiation. Furthermore, cGKII induction of chondrocyte hypertrophy was suppressed by cotransfection with a phosphorylation-deficient mutant of GSK-3beta. Analyses of mice with compound deficiencies in both protein kinases (Prkg2(-/-)Gsk3b(+/-)) demonstrated that the growth retardation and elongated growth plate associated with cGKII deficiency were partially rescued by haploinsufficiency of Gsk3b. We found that beta-catenin levels decreased in Prkg2(-/-) mice, while overexpression of cGKII increased the accumulation and transactivation function of beta-catenin in mouse chondroprogenitor ATDC5 cells. This effect was blocked by coexpression of phosphorylation-deficient GSK-3beta. These data indicate that hypertrophic differentiation of growth plate chondrocytes during skeletal growth is promoted by phosphorylation and inactivation of GSK-3beta by cGKII. |
| Starting Page | 185 |
| Ending Page | 188 |
| Page Count | 4 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://dm5migu4zj3pb.cloudfront.net/manuscripts/33000/33637C1/JCI0833637C1.v1.pdf |
| Alternate Webpage(s) | http://dm5migu4zj3pb.cloudfront.net/manuscripts/35000/35243/JCI0835243.v2.pdf |
| PubMed reference number | 18551195v1 |
| Alternate Webpage(s) | https://doi.org/10.1172/JCI35243 |
| DOI | 10.1172/jci35243 |
| Journal | The Journal of clinical investigation |
| Volume Number | 118 |
| Issue Number | 7 |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Catenins Cell Differentiation process Cyclic GMP Epiphysial cartilage Glycogen (Starch) Synthase Growth retardation Haploinsufficiency Lesch-Nyhan Syndrome MARK2 gene PRKG2 gene PRKG2 protein, human Protein Kinases Protein-Serine-Threonine Kinases Threonine Trans-Activation, Genetic beta Thalassemia beta catenin chondrocyte hypertrophy eIF-2 Kinase glycogen synthase kinase 3 beta |
| Content Type | Text |
| Resource Type | Article |
