IGF2-driven PI3 kinase and TGFbeta signaling pathways in chondrogenesis.
Insulin-like growth factor-2 (IGF2) is essential for fetal development as well as maintenance of adult organs such as brain and liver. Although genetic polymorphisms of IGF2 are linked to cytoskeletal variations little is known about the mechanisms of IGF2 action in proliferation and differentiation of chondrocytes for skeletal growth. A genome-wide mRNA expression analysis using C28/I2 chondrocyte cells studied potential signaling pathways underlying the responses to IGF2. Microarray data predicted involvement of the phosphatidylinositol 3-kinase (PI3K) and transforming growth factor beta (TGFbeta) signaling pathways. Protein analyses revealed IGF2 administration activated phosphorylation of Akt and GSK3beta in the PI3K pathway. LY294002 (selective inhibitor of PI3K) blocked Akt phosphorylation and abolished IGF2-driven elevation of the mRNA levels of the proteoglycans, Aggrecan and Versican. LY294002 did not suppress upregulation of TGFbeta mRNA induced by IGF2, so IGF2 activates PI3K and TGFbeta pathways. IGF2-driven transcriptional activation of proteoglycan genes such as Aggrecan and Versican is mediated by the PI3K pathway.
Hamamura
Kazunori
K
Department of Biomedical Engineering, Indiana University - Purdue University Indianapolis, Indianapolis, IN 46202, USA.
Zhang
Ping
P
Yokota
Hiroki
H
D053674:Aggrecans / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000502:physiology; D020219:Chondrogenesis / Q000502:physiology*; D002867:Chromones / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D020869:Gene Expression Profiling; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D046228:Microarray Analysis; D009025:Morpholines / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053675:Versicans / Q000235:genetics / Q000378:metabolism
C508319:ACAN protein, human; D053674:Aggrecans; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D016212:Transforming Growth Factor beta; C508322:VCAN protein, human; D053675:Versicans; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D007335:Insulin-Like Growth Factor II; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3