title: Suppression of Nkx3.2 by phosphatidylinositol-3-kinase signaling regulates cartilage development by modulating chondrocyte hypertrophy.
abstract: Phosphatidylinositol-3-kinase (PI3K) is a key regulator of diverse biological processes including cell proliferation, migration, survival, and differentiation. While a role of PI3K in chondrocyte differentiation has been suggested, its precise mechanisms of action are poorly understood. Here we show that PI3K signaling can down-regulate Nkx3.2 at both mRNA and protein levels in various chondrocyte cultures in vitro. In addition, we have intriguingly found that p85β, not p85α, is specifically employed as a regulatory subunit for PI3K-mediated Nkx3.2 suppression. Furthermore, we found that regulation of Nkx3.2 by PI3K requires Rac1-PAK1, but not Akt, signaling downstream of PI3K. Finally, using embryonic limb bud cultures, ex vivo long bone cultures, and p85β knockout mice, we demonstrated that PI3K-mediated suppression of Nkx3.2 in chondrocytes plays a role in the control of cartilage hypertrophy during skeletal development in vertebrates.
authors.affiliation: Department of Biochemistry, Yonsei University, Seoul, Republic of Korea.
authors.forename: Jeong-Ah
authors.initials: JA
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, Yonsei University, Seoul, Republic of Korea.
authors.forename: Suhjean
authors.initials: S
authors.lastname: Im
authors.affiliation: Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, NY, USA.
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.affiliation: Department of Biochemistry, Yonsei University, Seoul, Republic of Korea. Electronic address: kimdw@yonsei.ac.kr.
authors.forename: Dae-Won
authors.initials: DW
authors.lastname: Kim
mesh_terms: D000818:Animals; D002356:Cartilage / Q000473:pathology; D049108:Cell Enlargement; D049109:Cell Proliferation; D019902:Chondrocytes / Q000502:physiology*; D020219:Chondrogenesis; D020868:Gene Silencing; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006984:Hypertrophy / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D054462:p21-Activated Kinases / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C491536:NKX3-2 protein, human; C107953:RAC1 protein, human; D012333:RNA, Messenger; D014157:Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein
keywords: Cartilage development; Chondrocyte differentiation; Nkx3.2 (Bapx1); PI-3-Kinase