Lkb1/Stk11 regulation of mTOR signaling controls the transition of chondrocyte fates and suppresses skeletal tumor formation.
Liver kinase b1 (Lkb1) protein kinase activity regulates cell growth and cell polarity. Here, we show Lkb1 is essential for maintaining a balance between mitotic and postmitotic cell fates in development of the mammalian skeleton. In this process, Lkb1 activity controls the progression of mitotic chondrocytes to a mature, postmitotic hypertrophic fate. Loss of this Lkb1-dependent switch leads to a dramatic expansion of immature chondrocytes and formation of enchondroma-like tumors. Pathway analysis points to a mammalian target of rapamycin complex 1-dependent mechanism that can be partially suppressed by rapamycin treatment. These findings highlight a critical requirement for integration of mammalian target of rapamycin activity into developmental decision-making during mammalian skeletogenesis.
Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad-California Institute for Regenerative Medicine Center for Regenerative Medicine and Stem Cell Research, University of Southern California Keck School of Medicine, Los Angeles, CA 90089.
Lick Pui
LP
Lai
Brendan N
BN
Lilley
Joshua R
JR
Sanes
Andrew P
AP
McMahon
D055372:AMP-Activated Protein Kinases; D000704:Analysis of Variance; D000818:Animals; D001973:Bromodeoxyuridine; D002454:Cell Differentiation / Q000502:physiology*; D019902:Chondrocytes / Q000166:cytology*; D006652:Histological Techniques; D017403:In Situ Hybridization; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D010671:Phenylurea Compounds; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D046912:Multiprotein Complexes; D010671:Phenylurea Compounds; C032766:ethylene diurea; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D001973:Bromodeoxyuridine; D020123:Sirolimus
cell death; chondrocyte differentiation; endochondral ossification; hypoxia