Myogenic signaling of phosphatidylinositol 3-kinase requires the serine-threonine kinase Akt/protein kinase B.
The oncogene p3k, coding for a constitutively active form of phosphatidylinositol 3-kinase (PI 3-kinase), strongly activates myogenic differentiation. Inhibition of endogenous PI 3-kinase activity with the specific inhibitor LY294002, or with dominant-negative mutants of PI 3-kinase, interferes with myotube formation and with the expression of muscle-specific proteins. Here we demonstrate that a downstream target of PI 3-kinase, serine-threonine kinase Akt, plays an important role in myogenic differentiation. Expression of constitutively active forms of Akt dramatically enhances myotube formation and expression of the muscle-specific proteins MyoD, creatine kinase, myosin heavy chain, and desmin. Transdominant negative forms of Akt inhibit myotube formation and the expression of muscle-specific proteins. The inhibition of myotube formation and the reduced expression of muscle-specific proteins caused by the PI 3-kinase inhibitor LY294002 are completely reversed by constitutively active forms of Akt. Wild-type cellular Akt effects a partial reversal of LY294002-induced inhibition of myogenic differentiation. This result suggests that Akt can substitute for PI 3-kinase in the stimulation of myogenesis; Akt may be an essential downstream component of PI 3-kinase-induced muscle differentiation.
The Scripps Research Institute, BCC-239, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
B H
BH
Jiang
M
M
Aoki
J Z
JZ
Zheng
J
J
Li
P K
PK
Vogt
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D002642:Chick Embryo; D002867:Chromones / Q000494:pharmacology; D003402:Creatine Kinase / Q000235:genetics; D003893:Desmin / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D009025:Morpholines / Q000494:pharmacology; D009124:Muscle Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000166:cytology* / Q000502:physiology; D017570:MyoD Protein / Q000235:genetics; D018995:Myosin Heavy Chains / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
D002867:Chromones; D003402:Creatine Kinase; D003893:Desmin; D004791:Enzyme Inhibitors; D009025:Morpholines; D009124:Muscle Proteins; D017570:MyoD Protein; D018995:Myosin Heavy Chains; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one