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Departament de Bioquímica i Biologia Molecular (P.K.,
J.C., X.T., M.P., A.Z.) Facultat de Biologia Universitat de
Barcelona 08028 Barcelona, Spain
Department of
Biochemistry and Molecular Biology (P.R.S., C.A.B.) University
College London, United Kingdom W1P8BT
Phosphatidylinositol 3 (PI 3)-kinases are potently
inhibited by two structurally unrelated membrane-permeant reagents:
wortmannin and LY294002. By using these two inhibitors we first
suggested the involvement of a PI 3-kinase activity in muscle cell
differentiation. However, several reports have described that these
compounds are not as selective for PI 3-kinase activity as assumed.
Here we show that LY294002 blocks the myogenic pathway elicited by
insulin-like growth factors (IGFs), and we confirm the specific
involvement of PI 3-kinase in IGF-induced myogenesis by overexpressing
in L6E9 myoblasts a dominant negative p85 PI 3-kinase-regulatory
subunit (L6E9-
p85). IGF-I, des(1–3)IGF-I, or IGF-II induced L6E9
skeletal muscle cell differentiation as measured by myotube formation,
myogenin gene expression, and GLUT4 glucose carrier induction. The
addition of LY294002 to the differentiation medium totally inhibited
these IGF-induced myogenic events without altering the expression of a
non-muscle-specific protein, ß1-integrin. Independent clones of L6E9
myoblasts expressing a dominant negative mutant of the p85-regulatory
subunit (p85) showed markedly impaired glucose transport activity
and formation of p85/p110 complexes in response to insulin, consistent
with the inhibition of PI 3-kinase activity. IGF-induced myogenic
parameters in L6E9-p85 cells, i.e. cell fusion and
myogenin gene and GLUT4 expression, were severely impaired compared
with parental cells or L6E9 cells expressing wild-type p85. In all,
data presented here indicate that PI 3-kinase is essential for
IGF-induced muscle differentiation and that the specific PI 3-kinase
subclass involved in myogenesis is the heterodimeric p85-p110 enzyme.
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J. Canicio, E. Gallardo, I. Illa, X. Testar, M. Palacin, A. Zorzano, and P. Kaliman p70 S6 Kinase Activation Is Not Required for Insulin-Like Growth Factor-Induced Differentiation of Rat, Mouse, or Human Skeletal Muscle Cells Endocrinology, December 1, 1998; 139(12): 5042 - 5049. [Abstract] [Full Text] [PDF]
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B.-H. Jiang, J. Z. Zheng, and P. K. Vogt An essential role of phosphatidylinositol 3-kinase in myogenic differentiation PNAS, November 24, 1998; 95(24): 14179 - 14183. [Abstract] [Full Text] [PDF]
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L. Wei, W. Zhou, J. D. Croissant, F.-E. Johansen, R. Prywes, A. Balasubramanyam, and R. J. Schwartz RhoA Signaling via Serum Response Factor Plays an Obligatory Role in Myogenic Differentiation J. Biol. Chem., November 13, 1998; 273(46): 30287 - 30294. [Abstract] [Full Text] [PDF]
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Q. Xu and Z. Wu The Insulin-like Growth Factor-Phosphatidylinositol 3-Kinase-Akt Signaling Pathway Regulates Myogenin Expression in Normal Myogenic Cells but Not in Rhabdomyosarcoma-derived RD Cells J. Biol. Chem., November 17, 2000; 275(47): 36750 - 36757. [Abstract] [Full Text] [PDF]
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Y. Tamir and E. Bengal Phosphoinositide 3-Kinase Induces the Transcriptional Activity of MEF2 Proteins during Muscle Differentiation J. Biol. Chem., October 27, 2000; 275(44): 34424 - 34432. [Abstract] [Full Text] [PDF]
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L. L. Tortorella, D. J. Milasincic, and P. F. Pilch Critical Proliferation-independent Window for Basic Fibroblast Growth Factor Repression of Myogenesis via the p42/p44 MAPK Signaling Pathway J. Biol. Chem., April 20, 2001; 276(17): 13709 - 13717. [Abstract] [Full Text] [PDF]
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J. Canicio, P. Ruiz-Lozano, M. Carrasco, M. Palacin, K. Chien, A. Zorzano, and P. Kaliman Nuclear Factor kappa B-inducing Kinase and Ikappa B Kinase-alpha Signal Skeletal Muscle Cell Differentiation J. Biol. Chem., June 1, 2001; 276(23): 20228 - 20233. [Abstract] [Full Text] [PDF]
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Q. Kang, Y. Cao, and A. Zolkiewska Direct Interaction between the Cytoplasmic Tail of ADAM 12 and the Src Homology 3 Domain of p85alpha Activates Phosphatidylinositol 3-Kinase in C2C12 Cells J. Biol. Chem., June 29, 2001; 276(27): 24466 - 24472. [Abstract] [Full Text] [PDF]
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