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Vol. 16, Issue 9, 4454-4461, September 2005

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Sprouty-2 Overexpression in C2C12 Cells Confers Myogenic Differentiation Properties in the Presence of FGF2

Cristina de Alvaro ^* , Natalia Martinez  , Jose M. Rojas , and Margarita Lorenzo ^*

^* Departamento de Bioquimica y Biologia Molecular, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain; Unidad de Biologia Celular, Centro Nacional de Microbiologia, Instituto de Salud Carlos III, 28220 Majadahonda, Madrid, Spain

Submitted May 11, 2005; Revised June 16, 2005; Accepted June 24, 2005
Monitoring Editor: Marianne Bronner-Fraser

Myoblast C2C12 cells cultured in the presence of FGF2 actively proliferate and showed a differentiation-defective phenotype compared with cells cultured in low serum or in the presence of insulin. These FGF2 effects are associated with sustained activation of p44/p42-MAPK and lack of activation of AKT. Here we demonstrate that Sprouty-2, a protein involved in the negative feedback of receptor tyrosine kinase signaling, when stably overexpressed in C2C12 cells and in the presence of FGF2 produces growth arrest (precluding the expression of PCNA and the phosphorylation of retinoblastoma and inducing the expression of p21^CIP) and myogenesis (multinucleated myotubes formation, induction of creatine kinase and expression of myosin heavy chain protein). These events were accompanied by repression of p44/p42-MAPK and activation of AKT. When C2C12 cells were stably transfected with a Sprouty-2 (Y55F) mutant defective in inhibiting p44/p42-MAPK activation by FGF, myoblasts in the presence of FGF continue to grow and completely fail to form myotubes. This work is the first evidence of the contribution of sprouty genes to myogenic differentiation in the presence of FGF2.

Abbreviations used: FGF, fibroblast growth factor; FS, fetal serum; HS, horse serum; IGF, insulin-like growth factor; MAPK, mitogen-activated protein kinase; MHC, myosin heavy chain; PI3K, phosphatidylinositol 3 kinase; Rb, retinoblastoma; RTK, receptor tyrosine kinase; Spry, Sprouty.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

These authors contributed equally to this work.

Address correspondence to: Margarita Lorenzo (mlorenzo{at}farm.ucm.es).

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