title: Epidermal growth factor receptor down-regulation triggers human myoblast differentiation.
abstract: Initiation of human myoblast differentiation requires a negative shift (hyperpolarization) of the resting potential of myoblasts that depends on the activation of Kir2.1 potassium channels. These channels are regulated by a tyrosine phosphorylation. Using human primary myoblast culture, we investigated a possible role of various receptor tyrosine kinases in the induction of the differentiation process. We found that Epidermal Growth Factor Receptor (EGFR) is a key regulator of myoblast differentiation. EGFR activity is down-regulated during early human myoblast differentiation, and this event is required for normal differentiation to take place. Furthermore, EGFR silencing in proliferation conditions was able to trigger the differentiation program. This occurs through an increase of Kir2.1 channel activity that, via a rise of store-operated Ca(2+) entry, leads to the expression of myogenic transcription factors and muscle specific proteins (Myogenin, Myocyte Enhancer Factor 2 (MEF2), Myosin Heavy Chain (MyHC)). Finally, blocking myoblast cell cycle in proliferation conditions using a cdk4 inhibitor greatly decreased myoblast proliferation but was not able, on its own, to promote myoblast differentiation. Taken together, these results show that EGFR down-regulation is an early event that is required for the induction of myoblast differentiation.
authors: Department of Basic Neurosciences, University Medical Center, Geneva, Switzerland.
authors: Marina C
authors: MC
authors: Leroy
authors: Julie
authors: J
authors: Perroud
authors: Basile
authors: B
authors: Darbellay
authors: Laurent
authors: L
authors: Bernheim
authors: Stephane
authors: S
authors: Konig
mesh_terms: D059447:Cell Cycle Checkpoints; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D032446:Myoblasts / Q000166:cytology* / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: C489461:Kir2.1 channel; D024661:Potassium Channels, Inwardly Rectifying; D066246:ErbB Receptors
references: Cell Signal. 2004 Mar;16(3):333-41
references: 14687663
references: Jpn J Physiol. 2001 Aug;51(4):501-9
references: 11564287
references: Curr Opin Genet Dev. 1996 Aug;6(4):445-53
references: 8791524
references: Gene. 2006 Jan 17;366(1):2-16
references: 16377102
references: Mol Cell Endocrinol. 2013 Jun 15;372(1-2):23-9
references: 23541948
references: FEBS Lett. 1999 Oct 1;459(1):100-4
references: 10508925
references: Trends Cell Biol. 2005 Dec;15(12):666-73
references: 16243526
references: Cell Growth Differ. 1993 Mar;4(3):203-13
references: 8466858
references: Cell. 1978 Nov;15(3):855-64
references: 728992
references: J Biol Chem. 1997 Mar 7;272(10):6653-62
references: 9045696
references: Muscle Nerve. 1993 May;16(5):498-505
references: 8515758
references: J Physiol. 1998 Jul 15;510 ( Pt 2):467-76
references: 9705997
references: J Biol Chem. 2004 Jul 2;279(27):28187-96
references: 15084602
references: J Clin Oncol. 2006 Feb 10;24(5):816-22
references: 16391296
references: J Cell Physiol. 1989 Feb;138(2):311-5
references: 2918032
references: J Cell Biol. 1988 Aug;107(2):761-9
references: 2843547
references: Histopathology. 2009 Jun;54(7):873-9
references: 19469909
references: Development. 2008 Mar;135(5):859-67
references: 18216177
references: Mol Cell. 2011 Sep 2;43(5):723-37
references: 21884975
references: J Cell Physiol. 2009 Mar;218(3):460-6
references: 19006176
references: Am J Physiol Cell Physiol. 2007 Jan;292(1):C106-14
references: 16837648
references: Pflugers Arch. 2008 May;456(2):413-23
references: 18087715
references: Biochem Biophys Res Commun. 2006 Jul 14;345(4):1425-33
references: 16729973
references: J Biol Chem. 1998 Dec 18;273(51):34063-8
references: 9852063
references: Int J Biochem Cell Biol. 2007;39(6):1177-89
references: 17433758
references: Mol Cell Biol. 2000 Jun;20(11):3951-64
references: 10805738
references: J Biol Chem. 1998 Apr 24;273(17):10436-44
references: 9553102
references: Exp Cell Res. 2007 Jan 15;313(2):341-56
references: 17123512
references: Crit Rev Oncol Hematol. 1995 Jul;19(3):183-232
references: 7612182
references: Biochim Biophys Acta. 2011 Aug;1808(8):1993-9
references: 21570948
references: J Cell Biol. 1987 Aug;105(2):949-56
references: 3624313
references: J Cell Physiol. 2006 Aug;208(2):435-45
references: 16688780
references: Nucleic Acids Res. 2008 Aug;36(13):4337-51
references: 18586824
references: Oncogene. 1999 Sep 16;18(37):5167-76
references: 10498866
references: J Cell Biol. 2001 May 14;153(4):677-86
references: 11352930
references: J Biomed Sci. 2002 Jul-Aug;9(4):321-6
references: 12145529
references: J Biol Chem. 2009 Feb 20;284(8):5370-80
references: 19088073
references: Mol Syst Biol. 2005;1:2005.0010
references: 16729045
references: Biophys J. 2007 Jul 15;93(2):684-98
references: 17468161
references: J Biol Chem. 2003 Oct 3;278(40):38360-7
references: 12874275
references: In Vivo. 2009 Sep-Oct;23(5):779-96
references: 19779115
references: Annu Rev Cell Dev Biol. 1998;14:167-96
references: 9891782
references: Int J Biochem Cell Biol. 1999 Jun;31(6):637-43
references: 10404636
references: Br J Cancer. 2004 Jan 26;90(2):289-93
references: 14735165
references: Science. 1995 Feb 17;267(5200):1018-21
references: 7863327