Regulation of myoblast differentiation by the nuclear envelope protein NET39.
Recently, several transmembrane proteins of the nuclear envelope have been implicated in regulation of signaling and gene expression. Here we demonstrate that the nuclear lamina-associated nuclear envelope transmembrane protein NET39 (Ppapdc3) functions as a negative regulator of myoblast differentiation, in part through effects on mTOR signaling. We found that NET39 is highly expressed in cardiac and skeletal muscle tissues and becomes strongly upregulated during cultured myoblast differentiation. Knockdown of NET39 by RNA interference in myoblasts strongly promoted differentiation, whereas overexpression of NET39 repressed myogenesis. Proteomic analysis of NET39 complexes immunoprecipitated from myotubes, in combination with other methods, identified mTOR as an interaction partner of NET39. We found that ectopic expression of NET39 in myoblasts negatively regulated myogenesis by diminishing mTOR activity, which in turn decreased insulin-like growth factor II production and autocrine signaling. Our results indicate that NET39 is part of the regulatory machinery for myogenesis and raise the possibility that it may be important for muscle homeostasis.
Liu
Guang-Hui
GH
Department of Cell Biology, IMM-10, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Guan
Tinglu
T
Datta
Kaustuv
K
Coppinger
Judith
J
Yates
John
J
Gerace
Larry
L
D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D024510:Muscle Development; D054792:Muscle, Striated / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology* / Q000378:metabolism*; D009685:Nuclear Envelope / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism; D040901:Proteomics; D058570:TOR Serine-Threonine Kinases
D008565:Membrane Proteins; C544747:Net39 protein, mouse; D009687:Nuclear Proteins; D007335:Insulin-Like Growth Factor II; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
Proc Natl Acad Sci U S A. 2004 Feb 3;101(5):1206-10
14745025
Gene. 2007 Sep 15;399(2):174-80
17590538
Genes Dev. 2006 Feb 15;20(4):486-500
16481476
J Biol Chem. 2007 Jul 20;282(29):21160-8
17491015
Bioinformatics. 2004 Aug 4;20 Suppl 1:i49-54
15262780
Nat Biotechnol. 2001 Mar;19(3):242-7
11231557
Science. 2003 Sep 5;301(5638):1380-2
12958361
Cell Stem Cell. 2008 Jan 10;2(1):50-9
18371421
J Biol Chem. 2007 Mar 23;282(12):9017-28
17242400
J Biol Chem. 2006 Apr 7;281(14):9490-7
16464866
J Biol Chem. 2002 Aug 2;277(31):28127-34
12000755
J Cell Sci. 2008 Feb 1;121(Pt 3):282-9
18198186
FEBS J. 2007 Mar;274(6):1374-82
17489095
J Biol Chem. 1997 Sep 26;272(39):24572-8
9305923
Endocrinology. 2008 Mar;149(3):1407-14
18079193
BMC Cell Biol. 2006 Oct 24;7:38
17062158
FEBS J. 2007 Mar;274(6):1353
17309738
Cancer Res. 2007 Jan 1;67(1):1-4
17210675
Annu Rev Physiol. 1991;53:201-16
2042960
J Cell Biol. 2008 Nov 17;183(4):653-66
19015316
Proc Natl Acad Sci U S A. 1989 Mar;86(5):1543-7
2537977
J Cell Biol. 2008 Sep 8;182(5):979-91
18762576
J Am Soc Mass Spectrom. 1994 Nov;5(11):976-89
24226387
J Biol Chem. 2001 Sep 28;276(39):36079-82
11500483
J Cell Biol. 2003 Dec 8;163(5):931-6
14662739
Nat Cell Biol. 2007 Mar;9(3):316-23
17277771
Anal Chem. 2001 Dec 1;73(23):5683-90
11774908
Cell. 1987 Dec 24;51(6):987-1000
3690668
Genes Dev. 2004 Aug 15;18(16):1926-45
15314020
Biochim Biophys Acta. 2008 May;1783(5):713-27
18241676
EMBO J. 2004 Jan 14;23(1):33-44
14685263
Biochem J. 2005 Apr 15;387(Pt 2):281-93
15801912
Mol Cell Biol. 2008 May;28(9):2941-51
18316399
Nat Cell Biol. 2001 Nov;3(11):1009-13
11715022
EMBO Rep. 2007 Oct;8(10):914-9
17906672
Development. 2003 Oct;130(19):4623-37
12925589
Nat Genet. 2001 Feb;27(2):195-200
11175789
Dev Biol. 1992 Dec;154(2):261-72
1330787
Hum Mol Genet. 2006 Feb 15;15(4):637-51
16403804
Physiol Rev. 2004 Jan;84(1):209-38
14715915
Cell. 2002 Jul 26;110(2):163-75
12150925
Curr Opin Cell Biol. 1999 Dec;11(6):683-8
10600704
Hum Mol Genet. 2007 Aug 1;16(15):1884-95
17567779
Mol Cell Biol. 2007 Jan;27(2):518-25
17101791
J Proteome Res. 2002 Jan-Feb;1(1):21-6
12643522
FEBS J. 2007 Mar;274(6):1362-73
17489094
J Biol Chem. 1991 Aug 25;266(24):15917-23
1651927
J Cell Biol. 1990 Sep;111(3):807-16
2391365
Exp Cell Res. 2005 Sep 10;309(1):211-9
15963500
Cell. 1993 Dec 31;75(7):1241-4
8269506
Biochem J. 2008 Apr 15;411(2):371-7
18215144