title: Identification of Erbin interlinking MuSK and ErbB2 and its impact on acetylcholine receptor aggregation at the neuromuscular junction.
abstract: Erbin, a binding partner of ErbB2, was identified as the first member of the LAP family of proteins. Erbin was shown at postsynaptic membranes of the neuromuscular junction (NMJ) or in cultured C2C12 myotubes (1) to be concentrated, (2) to regulate the Ras-Raf-Mek pathway, and (3) to inhibit TGF-beta signaling. In the CNS, Erbin interacts with PSD-95. Furthermore, agrin-MuSK signaling initiates formation of AChR aggregates at the postsynaptic membrane. In search of proteins interacting with MuSK, we identified Erbin as a MuSK binding protein. We verified the interaction of MuSK with Erbin, or both concomitantly with ErbB2 by coimmunoprecipitation, and we mapped the interacting epitopes between Erbin and MuSK. We demonstrated elevated mRNA levels of Erbin at synaptic nuclei and colocalized Erbin and MuSK at postsynaptic membranes. We identified several Erbin isoforms at the NMJ, all of which contained the MuSK binding domain. By knocking down Erbin, we observed agrin-dependent AChR aggregates on murine primary skeletal myotubes and C2C12 cells, and in the absence of agrin, microclusters, both of significantly lower density. Complementary, AChR-epsilon-reporter expression was reduced in myotubes overexpressing Erbin. We show that myotubes also express other LAP protein family members, namely Scribble and Lano, and that both affect physical dimensions of agrin-dependent AChR aggregates and density of microclusters formed in the absence of agrin. Moreover, MuSK-Erbin-ErbB2 signaling influences TGF-beta signaling. Our data define the requirement of Erbin on the cross talk between agrin and neuregulin signaling pathways at the NMJ.
authors.affiliation: Institut für Biochemie, Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany.
authors.forename: Luca
authors.initials: L
authors.lastname: Simeone
authors.forename: Marion
authors.initials: M
authors.lastname: Straubinger
authors.forename: Muhammad Amir
authors.initials: MA
authors.lastname: Khan
authors.forename: Nancy
authors.initials: N
authors.lastname: Nalleweg
authors.forename: Tatiana
authors.initials: T
authors.lastname: Cheusova
authors.forename: Said
authors.initials: S
authors.lastname: Hashemolhosseini
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009469:Neuromuscular Junction / Q000378:metabolism*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011950:Receptors, Cholinergic / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D011950:Receptors, Cholinergic; C413364:ERBIN protein, human; C498804:Erbb2ip protein, mouse; C517630:erbin protein, rat; C508053:ERBB2 protein, human; C524056:Erbb2 protein, mouse; C483804:Erbb2 protein, rat; C095714:MUSK protein, human; C511695:MuSK protein, mouse; C475048:MuSK protein, rat
references.citation: Neuron. 2000 May;26(2):443-55
references.pmid: 10839362
references.citation: Nat Rev Neurosci. 2003 Feb;4(2):113-20
references.pmid: 12563282
references.citation: Dev Cell. 2009 Mar;16(3):433-44
references.pmid: 19289088
references.citation: Cell. 1993 Mar 12;72(5):801-15
references.pmid: 8453670
references.citation: Neuron. 1995 Sep;15(3):573-84
references.pmid: 7546737
references.citation: Dev Dyn. 2000 Mar;217(3):250-6
references.pmid: 10741419
references.citation: Dev Biol. 1995 Nov;172(1):158-69
references.pmid: 7589796
references.citation: Development. 1997 Jul;124(13):2659-70
references.pmid: 9217007
references.citation: J Biol Chem. 2006 Jan 13;281(2):927-33
references.pmid: 16301319
references.citation: J Biol Chem. 2003 Jan 10;278(2):1108-14
references.pmid: 12379659
references.citation: Neuron. 2002 Aug 1;35(3):489-505
references.pmid: 12165471
references.citation: Mol Cell. 1998 Mar;1(4):611-7
references.pmid: 9660945
references.citation: Cell. 1996 May 17;85(4):501-12
references.pmid: 8653786
references.citation: J Biol Chem. 2001 Jun 1;276(22):19318-26
references.pmid: 11279080
references.citation: J Neurosci. 1996 Nov 1;16(21):6839-52
references.pmid: 8824323
references.citation: J Cell Biol. 2000 Jul 10;150(1):205-12
references.pmid: 10893268
references.citation: Oncogene. 2005 Jun 23;24(27):4330-9
references.pmid: 15806148
references.citation: Genes Dev. 2001 Nov 15;15(22):2950-66
references.pmid: 11711431
references.citation: Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3596-601
references.pmid: 10725395
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18812-7
references.pmid: 19020093
references.citation: Annu Rev Biochem. 1995;64:287-314
references.pmid: 7574483
references.citation: Mol Cell Neurosci. 2006 Feb;31(2):334-45
references.pmid: 16278083
references.citation: Nat Cell Biol. 2000 Jul;2(7):407-14
references.pmid: 10878805
references.citation: Annu Rev Neurosci. 1999;22:389-442
references.pmid: 10202544
references.citation: J Neurosci. 2006 Jan 11;26(2):655-61
references.pmid: 16407563
references.citation: J Biol Chem. 2004 Jul 23;279(30):31622-8
references.pmid: 15155732
references.citation: J Biol Chem. 1997 Apr 18;272(16):10367-71
references.pmid: 9099674
references.citation: Mol Cell Neurosci. 2000 Dec;16(6):697-707
references.pmid: 11124891
references.citation: Hum Mol Genet. 2003 Jan 15;12(2):87-98
references.pmid: 12499390
references.citation: J Biol Chem. 2005 Mar 25;280(12):11790-7
references.pmid: 15659388
references.citation: J Biol Chem. 2001 Aug 24;276(34):32051-5
references.pmid: 11440998
references.citation: Mol Cell Biol. 2007 Sep;27(17):6183-94
references.pmid: 17591701
references.citation: EMBO J. 1995 Sep 1;14(17):4258-66
references.pmid: 7556067
references.citation: J Neurosci. 1999 May 1;19(9):3376-83
references.pmid: 10212297
references.citation: J Biol Chem. 2001 Aug 31;276(35):32427-36
references.pmid: 11375975
references.citation: J Biol Chem. 1994 Jan 21;269(3):1587-90
references.pmid: 8294401
references.citation: Mol Cell Neurosci. 2004 Aug;26(4):558-69
references.pmid: 15276157
references.citation: Nature. 1985 Sep 5-11;317(6032):66-8
references.pmid: 3839905
references.citation: Science. 2005 Jun 24;308(5730):1920-3
references.pmid: 15976301
references.citation: J Neurosci. 2000 Dec 1;20(23):8762-70
references.pmid: 11102484
references.citation: Nat Genet. 1995 Dec;11(4):415-21
references.pmid: 7493022
references.citation: J Neurochem. 2006 Oct;99(2):450-7
references.pmid: 16899069
references.citation: Nat Genet. 1995 Dec;11(4):409-14
references.pmid: 7493021
references.citation: Cell. 2008 Oct 17;135(2):334-42
references.pmid: 18848351
references.citation: Genes Dev. 2006 Jul 1;20(13):1800-16
references.pmid: 16818610
references.citation: J Neurosci. 2006 May 3;26(18):4841-51
references.pmid: 16672658
references.citation: EMBO J. 1995 Dec 1;14(23):5842-8
references.pmid: 8846777
references.citation: Neurosci Lett. 1994 Aug 15;177(1-2):151-4
references.pmid: 7824170
references.citation: J Neurosci. 2006 Jul 26;26(30):7919-32
references.pmid: 16870737
references.citation: Neuroscience. 2000;97(4):735-42
references.pmid: 10842018
references.citation: Cell. 1986 Jun 6;45(5):649-57
references.pmid: 2871941