title: Differential effects of myopathy-associated caveolin-3 mutants on growth factor signaling.
abstract: Caveolin-3 is an important scaffold protein of cholesterol-rich caveolae. Mutations of caveolin-3 cause hereditary myopathies that comprise remarkably different pathologies. Growth factor signaling plays an important role in muscle physiology; it is influenced by caveolins and cholesterol-rich rafts and might thus be affected by caveolin-3 dysfunction. Prompted by the observation of a marked chronic peripheral neuropathy in a patient suffering from rippling muscle disease due to the R26Q caveolin-3 mutation and because TrkA is expressed by neuronal cells and skeletal muscle fibers, we performed a detailed comparative study on the effect of pathogenic caveolin-3 mutants on the signaling and trafficking of the TrkA nerve growth factor receptor and, for comparison, of the epidermal growth factor receptor. We found that the R26Q mutant slightly and the P28L strongly reduced nerve growth factor signaling in TrkA-transfected cells. Surface biotinylation experiments revealed that the R26Q caveolin-3 mutation markedly reduced the internalization of TrkA, whereas the P28L did not. Moreover, P28L expression led to increased, whereas R26Q expression decreased, epidermal growth factor signaling. Taken together, we found differential effects of the R26Q and P28L caveolin-3 mutants on growth factor signaling. Our findings are of clinical interest because they might help explain the remarkable differences in the degree of muscle lesions caused by caveolin-3 mutations and also the co-occurrence of peripheral neuropathy in the R26Q caveolinopathy case presented.
authors.affiliation: Institute of Medical Microbiology, Medical Faculty, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Brauers
authors.forename: Agnes
authors.initials: A
authors.lastname: Dreier
authors.forename: Andreas
authors.initials: A
authors.lastname: Roos
authors.forename: Berthold
authors.initials: B
authors.lastname: Wormland
authors.forename: Joachim
authors.initials: J
authors.lastname: Weis
authors.forename: Alexander
authors.initials: A
authors.lastname: Krüttgen
mesh_terms: D000328:Adult; D000818:Animals; D051244:Caveolin 3 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009135:Muscular Diseases / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D020932:Nerve Growth Factor / Q000378:metabolism*; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D051244:Caveolin 3; D020800:Receptor, Nerve Growth Factor; D004815:Epidermal Growth Factor; D020932:Nerve Growth Factor; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases
references.citation: J Biol Chem. 2005 Apr 8;280(14):13483-6
references.pmid: 15699039
references.citation: J Biol Chem. 2002 May 17;277(20):17944-9
references.pmid: 11884389
references.citation: Annu Rev Neurosci. 1996;19:463-89
references.pmid: 8833451
references.citation: J Biol Chem. 1995 Aug 4;270(31):18285-94
references.pmid: 7629148
references.citation: Hum Mol Genet. 2000 Sep 22;9(15):2335-40
references.pmid: 11001938
references.citation: J Biol Chem. 2000 Dec 1;275(48):37846-52
references.pmid: 10982788
references.citation: J Neurosci. 2005 Nov 23;25(47):10930-40
references.pmid: 16306406
references.citation: Neuroscience. 2003;120(1):31-40
references.pmid: 12849738
references.citation: J Neuroimmunol. 2005 Aug;165(1-2):11-20
references.pmid: 15925413
references.citation: J Biol Chem. 1999 Jan 1;274(1):257-63
references.pmid: 9867838
references.citation: Int Anesthesiol Clin. 2006 Spring;44(2):21-76
references.pmid: 16849956
references.citation: Am J Pathol. 1996 Jun;148(6):1807-18
references.pmid: 8669468
references.citation: Exp Mol Med. 2003 Dec 31;35(6):538-44
references.pmid: 14749532
references.citation: Biochim Biophys Acta. 1993 Jun 5;1148(2):249-56
references.pmid: 8389198
references.citation: J Pharmacol Exp Ther. 2005 May;313(2):485-91
references.pmid: 15608075
references.citation: J Histochem Cytochem. 2003 Sep;51(9):1113-8
references.pmid: 12923236
references.citation: Am J Physiol Heart Circ Physiol. 2008 Jan;294(1):H392-401
references.pmid: 17982011
references.citation: Am J Physiol Cell Physiol. 2003 Nov;285(5):C1150-60
references.pmid: 12839838
references.citation: J Biol Chem. 1997 Nov 28;272(48):30429-38
references.pmid: 9374534
references.citation: Am J Pathol. 2003 Dec;163(6):2619-34
references.pmid: 14633633
references.citation: Dev Neurobiol. 2007 Aug;67(9):1183-203
references.pmid: 17514710
references.citation: Acta Neuropathol. 1998 Nov;96(5):495-501
references.pmid: 9829813
references.citation: J Biol Chem. 1993 Sep 5;268(25):19000-3
references.pmid: 8395524
references.citation: Nat Cell Biol. 2003 May;5(5):382-4
references.pmid: 12724770
references.citation: Dev Dyn. 2000 Jul;218(3):438-51
references.pmid: 10878609
references.citation: Hum Mol Genet. 1998 May;7(5):871-7
references.pmid: 9536092
references.citation: Neurology. 2004 Feb 24;62(4):538-43
references.pmid: 14981167
references.citation: Sci STKE. 2005 Jan 18;2005(267):pe1
references.pmid: 15657262
references.citation: Nature. 1984 May 31-Jun 6;309(5967):418-25
references.pmid: 6328312
references.citation: J Neurosci. 1999 Aug 1;19(15):6538-48
references.pmid: 10414982
references.citation: Neurology. 2001 Dec 26;57(12):2273-7
references.pmid: 11756609
references.citation: J Neurol Neurosurg Psychiatry. 2002 Jul;73(1):65-7
references.pmid: 12082049
references.citation: Brain Res. 1998 Sep 7;804(2):177-92
references.pmid: 9841091
references.citation: Oncogene. 2005 May 5;24(20):3309-18
references.pmid: 15735700
references.citation: FEBS Lett. 1996 Jan 2;378(1):108-12
references.pmid: 8549793
references.citation: Nat Rev Mol Cell Biol. 2000 Oct;1(1):31-9
references.pmid: 11413487
references.citation: Diabetes. 2009 Nov;58(11):2677-86
references.pmid: 19675140
references.citation: Mol Cell Neurosci. 2005 Mar;28(3):571-87
references.pmid: 15737746
references.citation: Sci Signal. 2009 Jul 28;2(81):ra38
references.pmid: 19638615
references.citation: Methods Mol Biol. 1999;116:51-60
references.pmid: 10399145
references.citation: Int J Dev Neurosci. 2000 Dec;18(8):869-85
references.pmid: 11154856
references.citation: J Cell Biol. 2007 Oct 22;179(2):341-56
references.pmid: 17938246
references.citation: Curr Opin Neurobiol. 2002 Oct;12(5):542-9
references.pmid: 12367633
references.citation: J Biol Chem. 2004 Aug 13;279(33):34614-23
references.pmid: 15190056
references.citation: Am J Med Genet. 2001 Apr 1;99(4):303-7
references.pmid: 11251997
references.citation: Mol Neurobiol. 2007 Apr;35(2):151-9
references.pmid: 17917104
references.citation: Biochem Biophys Res Commun. 2009 Sep 18;387(2):360-4
references.pmid: 19607811
references.citation: Neurosci Lett. 2001 Mar 30;301(2):107-10
references.pmid: 11248434
references.citation: Int J Cancer. 2009 Sep 15;125(6):1257-65
references.pmid: 19499547
references.citation: J Biol Chem. 1999 Sep 3;274(36):25632-41
references.pmid: 10464299
references.citation: Lab Invest. 2008 Mar;88(3):275-83
references.pmid: 18253147
references.citation: Cancer Res. 2007 Oct 15;67(20):9986-95
references.pmid: 17942932
references.citation: J Biol Chem. 1999 Oct 22;274(43):30636-43
references.pmid: 10521449