MBNL142 and MBNL143 gene isoforms, overexpressed in DM1-patient muscle, encode for nuclear proteins interacting with Src family kinases.
Myotonic dystrophy type-1 (DM1) is the most prevalent form of muscular dystrophy in adults. This disorder is an RNA-dominant disease, caused by expansion of a CTG repeat in the DMPK gene that leads to a misregulation in the alternative splicing of pre-mRNAs. The longer muscleblind-like-1 (MBNL1) transcripts containing exon 5 and the respective protein isoforms (MBNL142-43) were found to be overexpressed in DM1 muscle and localized exclusively in the nuclei. In vitro assays showed that MBNL142-43 bind the Src-homology 3 domain of Src family kinases (SFKs) via their proline-rich motifs, enhancing the SFK activity. Notably, this association was also confirmed in DM1 muscle and myotubes. The recovery, mediated by an siRNA target to Ex5-MBNL142-43, succeeded in reducing the nuclear localization of both Lyn and MBNL142-43 proteins and in decreasing the level of tyrosine phosphorylated proteins. Our results suggest an additional molecular mechanism in the DM1 pathogenesis, based on an altered phosphotyrosine signalling pathway.
Department of Biomedicine and Prevention, University 'Tor Vergata', Roma 00133, Italy.
A
A
Botta
A
A
Malena
E
E
Tibaldi
L
L
Rocchi
E
E
Loro
E
E
Pena
L
L
Cenci
E
E
Ambrosi
M C
MC
Bellocchi
M A
MA
Pagano
G
G
Novelli
G
G
Rossi
H L
HL
Monaco
E
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Gianazza
B
B
Pantic
V
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Romeo
O
O
Marin
A M
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Brunati
L
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Vergani
D000328:Adult; D016022:Case-Control Studies; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008954:Models, Biological; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D009132:Muscles / Q000378:metabolism* / Q000473:pathology; D009223:Myotonic Dystrophy / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D018909:src Homology Domains; D019061:src-Family Kinases / Q000378:metabolism*
C493663:MBNL1 protein, human; D009687:Nuclear Proteins; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D019000:Phosphotyrosine; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases