Alternative splicing modulates autoinhibition and SH3 accessibility in the Src kinase Fyn.
Src family kinases are central regulators of a large number of signaling pathways. To adapt to the idiosyncrasies of different cell types, these kinases may need a fine-tuning of their intrinsic molecular control mechanisms. Here, we describe on a molecular level how the Fyn kinase uses alternative splicing to adapt to different cellular environments. Using structural analysis, site-directed mutagenesis, and functional analysis, we show how the inclusion of either exon 7A or 7B affects the autoinhibition of Fyn and how this changes the SH3-dependent interaction and tyrosine phosphorylation of Sam68, with functional consequences for the Sam68-regulated survival of epithelial cells. Our results illustrate a novel mechanism of evolution that may contribute to the complexity of Src kinase regulation.
Brignatz
C
C
UMR891 INSERM, Centre de Recherche sur le Cancer de Marseille, 27 Boulevard Leï Roure, 13009 Marseille, France.
Paronetto
M P
MP
Opi
S
S
Cappellari
M
M
Audebert
S
S
Feuillet
V
V
Bismuth
G
G
Roche
S
S
Arold
S T
ST
Sette
C
C
Collette
Y
Y
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D005091:Exons; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D051076:Proto-Oncogene Proteins c-fyn / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology; D014018:Tissue Distribution; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D007527:Isoenzymes; C489559:KHDRBS1 protein, human; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D051020:bcl-X Protein; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn