Cross-talk between signaling pathways regulates alternative splicing: a novel role for JNK.
The regulation of alternative splicing by extracellular signals represents a key event in the control of gene expression. There is increasing evidence showing that many extracellular cues regulate alternative splicing. Nevertheless, the broad picture regarding the role of different signaling pathways and their interaction remains incomplete. Using the fibronectin gene as a model, we show that a laminin-rich basement membrane regulates the alternative splicing of two out of three regions of the transcript (extra domain I and type III connecting segment) in mammary epithelial cells, through a non-stress c-Jun N-terminal kinase (JNK) signaling pathway. We propose that dephosphorylation of the extracellular signal-regulated kinase is involved in this regulatory process. Furthermore, the laminin-rich basement membrane blocks the effect of a mammary mesenchymal cell-conditioned medium, which stimulates the inclusion of extra domain I and type III connecting segment through a phosphatidylinositol3-kinase-dependent cascade, indicating that JNK signaling can inhibit the phosphatidylinositol 3-kinase-mediated splicing regulation. These results implicate JNK in the regulation of alternative splicing and provide new evidence on how extracellular stimuli are converted into changes in splicing patterns, strengthening the view that the control of alternative splicing is as complex and relevant as transcriptional control, together accounting for the spatiotemporal requirements of gene expression.
Pelisch
Federico
F
Biología Molecular y Neurociencias-Consejo Nacional de Investigaciones Científicas y Técnicas, Departamento de Fisiología, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires, Argentina.
Blaustein
Matías
M
Kornblihtt
Alberto R
AR
Srebrow
Anabella
A
D017398:Alternative Splicing / Q000502:physiology*; D001485:Basement Membrane / Q000378:metabolism; D001943:Breast Neoplasms; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000235:genetics*; D014162:Transfection
D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D007797:Laminin; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt