Regulation of alternative splicing by the extracellular matrix

FEDERICO PELISCH; MATÍAS BLAUSTEIN; ALBERTO R. KORNBLIHTT; ANABELLA SREBROW

Iguazú, Argentina

Congreso; Reunión Anual de la Sociedad Argentina de Investigaciones Bioquímicas - SAIB; 2004

The regulation of alternative splicing by extracellular signals represents a key event in the control of gene expression. There is increasing evidence 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 (FN) gene as a model, we show that a laminin-rich basement membrane (lr-BM) regulates alternative splicing of two regions of the transcript (EDI and IIICS) in mammary epithelial cells, through a nonstress JNK signaling pathway. We propose that dephosphorylation of ERK is involved in this regulatory process. This effect is exon-specific, as EDII, another alternative splicing  region in the same gene, is not affected by this signal-induced splicing regulation. Furthermore, the lr-BM blocks the effect of a mammary mesenchymal cell-conditioned medium, which stimulates the inclusion of EDI and IIICS through a PI 3-kinase-dependent cascade, indicating that JNK signaling can inhibit the PI 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.