Regulation of alternative pre-mRNA splicing by the ERK MAP-kinase pathway

• Published in: The EMBO journal Vol. 20; no. 15; pp. 4194 - 4203
• Main Authors: Weg-Remers, Susanne, Ponta, Helmut, Herrlich, Peter, König, Harald
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.08.2001; Blackwell Publishing Ltd; Oxford University Press
• Subjects: Alternative Splicing; Animals; CD44; CD44 antigen; Cells, Cultured; ERK kinase; ERK protein; Exons; Gene Expression Regulation; Gene Silencing; Genes, Reporter; Hyaluronan Receptors - genetics; Hyaluronan Receptors - metabolism; Immune response; luciferase; Luciferases - genetics; Lymphocytes; MAP kinase; MAP Kinase Kinase 1; MAP Kinase Kinase 2; MAP Kinase Signaling System; MEK protein; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinase Kinases - metabolism; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; Protein Isoforms - genetics; Protein Isoforms - metabolism; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins c-raf - metabolism; Proto-Oncogene Proteins p21(ras) - metabolism; Raf protein; Ras protein; RNA Precursors; signal transduction; T cells; T-Lymphocytes - cytology; T-Lymphocytes - metabolism; Tumor Cells, Cultured; Up-Regulation
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1093/emboj/20.15.4194

Differential gene expression through alternative pre‐mRNA splicing is crucial to various physiological and pathological conditions. Upon activation of B and T lymphocytes during an immune response, variant isoforms of the cell surface molecule CD44 are generated by alternative pre‐mRNA splicing. We show here that in primary mouse T cells as well as in the murine LB‐17 T‐cell line upregulation of variant CD44 mRNA species upon T‐cell activation requires activation of the MEK–ERK pathway. By employing mutant signaling molecules and a novel luciferase‐based splice reporter system we demonstrate that the Ras–Raf–MEK–ERK signaling cascade, but not the p38 MAP‐kinase pathway, activates a mechanism that retains variant CD44 exon v5 sequence in mature mRNA. The findings demonstrate that a highly conserved pleiotropic signaling pathway links extracellular cues to splice regulation, providing an avenue for tissue‐specific, developmental or pathology‐associated splicing decisions.