title: Exon-centric regulation of pyruvate kinase M alternative splicing via mutually exclusive exons.
abstract: Alternative splicing of the pyruvate kinase M gene (PK-M) can generate the M2 isoform and promote aerobic glycolysis and tumor growth. However, the cancer-specific alternative splicing regulation of PK-M is not completely understood. Here, we demonstrate that PK-M is regulated by reciprocal effects on the mutually exclusive exons 9 and 10, such that exon 9 is repressed and exon 10 is activated in cancer cells. Strikingly, exonic, rather than intronic, cis-elements are key determinants of PK-M splicing isoform ratios. Using a systematic sub-exonic duplication approach, we identify a potent exonic splicing enhancer in exon 10, which differs from its homologous counterpart in exon 9 by only two nucleotides. We identify SRSF3 as one of the cognate factors, and show that this serine/arginine-rich protein activates exon 10 and mediates changes in glucose metabolism. These findings provide mechanistic insights into the complex regulation of alternative splicing of a key regulator of the Warburg effect, and also have implications for other genes with a similar pattern of alternative splicing.
authors: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors: Zhenxun
authors: Z
authors: Wang
authors: Deblina
authors: D
authors: Chatterjee
authors: Hyun Yong
authors: HY
authors: Jeon
authors: Martin
authors: M
authors: Akerman
authors: Matthew G
authors: MG
authors: Vander Heiden
authors: Lewis C
authors: LC
authors: Cantley
authors: Adrian R
authors: AR
authors: Krainer
mesh_terms: D017398:Alternative Splicing; D001483:Base Sequence; D002460:Cell Line; D005091:Exons; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007438:Introns; D008969:Molecular Sequence Data; D011770:Pyruvate Kinase / Q000235:genetics* / Q000378:metabolism
chemical_list: D011770:Pyruvate Kinase