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Updated: May 25, 2026

Exploring Sequence Space to Identify Binding Sites for Regulatory RNA-Binding Proteins
Published on: August 9, 2019
Concentration-dependent control of pyruvate kinase M mutually exclusive splicing by hnRNP proteins
Mo Chen1, Charles J David, James L Manley
1Department of Biological Sciences, Columbia University, New York, New York, USA.
Abstract:
Expression of the mammalian pyruvate kinase M (PKM) gene provides an important example of mutually exclusive splicing. We showed previously that the hnRNP proteins A1, A2 and PTB have a crucial role in this process. Here we provide evidence that concentration-dependent interactions involving a network of these proteins are sufficient to determine the outcome of PKM splicing. At high concentrations, such as those found in most cancer cells, hnRNPA1 binding to two sites in the upstream regulated exon (exon 9) orchestrates cooperative interactions leading to exon 9 exclusion. At lower concentrations, binding shifts to downstream intronic sites, such that exon 9 is included and exon 10 mainly excluded, with any mRNA including both exons degraded by nonsense-mediated decay. Together, our results provide a mechanism by which a few general factors control alternative splicing of a widely expressed transcript.
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