AMP-activated protein kinase regulates β-catenin protein synthesis by phosphorylating serine/arginine-rich splicing factor 9

Biochem Biophys Res Commun. 2021 Jan 1:534:347-352. doi: 10.1016/j.bbrc.2020.11.079. Epub 2020 Nov 25.

Abstract

β-catenin is a multi-functional protein with a central role in regulating embryonic development and tissue homeostasis. The abnormal accumulation of β-catenin, due to disrupted β-catenin degradation or unregulated β-catenin synthesis, causes the development of cancer. A recent study showed that the overexpression of proto-oncogene serine/arginine-rich splicing factor 9 (SRSF9) promotes β-catenin accumulation via binding β-catenin mRNA and enhancing its translation in a manner that is dependent on the mechanistic target of rapamycin (mTOR). However, the regulation of the interaction between SRSF9 and mRNA of β-catenin remains unclear. Here, we show that AMP-activated protein kinase (AMPK) phosphorylates SRSF9 at the RNA-interacting SWQDLKD motif that plays a major role in determining substrate specificity. The phosphorylation by AMPK inhibits the binding of SRSF9 to β-catenin mRNA and suppresses β-catenin protein synthesis caused by SRSF9 overexpression without changing the β-catenin mRNA levels. Our findings suggest that AMPK activators are potential therapeutic targets for SRSF9-derived overproduction of β-catenin in cancer cells.

Keywords: AMPK; SRSF9; mTORC1; β-catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Binding Sites
  • HEK293 Cells
  • Humans
  • In Vitro Techniques
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mutagenesis, Site-Directed
  • Phosphorylation
  • Protein Binding
  • Proto-Oncogene Mas
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Serine-Arginine Splicing Factors / chemistry
  • Serine-Arginine Splicing Factors / genetics
  • Serine-Arginine Splicing Factors / metabolism*
  • Substrate Specificity
  • beta Catenin / biosynthesis*
  • beta Catenin / genetics

Substances

  • CTNNB1 protein, human
  • MAS1 protein, human
  • Proto-Oncogene Mas
  • RNA, Messenger
  • Recombinant Fusion Proteins
  • SRSF9 protein, human
  • beta Catenin
  • Serine-Arginine Splicing Factors
  • Mechanistic Target of Rapamycin Complex 1
  • AMP-Activated Protein Kinases