ACLY is the novel signaling target of PIP2/PIP3 and Lyn in acute myeloid leukemia

Johnvesly Basappa, Mevlut Citir, Qian Zhang, Hong Y. Wang, Xiaobin Liu, Olga Melnikov, Hafiz Yahya, Frank Stein, Rainer Muller, Alexis Traynor-Kaplan, Carsten Schultz, Mariusz A. Wasik, Andrzej Ptasznik

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

A fundamental feature of tumor progression is reprogramming of metabolic pathways. ATP citrate lyase (ACLY) is a key metabolic enzyme that catalyzes the generation of Acetyl-CoA and is upregulated in cancer cells and required for their growth. The phosphoinositide 3-kinase (PI3K) and Src-family kinase (SFK) Lyn are constitutively activate in many cancers. We show here, for the first time, that both the substrate and product of PI3K, phosphatidylinositol-(4,5)-bisphosphate (PIP2) and phosphatidylinositol-(3,4,5)-trisphosphate (PIP3), respectively, bind to ACLY in Acute Myeloid Leukemia (AML) patient-derived, but not normal donor-derived cells. We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells. These results indicate a novel function for Lyn, as a regulator of Acetyl-CoA-mediated metabolic pathways.

Original languageEnglish (US)
Article numbere03910
JournalHeliyon
Volume6
Issue number5
DOIs
StatePublished - May 2020

Keywords

  • ACLY
  • Acetyl-CoA
  • Biochemistry
  • Biological sciences
  • Cancer
  • Cancer research
  • Health sciences
  • Lyn
  • Metabolism
  • PI3K
  • Src

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'ACLY is the novel signaling target of PIP<sub>2</sub>/PIP<sub>3</sub> and Lyn in acute myeloid leukemia'. Together they form a unique fingerprint.

Cite this