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ACLY is the Novel Signaling Target of PIP 2/PIP 3 and Lyn in Cancer

30 Pages Posted: 16 Jan 2020 Sneak Peek Status: Review Complete

See all articles by Johnvesly Basappa

Johnvesly Basappa

Fox Chase Cancer Center

Mevlut Citir

European Molecular Biology Laboratory (EMBL)- Germany

Qian Zhang

University of Pennsylvania

Hong Y. Wang

University of Pennsylvania

Xiaobin Liu

University of Pennsylvania

Olga Melnikov

Fox Chase Cancer Center

Hafiz Yahya

Fox Chase Cancer Center

Frank Stein

European Molecular Biology Laboratory (EMBL)- Germany

Rainer Muller

European Molecular Biology Laboratory (EMBL)- Germany

Alexis Traynor-Kaplan

ATK Innovation, Analytics and Discovery; University of Washington

Carsten Schultz

European Molecular Biology Laboratory (EMBL)- Germany

Mariusz A. Wasik

Fox Chase Cancer Center

Andrzej Ptasznik

Fox Chase Cancer Center

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Abstract

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, the 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.

Keywords: Cancer, Metabolism, Src, Lyn, PI3K, ACLY, acetyl-CoA

Suggested Citation

Basappa, Johnvesly and Citir, Mevlut and Zhang, Qian and Wang, Hong Y. and Liu, Xiaobin and Melnikov, Olga and Yahya, Hafiz and Stein, Frank and Muller, Rainer and Traynor-Kaplan, Alexis and Schultz, Carsten and Wasik, Mariusz A. and Ptasznik, Andrzej, ACLY is the Novel Signaling Target of PIP 2/PIP 3 and Lyn in Cancer. ISCIENCE-D-19-01396. Available at SSRN: https://ssrn.com/abstract=3520242 or http://dx.doi.org/10.2139/ssrn.3520242
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Johnvesly Basappa

Fox Chase Cancer Center

333 Cottman Ave
Philadelphia, PA 19107
United States

Mevlut Citir

European Molecular Biology Laboratory (EMBL)- Germany

Meyerhofstraße 1
Heidelberg, 69117
Germany

Qian Zhang

University of Pennsylvania

Philadelphia, PA 19104
United States

Hong Y. Wang

University of Pennsylvania

Philadelphia, PA 19104
United States

Xiaobin Liu

University of Pennsylvania

Philadelphia, PA 19104
United States

Olga Melnikov

Fox Chase Cancer Center

333 Cottman Ave
Philadelphia, PA 19107
United States

Hafiz Yahya

Fox Chase Cancer Center

333 Cottman Ave
Philadelphia, PA 19107
United States

Frank Stein

European Molecular Biology Laboratory (EMBL)- Germany

Meyerhofstraße 1
Heidelberg, 69117
Germany

Rainer Muller

European Molecular Biology Laboratory (EMBL)- Germany

Meyerhofstraße 1
Heidelberg, 69117
Germany

Alexis Traynor-Kaplan

ATK Innovation, Analytics and Discovery ( email )

Seattle, WA
United States

University of Washington

Seattle, WA 98195
United States

Carsten Schultz

European Molecular Biology Laboratory (EMBL)- Germany

Meyerhofstraße 1
Heidelberg, 69117
Germany

Mariusz A. Wasik

Fox Chase Cancer Center

333 Cottman Ave
Philadelphia, PA 19107
United States

Andrzej Ptasznik (Contact Author)

Fox Chase Cancer Center ( email )

333 Cottman Ave
Philadelphia, PA 19107
United States

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