ERK5 Interacts with Mitochondrial Glutaminase and Regulates Its Expression

• Published in: International journal of molecular sciences Vol. 25; no. 6; p. 3273
• Main Authors: Guillén-Pérez, Yolanda María, Ortiz-Ruiz, María Jesús, Márquez, Javier, Pandiella, Atanasio, Esparís-Ogando, Azucena
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01-03-2024; MDPI
• Subjects: Antibodies; Aprotinin; Cell Line, Tumor; Cellular proteins; Cellular signal transduction; Development and progression; energy metabolism; Enzymes; ERK5; Ethylenediaminetetraacetic acid; GLS isoforms; glutaminase; Glutaminase - genetics; Glutaminase - metabolism; Glutamine; Glutamine - metabolism; Health aspects; Humans; International economic relations; Kinases; Lung cancer; Lung Neoplasms - metabolism; Mass spectrometry; Metabolism; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Molecular weight; Pancreatic cancer; Peptides; Phosphorylation; Protein kinases; Proteins; proteomics; RNA; RNA Interference; Scientific equipment and supplies industry; Signal Transduction; Tumors; United States; Massachusetts; Germany; Spain; cancer therapy; proteomics; GLS isoforms; mitochondria; ERK5; glutaminase; energy metabolism
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25063273

Many of the biological processes of the cell, from its structure to signal transduction, involve protein-protein interactions. On this basis, our aim was to identify cellular proteins that interact with ERK5, a serine/threonine protein kinase with a key role in tumor genesis and progression and a promising therapeutic target in many tumor types. Using affinity chromatography, immunoprecipitation, and mass spectrometry techniques, we unveiled an interaction between ERK5 and the mitochondrial glutaminase GLS in pancreatic tumor cells. Subsequent co-immunoprecipitation and immunofluorescence studies supported this interaction in breast and lung tumor cells as well. Genetic approaches using RNA interference techniques and CRISPR/Cas9 technology demonstrated that the loss of ERK5 function led to increased protein levels of GLS isoforms (KGA/GAC) and a concomitant increase in their activity in tumor cells. It is well known that the tumor cell reprograms its intermediary metabolism to meet its increased metabolic needs. In this sense, mitochondrial GLS is involved in the first step of glutamine catabolism, one of the main energy sources in the context of cancer. Our data suggest that ERK5 contributes to the regulation of tumor cell energy metabolism via glutaminolysis.