Biology subjects

Mashadova, O.

Publications and source records attributed to Mashadova, O..

3 recordsLinked to original sources

bioRxiv2023

LKB1 suppresses growth and promotes the internalization of EGFR through the PIKFYVE lipid kinase

The tumor suppressor LKB1 is a serine/threonine protein kinase that is frequently mutated in human lung adenocarcinoma (LUAD). LKB1 regulates a complex signaling network that is known to control cell polarity and metabolism; however, the pathways that mediate the tumor suppressive activity of LKB1 are incompletely defined. To identify mechanisms of LKB1- mediated growth suppression we developed a spheroid-based cell culture assay to study LKB1- dependent growth. Using this assay, along with genome-wide CRISPR screens and validation with orthogonal methods, we discovered that LKB1 suppresses growth, in part, by activating the PIKFYVE lipid kinase, which promotes the internalization of wild-type EGFR. Our findings reveal a new mechanism of regulation of EGFR, which may have implications for the treatment of LKB1-mutant LUAD.

cancer biology↗

bioRxiv2019

Tissue of Origin Dictates GOT1 Dependence and Confers Synthetic Lethality to Radiotherapy

Metabolic programs in cancer cells are influenced by genotype and the tissue of origin. We have previously shown that central carbon metabolism is rewired in pancreatic ductal adenocarcinoma (PDA) to support proliferation through a glutamate oxaloacetate transaminase 1 (GOT1)-dependent pathway. Here we tested if tissue type impacted GOT1 dependence by comparing PDA and colorectal cancer (CRC) cell lines and tumor models of similar genotype. We found CRC to be insensitive to GOT1 inhibition, contrasting markedly with PDA, which exhibit profound growth inhibition upon GOT1 knockdown. Utilizing a combination of metabolomics strategies and computational modeling, we found that GOT1 inhibition disrupted glycolysis, nucleotide metabolism, and redox homeostasis in PDA but not CRC. These insights were leveraged in PDA, where we demonstrate that radiotherapy potently enhanced the effect of GOT1 inhibition on tumor growth. Taken together, these results illustrate the role of tissue type in dictating metabolic dependencies and provide new insights for targeting metabolism to treat PDA.

cancer biology↗

bioRxiv2018

PIP4Ks Suppress Insulin Signaling Through a Catalytic-Independent Mechanism

Insulin stimulates conversion of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) to phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3), which mediates downstream cellular responses. PI(4,5)P2 is produced by phosphatidylinositol-4-phosphate 5-kinases (PIP5Ks) and byphosphatidylinositol-5-phosphate 4-kinases (PIP4Ks). Here we show that deletion of the three genes that encode PIP4Ks (PIP4K2A, PIP4K2B and PIP4K2C) in vitro results in a paradoxical increase in PI(4,5)P2 and a subsequent increase in insulin-stimulated production of PI(3,4,5)P3. Surprisingly, reintroduction of either wild-type or kinase-dead forms of the PIP4Ks restored cellular PI(4,5)P2 levels and insulin stimulation of the PI3K pathway. These effects are explained by an increase in PIP5K activity upon deletion of PIP4Ks, which we demonstrate can suppress PIP5K activity in vitro through a direct binding interaction. Collectively, our work reveals an important non-catalytic function of PIP4Ks in suppressing PIP5K-mediated PI(4,5)P2 synthesis and insulin-dependent conversion to PI(3,4,5)P3 by PI3K enzymes and suggests that pharmacological depletion of PIP4K enzymes using emerging degrader technologies could represent a novel strategy for stimulating insulin signaling.

cell biology↗