Control of cell metabolism by the epidermal growth factor receptor

Orofiamma, Laura; Vural, Dafne; Antonescu, Costin N.

doi:10.1016/j.bbamcr.2022.119359

Cited by 14 publications

(13 citation statements)

References 287 publications

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“…A key outcome of EGFR stimulation is the synthesis of PtdIns(3,4,5)P 3 and/or PtdIns(3,4)P 2 levels by activating the PI3Ks (Hu et al, 1992; Orofiamma et al, 2022; Rodrigues et al, 2000). To assess this, we transfected ARPE-19 and MDA-MB-231 cells with Akt-PH-GFP, a biosensor for 3-phosphorylated PtdInsPs (Várnai and Balla, 1998).…”

Section: Resultsmentioning

confidence: 99%

“…A key outcome of EGFR stimulation is the synthesis of PtdIns(3,4,5)P 3 and/or PtdIns(3,4)P 2 levels by activating the PI3Ks (Hu et al, 1992;Orofiamma et al, 2022;Rodrigues et al, 2000).…”

Section: Lclat1 Acyltransferase Silencing Reduces Ptdins(345)p 3 Synt...mentioning

confidence: 99%

“…PtdIns(4,5)P 2 regulates a number of functions including endocytosis, ion transport, and the cytoskeleton organization (Balla, 2013; Katan and Cockcroft, 2020; Sun et al, 2013). PtdIns(4,5)P 2 is also a precursor for other signalling intermediates regulated by growth factor receptors like the Epidermal Growth Factor (EGF) and its receptor, the EGF receptor (EGFR), a major receptor tyrosine kinase (Katan and Cockcroft, 2020; Orofiamma et al, 2022). EGF binds and dimerizes EGFR, leading to receptor trans-autophosphorylation on various tyrosine residues (Böni-Schnetzler and Pilch, 1987; Gullick et al, 1985; Honegger et al, 1987; Koland and Cerione, 1988; Linggi and Carpenter, 2006; Yarden and Schlessinger, 1987).…”

Section: Introductionmentioning

confidence: 99%

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The LCLAT1/LYCAT acyltransferase is required for EGF-mediated phosphatidylinositol-3,4,5-trisphosphate and Akt signalling

Chan

Bone

Anderson

et al. 2023

Preprint

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Receptor tyrosine kinases such as epidermal growth factor (EGF) receptor (EGFR) stimulate phosphatidylinositol 3-kinases (PI3Ks) to convert phosphaitydlinositol-4,5-bisphosophate [PtdIns(4,5)P2] into phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P3]. PtdIns(3,4,5)P3 then promotes various pathways leading to actin remodelling, changes in gene expression, and enhanced anabolic activity, cell survival and proliferation. In part, PtdIns(3,4,5)P3 achieves these functions by stimulating the kinase Akt, which phosphorylates numerous targets like Tsc2 and GSK3β. Overall, unchecked upregulation of PtdIns(3,4,5)P3-Akt signalling can promote tumourgenesis and cancer progression. Interestingly, 50-70% of PtdIns and PtdInsPs have stearate and arachidonate at sn-1 and sn-2 positions of glycerol, respectively, forming a species known as 38:4-PtdIns/PtdInsPs. It is thought that LCLAT1/LYCAT and MBOAT7/LPIAT1 acyltransferases are respectively responsible for enriching PtdIns with this acyl composition. We previously showed that disruption of LCLAT1 altered the acyl profile of bis-phosphorylated PtdInsPs, lowered PtdIns(4,5)P2, and perturbed endocytosis and endocytic trafficking. However, the role of LCLAT1 in receptor tyrosine kinase and PtdIns(3,4,5)P3 signaling was not explored. Here, we show that LCLAT1 silencing in MDA-MB-231 and ARPE-19 cells abated the levels of PtdIns(3,4,5)P3 in response to EGF signalling. Importantly, LCLAT1-silenced cells were also impaired for EGF-mediated Akt activation and downstream signalling, and consequently, were depressed for cell proliferation and survival. Thus, our work provides first evidence that the LCLAT1 acyltransferase supports receptor tyrosine kinase signalling through the PtdIns(3,4,5)P3-Akt axis and may represent a novel target for therapeutic development against cancers.

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Section: Resultsmentioning

confidence: 99%

“…A key outcome of EGFR stimulation is the synthesis of PtdIns(3,4,5)P 3 and/or PtdIns(3,4)P 2 levels by activating the PI3Ks (Hu et al, 1992;Orofiamma et al, 2022;Rodrigues et al, 2000).…”

Section: Lclat1 Acyltransferase Silencing Reduces Ptdins(345)p 3 Synt...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The LCLAT1/LYCAT acyltransferase is required for EGF-mediated phosphatidylinositol-3,4,5-trisphosphate and Akt signalling

Chan

Bone

Anderson

et al. 2023

Preprint

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“…Banding of ligand to EGFR induces receptor dimerization and tyrosine autophosphorylation, leading to downstream activation of many intracellular signaling pathways, such as mitogen‐activated protein kinase (MAPK) and PI3K/AKT. Eventually, multiple cellular events are changed, such as the cell cycle, apoptosis, cytoskeleton dynamics, cell migration, and cell invasion 38,39 . Mutation, overexpression, and dysregulation of EGFR are highly associated with tumorigenesis and tumor progression of various cancers, including cSCC 40,41 .…”

Section: Discussionmentioning

confidence: 99%

“…Eventually, multiple cellular events are changed, such as the cell cycle, apoptosis, cytoskeleton dynamics, cell migration, and cell invasion. 38,39 Mutation, overexpression, and dysregulation of EGFR are highly associated with tumorigenesis and tumor progression of various cancers, including cSCC. 40,41 In combination with our current results, we thought that PRR11 promoted cSCC proliferation, survival, and migration by activating the EGFR signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Proline‐rich 11 (PRR11) promotes the progression of cutaneous squamous cell carcinoma by activating the EGFR signaling pathway

Wang

Zhang

Lei

et al. 2023

Molecular Carcinogenesis

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Cutaneous squamous cell carcinoma (cSCC) is one of the most common skin malignancies, and its incidence rate is increasing worldwide. Proline-rich 11 (PRR11) has been reported to be involved in the occurrence and development of various tumors. However, the role of PRR11 in cSCC remains unknown. In the present study, we observed upregulated expression of PRR11 in cSCC tissues and cell lines. Knockdown of PRR11 in the cSCC cell lines A431 and SCL-1 inhibited cell proliferation by inducing cell cycle arrest during the G1/S phase transition, promoted cell apoptosis, and reduced cell migration and invasion in vitro. Conversely, overexpression of PRR11 promoted cell proliferation, decreased cell apoptosis, and enhanced cell migration and invasion. PRR11 knockdown also inhibited cSCC tumor growth in a mouse xenograft model.Mechanistic investigations by RNA sequencing revealed that 891 genes were differentially expressed genes between cells with PRR11 knockdown and control cells. Enrichment analysis of different genes showed that the epidermal growth factor receptor (EGFR) signaling pathway was the top enriched pathway. We further validated that PRR11 induced EGFR pathway activity, which contributed to cSCC progression. These data suggest that PRR11 may serve as a novel therapeutic target in cSCC.

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Hyperglycolysis in endothelial cells drives endothelial injury and microvascular alterations in peritoneal dialysis

Si,

Su,

Zhou

et al. 2023

Clinical & Translational Med

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BackgroundEndothelial cell (EC) dysfunction leading to microvascular alterations is a hallmark of technique failure in peritoneal dialysis (PD). However, the mechanisms underlying EC dysfunction in PD are poorly defined.MethodsWe combined RNA sequencing with metabolite set analysis to characterize the metabolic profile of peritoneal ECs from a mouse model of PD. This was combined with EC‐selective blockade of glycolysis by genetic or pharmacological inhibition of 6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase 3 (PFKFB3) in vivo and in vitro. We also investigated the association between peritoneal EC glycolysis and microvascular alterations in human peritoneal samples from patients with end‐stage kidney disease (ESKD).ResultsIn a mouse model of PD, peritoneal ECs had a hyperglycolytic metabolism that shunts intermediates into nucleotide synthesis. Hyperglycolytic mouse peritoneal ECs displayed a unique active phenotype with increased proliferation, permeability and inflammation. The active phenotype of mouse peritoneal ECs can be recapitulated in human umbilical venous ECs and primary human peritoneal ECs by vascular endothelial growth factor that was released from high glucose‐treated mesothelial cells. Importantly, reduction of peritoneal EC glycolysis, via endothelial deficiency of the glycolytic activator PFKFB3, inhibited PD fluid‐induced increases in peritoneal capillary density, vascular permeability and monocyte extravasation, thereby protecting the peritoneum from the development of structural and functional damages. Mechanistically, endothelial PFKFB3 deficiency induced the protective effects in part by inhibiting cell proliferation, VE‐cadherin endocytosis and monocyte‐adhesion molecule expression. Pharmacological PFKFB3 blockade induced a similar therapeutic benefit in this PD model. Human peritoneal tissue from patients with ESKD also demonstrated evidence of increased EC PFKFB3 expression associated with microvascular alterations and peritoneal dysfunction.ConclusionsThese findings reveal a critical role of glycolysis in ECs in mediating the deterioration of peritoneal function and suggest that strategies targeting glycolysis in peritoneal ECs may be of therapeutic benefit for patients undergoing PD.

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Control of cell metabolism by the epidermal growth factor receptor

Cited by 14 publications

References 287 publications

The LCLAT1/LYCAT acyltransferase is required for EGF-mediated phosphatidylinositol-3,4,5-trisphosphate and Akt signalling

The LCLAT1/LYCAT acyltransferase is required for EGF-mediated phosphatidylinositol-3,4,5-trisphosphate and Akt signalling

Proline‐rich 11 (PRR11) promotes the progression of cutaneous squamous cell carcinoma by activating the EGFR signaling pathway

Hyperglycolysis in endothelial cells drives endothelial injury and microvascular alterations in peritoneal dialysis

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