Cytosolic PKM2 stabilizes mutant EGFR protein expression through regulating HSP90–EGFR association

Yang, Ye; Cheng, Tsu‐Yao; Sm, Huang; Cy, Su; Pw, Yang; Lee, Jang-Ming; Ck, Chen; Hsiao, Michael; Kt, Hua; Kuo, Min-Liang

doi:10.1038/onc.2015.397

Cited by 49 publications

(44 citation statements)

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“…The association between eNOS and PKM2 appeared to be mediated by Hsp90, as both eNOS and Hsp90 could be detected in PKM2 immunoprecipitates from growth factor‐stimulated endothelial cells (Fig F). In line with the fact that PKM2 has been identified as an Hsp90 client protein in other cellular systems (Subbaramaiah et al , ; Yang et al , ), PKM2 and Hsp90 also formed complexes in HEK293 cells in the absence eNOS (Fig EV1B). To determine whether or not the increased association of PKM2 with eNOS was a consequence of the higher eNOS activity, experiments were repeated using a S633D‐eNOS mutant that also displays a higher NO output (Boo et al , ).…”

Section: Resultssupporting

confidence: 73%

Nitric oxide maintains endothelial redox homeostasis through PKM 2 inhibition

et al. 2019

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Decreased nitric oxide (NO) bioavailability and oxidative stress are hallmarks of endothelial dysfunction and cardiovascular diseases. Although numerous proteins are S-nitrosated, whether and how changes in protein S-nitrosation influence endothelial function under pathophysiological conditions remains unknown. We report that active endothelial NO synthase (eNOS) interacts with and S-nitrosates pyruvate kinase M2 (PKM2), which reduces PKM2 activity. PKM2 inhibition increases substrate flux through the pentose phosphate pathway to generate reducing equivalents (NADPH and GSH) and protect against oxidative stress. In mice, the Tyr656 to Phe mutation renders eNOS insensitive to inactivation by oxidative stress and prevents the decrease in PKM2 S-nitrosation and reducing equivalents, thereby delaying cardiovascular disease development. These findings highlight a novel mechanism linking NO bioavailability to antioxidant responses in endothelial cells through S-nitrosation and inhibition of PKM2.

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Section: Resultssupporting

confidence: 73%

Nitric oxide maintains endothelial redox homeostasis through PKM 2 inhibition

et al. 2019

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“…picard.ch/downloads/Hsp90interactors.pdf), including EGFR (Ahsan et al, 2012), AKT (Basso et al, 2002), SAPK (Tatebe and Shiozaki, 2003), p38 (Ota et al, 2010), PKC (Gould et al, 2009), FAK (Xiong et al, 2014), and DNA-PK (Solier et al, 2012). Hsp90 controls the maturation and intracellular trafficking of ErbB2family proteins, including EGFR (Xu et al, 2001(Xu et al, , 2002Yang et al, 2016). The biological function of Hsp90 relies on an inherent ATPase activity that is modulated by many of its co-chaperones.…”

Section: Ifits As Putative Co-chaperonesmentioning

confidence: 99%

Emerging Functions of Human IFIT Proteins in Cancer

Pidugu

et al. 2019

Front. Mol. Biosci.

116

105

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Interferon-induced protein with tetratricopeptide repeats (IFIT) genes are prominent interferon-stimulated genes (ISGs). The human IFIT gene family consists of four genes named IFIT1, IFIT2, IFIT3, and IFIT5. The expression of IFIT genes is very low in most cell types, whereas their expression is greatly enhanced by interferon treatment, viral infection, and pathogen-associated molecular patterns (PAMPs). The proteins encoded by IFIT genes have multiple tetratricopeptide repeat (TPR) motifs. IFIT proteins do not have any known enzymatic roles. However, they execute a variety of cellular functions by mediating protein-protein interactions and forming multiprotein complexes with cellular and viral proteins through their multiple TPR motifs. The versatile tertiary structure of TPR motifs in IFIT proteins enables them to be involved in distinct biological functions, including host innate immunity, antiviral immune response, virus-induced translation initiation, replication, double-stranded RNA signaling, and PAMP recognition. The current understanding of the IFIT proteins and their role in cellular signaling mechanisms is limited to the antiviral immune response and innate immunity. However, recent studies on IFIT protein functions and their involvement in various molecular signaling mechanisms have implicated them in cancer progression and metastasis. In this article, we focused on critical molecular, biological and oncogenic functions of human IFIT proteins by reviewing their prognostic significance in health and cancer. Research suggests that IFIT proteins could be novel therapeutic targets for cancer therapy.

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“…Protein concentration was determined using the BCA Protein Assay Kit (Pierce) according to the manufacturer's instructions. One thousand five hundred milligrams of protein were incubated with indicated antibodies overnight and then mixed with protein A or protein G‐agarose beads …”

Section: Methodsmentioning

confidence: 69%

“…In addition, we established a PKM2 knockdown approach in Y79 cells (Figure D), in which the levels of C‐MET also showed no significant differences (Figure D); however, we found that HGF‐induced Y79 cell proliferation was suppressed by PKM2 knockdown (Figure E). Previous studies have demonstrated that PKM2‐regulated tumourigenesis mainly depends on its nuclear translocation function . Therefore, in western blot analysis of PKM2 in Y79 cells after cytoplasmic nucleus separation, the results showed that HGF promoted nuclear translocation of PKM2, a process that was dependent on C‐MET function (Figure F).…”

Section: Resultsmentioning

confidence: 94%

“…HGF‐induced C‐MET–dependent signal transduction promoted PKM2 nuclear translocation, and the nuclear translocation of PKM2 directly determined C‐MET–dependent cell proliferation. ERK 1/2 is an important downstream molecule for signal transduction after C‐MET activation, and it is also upstream of PKM2 in EGFR activation‐induced glioblastoma growth . Previous studies have demonstrated that EGFR‐mediated ERK1/2 activation promotes PKM2 S37 phosphorylation that determines PKM2 nuclear translocation.…”

Section: Discussionmentioning

confidence: 99%

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C‐MET–dependent signal transduction mediates retinoblastoma growth by regulating PKM2 nuclear translocation

Dai

Zeng

Luo

2019

Cell Biochemistry & Function

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Mesenchymal epithelial transition (C-MET) factor overexpression has been found in many types of cancer and has served as an important molecular target for therapeutic intervention. However, the role of C-MET in retinoblastoma remains largely unclear.The present study aimed to investigate the potential role and mechanism of C-MET in Y79 retinoblastoma cells. We found that C-MET was highly expressed in Y79 retinoblastoma cells, and, in addition, the levels of C-MET were positively correlated with cell proliferation and retinoblastoma growth. Inhibition of C-MET suppressed Y79 retinoblastoma cell proliferation and tumour growth. Mechanistically, we showed that HGF-induced C-MET-dependent signal transduction resulted in ERK 1/2 phosphorylation, which subsequently promoted the nuclear translocation of PKM2. Nuclear PKM2 further interacted with histone H3 and contributed to C-MET-dependent cyclin D1 and c-Myc expression and cell proliferation. These findings highlight the role of C-MET in Y79 retinoblastoma cells and reveal a C-MET-dependent signal transduction mechanism. C-MET may be a potential therapeutic target for retinoblastoma.Significance of the study: We demonstrated a new target of retinoblastoma, C-MET. C-MET-dependent signal transduction promotes Y79 retinoblastoma cell proliferation and tumour growth through ERK 1/2/PKM2/histone H3 signalling pathway. C-MET may be a potential target for retinoblastoma therapy.

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Cytosolic PKM2 stabilizes mutant EGFR protein expression through regulating HSP90–EGFR association

Cited by 49 publications

References 50 publications

Nitric oxide maintains endothelial redox homeostasis through PKM 2 inhibition

Nitric oxide maintains endothelial redox homeostasis through PKM 2 inhibition

Emerging Functions of Human IFIT Proteins in Cancer

C‐MET–dependent signal transduction mediates retinoblastoma growth by regulating PKM2 nuclear translocation

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