Emerging roles of PHLPP phosphatases in metabolism

Cha, Jong-Ho; Jeong, Yoseok; Oh, Ah-Reum; Lee, Sang Bae; Hong, Soon‐Sun; Kim, KyeongJin

doi:10.5483/bmbrep.2021.54.9.095

Cited by 8 publications

(5 citation statements)

References 68 publications

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“…This PH domain is also present in the human PHLPP1 and PHLPP2 phosphatases, which are involved in apoptosis and the suppression of tumour growth (Brognard et al., 2007 ). These human PHLPP proteins share a domain composition that includes an N‐terminal PH domain, an LRR region, a phosphatase domain belonging to the PPM family, and a C‐terminal PDZ‐binding motif (Cha et al., 2021 ). The yeast homologue of PHLPP proteins, Cyr1, lacks the PH and PDZ domains but is fused to adenylate cyclase, while the Drosophila homologue retains the LRR, PPM and PDZ ligand but lacks the PH domain (Baker & Kelly, 2004 ).…”

Section: Discussionmentioning

confidence: 99%

Mining oomycete proteomes for phosphatome leads to the identification of specific expanded phosphatases in oomycetes

Qiu,

Sun,

et al. 2024

Molecular Plant Pathology

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Phosphatases are important regulators of protein phosphorylation and various cellular processes, and they serve as counterparts to kinases. In this study, our comprehensive analysis of oomycete complete proteomes unveiled the presence of approximately 3833 phosphatases, with most species estimated to have between 100 and 300 putative phosphatases. Further investigation of these phosphatases revealed a significant increase in protein serine/threonine phosphatases (PSP) within oomycetes. In particular, we extensively studied the metallo‐dependent protein phosphatase (PPM) within the PSP family in the model oomycete Phytophthora sojae. Our results showed notable differences in the expression patterns of PPMs throughout 10 life stages of P. sojae, indicating their vital roles in various stages of oomycete pathogens. Moreover, we identified 29 PPMs in P. sojae, and eight of them possessed accessory domains in addition to phosphate domains. We investigated the biological function of one PPM protein with an extra PH domain (PPM1); this protein exhibited high expression levels in both asexual developmental and infectious stages. Our analysis confirmed that PPM1 is indeed an active protein phosphatase, and its accessory domain does not affect its phosphatase activity. To delve further into its function, we generated knockout mutants of PPM1 and validated its essential roles in mycelial growth, sporangia and oospore production, as well as infectious stages. To the best of our knowledge, this study provides the first comprehensive inventory of phosphatases in oomycetes and identifies an important phosphatase within the expanded serine/threonine phosphatase group in oomycetes.

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Section: Discussionmentioning

confidence: 99%

Mining oomycete proteomes for phosphatome leads to the identification of specific expanded phosphatases in oomycetes

Qiu,

Sun,

et al. 2024

Molecular Plant Pathology

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“…In our analysis, we detected a very strong co-localization of GWAS signal with gene expression in the skeletal muscle (Figure 2B), thus pointing to a different mechanism of FTO gene regulation between skeletal muscle tissue and the brain. The second top most significant SMR signal on chromosome 16 was detected on the PHLPP2 gene, a phosphatase shown to be increased during obesity leading to lipid accumulation and glucose dysfunction 70 . In line with this, we detected a specific gene-trait association with LDL and cholesterol (Table S4).…”

Section: Discussionmentioning

confidence: 99%

Multi-omics and Mendelian Randomization network analysis of the association between metabolic and cognitive functions in the UK Biobank Database

Lorenzini,

Langley

2024

Preprint

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In obese individuals, low levels of leptin, an hormone regulating energy expenditure, have been claimed to be associated with neurodegeneration during ageing. Since leptin signalling system is less potent in the elderly, its protective anti-inflammatory effect in the brain is inhibited and people overweight in middle-age are at higher risk of developing dementia later in life. However, the causal association between obesity and cognitive decline has been inconsistent so far. We incorporated several metabolic and cognitive phenotypes from primary-care health records from European individuals in the UK Biobank to study comprehensively the genetic architecture of metabolic function and cognition. By GWAS analysis, we identified genetic loci in various traits associated with metabolic function and cognitive performance and investigated their genetic association by Mendelian Randomization. Importantly, we identified putatively causality amongst metabolism related traits and that higher adiposity is causally associated with a worse cognitive performance. We conducted a transcriptome-wide association study to identify regulatory effects of the susceptibility variants to pinpoint genes associated with gene expression changes. We integrated the GWAS results with transcriptome and single cell public data to identify tissues and cell types associated with the pathogenesis of metabolic dysfunction and cognition. Overall, this multi-omics approach have proven to be invaluable for demonstrating the causal association between adiposity and cognition and for the discovery of causal variants, genes, tissues and cell types underlying these phenotypes.

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“…PH domain Leucine-rich repeat Protein Phosphatase (PHLPP) isozymes comprise a well-known tumour suppressor family with two PHLPP1 and PHLPP2 members, play important role in several cellular processes such as metabolism, insulin resistance-related diseases and carcinogenesis [22][23][24][25]. Accumulation evidence have been accumulated that PHLPP family has different substrates which possess different biology in managing the activity and stability of kinases, inactivating the kinase Akt and inhibiting the Akt signalling pathway [26].…”

Section: Discussionmentioning

confidence: 99%

RNF149 confers cisplatin resistance in esophageal squamous cell carcinoma via destabilization of PHLPP2 and activating PI3K/AKT signalling

Zhu,

Tang,

et al. 2023

Med Oncol

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Chemo-resistance has been identi ed as a crucial factor contributing to tumor recurrence and a leading cause of worse prognosis in patients with ESCC. Therefore, unravel the critical regulators and effective strategies to overcome drug resistance will have a signi cant clinical impact on the disease. In our study we found that RNF149 was upregulated in ESCC and high RNF149 expression was associated with poor prognosis with ESCC patients. Functionally, we have demonstrated that overexpression of RNF149 confers CDDP resistance to ESCC; however, inhibition of RNF149 reversed this phenomenon both in vitro and in vivo. Mechanistically, we demonstrated that RNF149 interacts with PH domain and leucine rich repeat protein phosphatase 2 (PHLPP2) and induces E3 ligase-dependent protein degradation of PHLPP2, substantially activating the PI3K/AKT signalling in ESCC. Additionally, we found that inhibition of PI3K/AKT signalling by AKT siRNA or small molecule inhibitor signi cantly suppressed RNF149induced CDDP resistance. Importantly, RNF149 locus was also found to be ampli ed not only in ESCC but also in various human cancer types. Our data suggest that RNF149 might function as an oncogenic gene. Targeting the RNF149/PHLPP2/PI3K/Akt axis may be a promising prognostic factor and valuable therapeutic target for malignant tumours.

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Emerging roles of PHLPP phosphatases in metabolism

Cited by 8 publications

References 68 publications

Mining oomycete proteomes for phosphatome leads to the identification of specific expanded phosphatases in oomycetes

Mining oomycete proteomes for phosphatome leads to the identification of specific expanded phosphatases in oomycetes

Multi-omics and Mendelian Randomization network analysis of the association between metabolic and cognitive functions in the UK Biobank Database

RNF149 confers cisplatin resistance in esophageal squamous cell carcinoma via destabilization of PHLPP2 and activating PI3K/AKT signalling

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