The proteins that PHGDH interact with in mitchondria
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Liver
SUBMITTER: 
Ting Wang
LAB HEAD: Huafeng Zhang
PROVIDER: PXD036321 | Pride | 2022-10-06
REPOSITORIES: Pride
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Project description:D-3-Phosphoglycerate dehydrogenase (Phgdh; EC 1.1.1.95) is a necessary enzyme for de novo L-serine biosynthesis via the phosphorylated pathway. We demonstrated previously that Phgdh is expressed exclusively by neuroepithelium and radial glia in developing mouse brain and later mainly by astrocytes. Mutations in the human PHGDH gene cause serine deficiency disorders (SDD) associated with severe neurological symptoms such as congenital microcephaly, psychomotor retardation, and intractable seizures. We recently demonstrated that genetically engineered mice, in which the gene for Phgdh has been disrupted, have significantly decreased levels of serine and glycine, and exhibit malformation of brain such as microcephaly. The Phgdh null (KO) embryos exhibit lethal phenotype after gestational day 14, indicating that the phosphorylated pathway is essential for embryogenesis, especially for brain development. It is worth noting that the Phgdh knockout (KO) embryos primarily displayed microcephaly, which is the most conspicuous phenotype of patients with SDD. Thus, Phgdh KO mice are a useful animal model for studying the effect of diminished L-serine levels on development of the central nervous system and other organs. To better understand the mechanism underlying the molecular pathogenesis of SDD, we sought to examine whether gene expression is altered in the Phgdh KO mouse model. We identify genes that have altered expression in the head of the Phgdh KO embryos using the GeneChip array. Some of the genes identified by this method belong in functional categories that are relevant to the biochemical and morphological aberrations of the Phgdh deletion. Experiment Overall Design: Total RNA samples were prepared from head tissues from 2 embryos of Phgdh knockout and littermate wild-type controls. Experiment Overall Design: RNA of 4 biological replicates was hybridized to Affymetrix Mouse Genome 430 2.0 arrays. Five microgram total RNA was labelled according to the ENZO-protocol, fragmented and hybridized according to Affymetrix's protocols.
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Project description:Cancer metastasis requires the transient activation of cellular programs enabling dissemination and seeding in distant organs. Genetic, transcriptional and translational heterogeneity contributes to this dynamic process. Metabolic heterogeneity has also been observed, yet its role for cancer progression is less explored. Here, we discover that loss of phosphoglycerate dehydrogenase (PHGDH) potentiates metastatic dissemination. Specifically, we find that heterogeneous or low PHGDH expression in primary tumors of breast cancer patients is associated with decreased metastasis free survival time. In mice, circulating tumor cells and early metastatic lesions are enriched with PHGDH low cancer cells and silencing PHGDH in primary tumors increases metastasis formation. Mechanistically, PHGDH protein interacts with the glycolytic enzyme phosphofructokinase (PFK) and the loss of this interaction activates the hexosamine – sialic acid pathway, which provides precursors for protein glycosylation. Consequently, aberrant protein glycosylation including increased sialylation of integrin αvβ3 occurs, which potentiates cell migration and invasion. Inhibition of sialic acid metabolism counteracts the metastatic capacity of PHGDH low cancer cells. In conclusion, while the catalytic activity of PHGDH supports cancer cell proliferation, low PHGDH protein expression non-catalytically potentiates cancer dissemination and metastasis formation. Thus, the presence of PHDGH heterogeneity in primary tumors may be considered a sign of tumor aggressiveness.
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Project description:D-3-Phosphoglycerate dehydrogenase (Phgdh; EC 1.1.1.95) is a necessary enzyme for de novo L-serine biosynthesis via the phosphorylated pathway. We demonstrated previously that Phgdh is expressed exclusively by neuroepithelium and radial glia in developing mouse brain and later mainly by astrocytes. Mutations in the human PHGDH gene cause serine deficiency disorders (SDD) associated with severe neurological symptoms such as congenital microcephaly, psychomotor retardation, and intractable seizures. We recently demonstrated that genetically engineered mice, in which the gene for Phgdh has been disrupted, have significantly decreased levels of serine and glycine, and exhibit malformation of brain such as microcephaly. The Phgdh null (KO) embryos exhibit lethal phenotype after gestational day 14, indicating that the phosphorylated pathway is essential for embryogenesis, especially for brain development. It is worth noting that the Phgdh knockout (KO) embryos primarily displayed microcephaly, which is the most conspicuous phenotype of patients with SDD. Thus, Phgdh KO mice are a useful animal model for studying the effect of diminished L-serine levels on development of the central nervous system and other organs. To better understand the mechanism underlying the molecular pathogenesis of SDD, we sought to examine whether gene expression is altered in the Phgdh KO mouse model. We identify genes that have altered expression in the head of the Phgdh KO embryos using the GeneChip array. Some of the genes identified by this method belong in functional categories that are relevant to the biochemical and morphological aberrations of the Phgdh deletion. Keywords: genetic modification
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Project description:Here we show under glucose deficiency PHGDH is phosphorylated by p38 at Ser371, which promotes the cytosol-localized PHGDH translocation into the nucleus. Meanwhile, AMPK concurrently phosphorylates PHGDH-Ser55 and selectively increases PHGDH catalytic activity against malate oxidation, thus pushing the reduction of NAD+ towards NADH generation. In the nucleus, the altered PHGDH activity positively regulates NADH/NAD+ ratio and thus restricts NAD+ level, and thereby leads to repression of NAD+-dependent PARP1 activity. Moreover, PHGDH is found to be associated with Ser73-phosphorylated c-Jun and specifically inhibits PARP1-mediated c-Jun poly(ADP-ribosyl)ation, which accordingly led to the impaired c-Jun transcriptional activity against genes expression linking to cell growth inhibition.
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Project description:Live hepatocyte-specific Phgdh KO (LKO) mice were generated by introducing Albumin-Cre transgene into Phgdh flox/flox (Floxed) mice. LKO mice exhibited mild obesity and impaired glucose intolerance at 30 weeks old.
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Project description:Serine synthesis is crucial for tumor growth and survival, but its regulatory mechanism in cancer remains elusive. Here, using integrative metabolomics and transcriptomics analyses, we show a heterogeneity between metabolite and transcript profiles. Specifically, the level of serine in HCC tissues is increased, whereas the expression of phosphoglycerate dehydrogenase (PHGDH), the first rate-limiting enzyme in serine biosynthesis pathway, is dramatically downregulated. Interestingly, the increased serine level is obtained by enhanced PHGDH catalytic activity due to protein arginine methyltransferase 1 (PRMT1)-mediated methylation of PHGDH at arginine 236. PRMT1-mediated PHGDH methylation and activation potentiates serine synthesis, ameliorates oxidative stress, and promotes HCC growth in vitro and in vivo. FBXO7, an E3 ubiquitin ligase which is downregulated in human HCC tissues, ubiquitinates and downregulates PRMT1 to suppress PHGDH methylation and serine synthesis, leading to the inhibition of HCC cell growth. Furthermore, PRMT1-mediated PHGDH methylation correlates with PHGDH hyperactivation and serine accumulation in human HCC tissues, and is predictive of poor prognosis of HCC patients. Notably, blocking PHGDH methylation with a TAT-tagged non-methylated peptide inhibits serine synthesis and restrains HCC growth, both in an HCC patient-derived xenograft (PDX) model and subcutaneous HCC cell-derived xenograft model. Overall, our findings reveal a novel regulatory mechanism of PHGDH activity and serine synthesis, and suggest PHGDH methylation as a potential therapeutic vulnerability in HCC.
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Project description:Metabolic dysregulation is an important feature of malignant tumors. Serine synthesis pathway (SSP) reshapes tumor cells to enhance their growth and survival capabilities, especially under serine starvation. However, whether and how SSP is involved in the progression of liver cancer has not been clearly stated. We applied a combination of quantitative proteomics and transcriptomics and discovered the increased expression of PHGDH and PSAT1 in mice liver cancer induced by SB. PHGDH is the first rating-limited enzyme of SSP and the conditional knockout of PHGDH in liver impaired the advanced liver cancer formation. However, the specific inhibition of enzymatic activity of PHGDH in liver has no obvious suppressive effect on advanced liver cancer. Further, we explored a non-metabolic function of PHGDH, which used its ACT domain to bind and regulate cMyc transcriptional activity, then selectively activated genes expression of Lcn2, Got1, Fabp5 and Psat1, indicating PHGDH drives/links multiple metabolic pathways and augmented its function through its non-metabolic role. In addition, the mutant p53 would release the suppression of PHGDH in mice liver cancer model and clinical liver cancer samples. Hence, the mutant p53/PHGDH/cMyc axis could be a potential target to cure advanced liver cancer.
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