title: Tyr26 phosphorylation of PGAM1 provides a metabolic advantage to tumours by stabilizing the active conformation.
abstract: How oncogenic signalling coordinates glycolysis and anabolic biosynthesis in cancer cells remains unclear. We recently reported that the glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) regulates anabolic biosynthesis by controlling intracellular levels of its substrate 3-phosphoglycerate and product 2-phosphoglycerate. Here we report a novel mechanism in which Y26 phosphorylation enhances PGAM1 activation through release of inhibitory E19 that blocks the active site, stabilising cofactor 2,3-bisphosphoglycerate binding and H11 phosphorylation. We also report the crystal structure of H11-phosphorylated PGAM1 and find that phospho-H11 activates PGAM1 at least in part by promoting substrate 3-phosphoglycerate binding. Moreover, Y26 phosphorylation of PGAM1 is common in human cancer cells and contributes to regulation of 3-phosphoglycerate and 2-phosphoglycerate levels, promoting cancer cell proliferation and tumour growth. As PGAM1 is a negative transcriptional target of TP53, and is therefore commonly upregulated in human cancers, these findings suggest that Y26 phosphorylation represents an additional acute mechanism underlying phosphoglycerate mutase 1 upregulation.
authors: Department of Haematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors: Taro
authors: T
authors: Hitosugi
authors: Lu
authors: L
authors: Zhou
authors: Jun
authors: J
authors: Fan
authors: Shannon
authors: S
authors: Elf
authors: Liang
authors: L
authors: Zhang
authors: Jianxin
authors: J
authors: Xie
authors: Yi
authors: Y
authors: Wang
authors: Ting-Lei
authors: TL
authors: Gu
authors: Masa
authors: M
authors: Alečković
authors: Gary
authors: G
authors: LeRoy
authors: Yibin
authors: Y
authors: Kang
authors: Hee-Bum
authors: HB
authors: Kang
authors: Jae-Ho
authors: JH
authors: Seo
authors: Changliang
authors: C
authors: Shan
authors: Peng
authors: P
authors: Jin
authors: Weimin
authors: W
authors: Gong
authors: Sagar
authors: S
authors: Lonial
authors: Martha L
authors: ML
authors: Arellano
authors: Hanna J
authors: HJ
authors: Khoury
authors: Georgia Z
authors: GZ
authors: Chen
authors: Dong M
authors: DM
authors: Shin
authors: Fadlo R
authors: FR
authors: Khuri
authors: Titus J
authors: TJ
authors: Boggon
authors: Sumin
authors: S
authors: Kang
authors: Chuan
authors: C
authors: He
authors: Jing
authors: J
authors: Chen
mesh_terms: D019794:2,3-Diphosphoglycerate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004795:Enzyme Stability; D005988:Glyceric Acids / Q000378:metabolism; D006019:Glycolysis; D006639:Histidine / Q000378:metabolism; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000201:enzymology* / Q000378:metabolism* / Q000473:pathology; D010736:Phosphoglycerate Mutase / Q000737:chemistry* / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism*
chemical_list: D005988:Glyceric Acids; D019794:2,3-Diphosphoglycerate; D019000:Phosphotyrosine; C008885:2-phosphoglycerate; D006639:Histidine; C005156:3-phosphoglycerate; D010736:Phosphoglycerate Mutase
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