Mutant and Wild-Type Isocitrate Dehydrogenase 1 Share Enhancing Mechanisms Involving Distinct Tyrosine Kinase Cascades in Cancer.
Cell Line, Tumor
Disease Management
Humans
Isocitrate Dehydrogenase
/ chemistry
Janus Kinase 2
/ metabolism
Models, Biological
Mutation
NADP
/ metabolism
Neoplasms
/ genetics
Phosphorylation
Protein Binding
Protein Multimerization
Protein-Tyrosine Kinases
/ metabolism
fms-Like Tyrosine Kinase 3
/ genetics
Journal
Cancer discovery
ISSN: 2159-8290
Titre abrégé: Cancer Discov
Pays: United States
ID NLM: 101561693
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
07
09
2018
revised:
10
02
2019
accepted:
07
03
2019
pubmed:
14
3
2019
medline:
9
7
2020
entrez:
14
3
2019
Statut:
ppublish
Résumé
Isocitrate dehydrogenase 1 (IDH1) is important for reductive carboxylation in cancer cells, and the IDH1 R132H mutation plays a pathogenic role in cancers including acute myeloid leukemia (AML). However, the regulatory mechanisms modulating mutant and/or wild-type (WT) IDH1 function remain unknown. Here, we show that two groups of tyrosine kinases (TK) enhance the activation of mutant and WT IDH1 through preferential Y42 or Y391 phosphorylation. Mechanistically, Y42 phosphorylation occurs in IDH1 monomers, which promotes dimer formation with enhanced substrate (isocitrate or α-ketoglutarate) binding, whereas Y42-phosphorylated dimers show attenuated disruption to monomers. Y391 phosphorylation occurs in both monomeric and dimeric IDH1, which enhances cofactor (NADP
Identifiants
pubmed: 30862724
pii: 2159-8290.CD-18-1040
doi: 10.1158/2159-8290.CD-18-1040
pmc: PMC6548588
mid: NIHMS1523928
doi:
Substances chimiques
NADP
53-59-8
Isocitrate Dehydrogenase
EC 1.1.1.41
IDH1 protein, human
EC 1.1.1.42.
FLT3 protein, human
EC 2.7.10.1
Protein-Tyrosine Kinases
EC 2.7.10.1
fms-Like Tyrosine Kinase 3
EC 2.7.10.1
JAK2 protein, human
EC 2.7.10.2
Janus Kinase 2
EC 2.7.10.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
756-777Subventions
Organisme : NCI NIH HHS
ID : R01 CA173636
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197594
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA174786
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA140515
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA183594
Pays : United States
Organisme : NCI NIH HHS
ID : K08 CA181507
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA169937
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA120272
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
©2019 American Association for Cancer Research.
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