An Arf/Rab cascade controls the growth and invasiveness of glioblastoma.
ADP-Ribosylation Factors
/ metabolism
Allosteric Regulation
Animals
Brain Neoplasms
/ metabolism
Cell Line, Tumor
Cell Movement
Cell Proliferation
Cell Self Renewal
ErbB Receptors
/ metabolism
Glioblastoma
/ metabolism
Guanine Nucleotide Exchange Factors
/ chemistry
Humans
Male
Mice, Inbred NOD
Mice, SCID
Models, Biological
Neoplasm Invasiveness
Protein Binding
Protein Domains
Signal Transduction
Survival Analysis
rab GTP-Binding Proteins
/ metabolism
Journal
The Journal of cell biology
ISSN: 1540-8140
Titre abrégé: J Cell Biol
Pays: United States
ID NLM: 0375356
Informations de publication
Date de publication:
01 02 2021
01 02 2021
Historique:
received:
29
04
2020
revised:
27
10
2020
accepted:
23
11
2020
entrez:
14
1
2021
pubmed:
15
1
2021
medline:
2
9
2021
Statut:
ppublish
Résumé
Glioblastoma is the most common and deadly malignant brain cancer. We now demonstrate that loss of function of the endosomal GTPase Rab35 in human brain tumor initiating cells (BTICs) increases glioblastoma growth and decreases animal survival following BTIC implantation in mouse brains. Mechanistically, we identify that the GTPase Arf5 interacts with the guanine nucleotide exchange factor (GEF) for Rab35, DENND1/connecdenn, and allosterically enhances its GEF activity toward Rab35. Knockdown of either Rab35 or Arf5 increases cell migration, invasiveness, and self-renewal in culture and enhances the growth and invasiveness of BTIC-initiated brain tumors in mice. RNAseq of the tumors reveals up-regulation of the tumor-promoting transcription factor SPOCD1, and disruption of the Arf5/Rab35 axis in glioblastoma cells leads to strong activation of the epidermal growth factor receptor, with resulting enhancement of SPOCD1 levels. These discoveries reveal an unexpected cascade between an Arf and a Rab and indicate a role for the cascade, and thus endosomal trafficking, in brain tumors.
Identifiants
pubmed: 33443570
pii: 211682
doi: 10.1083/jcb.202004229
pmc: PMC7812876
pii:
doi:
Substances chimiques
Guanine Nucleotide Exchange Factors
0
ErbB Receptors
EC 2.7.10.1
RAB35 protein, human
EC 3.6.1.-
ADP-Ribosylation Factors
EC 3.6.5.2
ARF5 protein, human
EC 3.6.5.2
rab GTP-Binding Proteins
EC 3.6.5.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : CIHR
ID : MOP-123500
Pays : Canada
Organisme : CIHR
ID : MOP-123270
Pays : Canada
Informations de copyright
© 2021 Kulasekaran et al.
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