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PDGFR-β-activated ACK1-AKT signaling promotes glioma tumorigenesis.
- Source :
-
International journal of cancer [Int J Cancer] 2015 Apr 15; Vol. 136 (8), pp. 1769-80. Date of Electronic Publication: 2014 Oct 08. - Publication Year :
- 2015
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Abstract
- Aberrant PDGF-PDGFR signaling and its effects on downstream effectors have been implicated in glioma development. A crucial AKT regulator, ACK1 (TNK2) has been shown to be a downstream mediator of PDGF signaling; however, the exact underlying mechanisms in gliomas remain elusive. Here, we report that in glioma cells, PDGFR-β activation enhanced the interaction between ACK1 and AKT, resulting in AKT activation. PDGF treatment consistently promoted the formation of complexes containing PDGFR-β and ACK1. Mutational analysis suggested that Y635 of ACK1 is a PDGFR-β phosphorylation site and that the ACK1 Y635F mutant abrogated the sequential activation of AKT. Moreover, PDK1 interacted with ACK1 during PDGF stimulation, which is required for the binding of ACK1 to PDGFR-β. Further mutational analysis showed that T325 of ACK1 was crucial for the ACK1 and PDK1 interaction. ACK1 Y635F or T325A mutants abolished PDGFR-β-induced AKT activation, the subsequent nuclear translocation of β-catenin and the expression of cyclin D1. Glioma cell cycle progression, proliferation and tumorigenesis were accordingly blocked by ACK1 Y635F or T325A. In glioblastoma multiforme samples from 51 patients, increased ACK1 tyrosine phosphorylation correlated with upregulated PDGFR-β activity and AKT activation. Taken together, our data demonstrate that ACK1 plays a pivotal role in PDGF-PDGFR-induced AKT signaling in glioma tumorigenesis. This knowledge contributes to our understanding of glioma progression and may facilitate the identification of novel therapeutic targets for future glioma treatment.<br /> (© 2014 UICC.)
- Subjects :
- Carcinogenesis pathology
Cell Cycle genetics
Cell Line
Cell Line, Tumor
Cell Proliferation genetics
Cyclin D1 genetics
Cyclin D1 metabolism
Glioblastoma metabolism
HEK293 Cells
Humans
Phosphorylation genetics
Protein-Tyrosine Kinases metabolism
Proto-Oncogene Proteins c-akt metabolism
Receptor, Platelet-Derived Growth Factor beta metabolism
Up-Regulation genetics
beta Catenin genetics
beta Catenin metabolism
Carcinogenesis genetics
Glioblastoma genetics
Glioblastoma pathology
Protein-Tyrosine Kinases genetics
Proto-Oncogene Proteins c-akt genetics
Receptor, Platelet-Derived Growth Factor beta genetics
Signal Transduction genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1097-0215
- Volume :
- 136
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- International journal of cancer
- Publication Type :
- Academic Journal
- Accession number :
- 25257795
- Full Text :
- https://doi.org/10.1002/ijc.29234