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PDGFR-β-activated ACK1-AKT signaling promotes glioma tumorigenesis

Jiannan Zhang¹, Tao Chen, Qin Mao

¹Operation Room, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, People's Republic of China.

International Journal of Cancer

|September 27, 2014

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.

Insights

Aberrant PDGF-PDGFR signaling drives glioma. This study reveals ACK1 acts as a key mediator, linking PDGFR-beta to AKT activation, crucial for glioma cell proliferation and tumorigenesis.

Area of Science:

Oncology
Molecular Biology
Cell Signaling

Background:

Aberrant Platelet-Derived Growth Factor Receptor (PDGFR) signaling is a known factor in glioma development.
ACK1 (TNK2) is recognized as a regulator of AKT and a downstream mediator of PDGF signaling, but its precise role in gliomas is unclear.

Purpose of the Study:

To elucidate the molecular mechanisms by which ACK1 mediates PDGF-PDGFR signaling in glioma cells.
To investigate the role of specific ACK1 phosphorylation sites in AKT activation and downstream oncogenic events.
To assess the correlation between ACK1 activity and glioma patient outcomes.

Main Methods:

Utilized glioma cell lines and patient-derived glioblastoma multiforme samples.
Employed PDGF stimulation, co-immunoprecipitation, and mutational analysis (Y635F, T325A) of ACK1.
Assessed AKT activation, nuclear translocation of beta-catenin, cyclin D1 expression, and cell proliferation assays.

Main Results:

PDGFR-beta activation enhanced ACK1-AKT interaction, leading to AKT activation, with PDGF promoting PDGFR-beta/ACK1 complex formation.
ACK1 Y635 is a PDGFR-beta phosphorylation site; Y635F mutation abrogated AKT activation.
PDK1 interaction with ACK1 (dependent on ACK1 T325) is essential for ACK1 binding to PDGFR-beta.
ACK1 mutants (Y635F, T325A) blocked PDGFR-beta-induced AKT activation, beta-catenin nuclear translocation, and cyclin D1 expression, inhibiting glioma cell cycle progression, proliferation, and tumorigenesis.
Elevated ACK1 tyrosine phosphorylation correlated with PDGFR-beta activity and AKT activation in glioblastoma samples.

Conclusions:

ACK1 is a critical mediator in PDGF-PDGFR-induced AKT signaling, driving glioma tumorigenesis.
Specific interactions and phosphorylation events involving ACK1, PDGFR-beta, and PDK1 are essential for glioma cell proliferation.
Targeting the ACK1-AKT pathway presents a potential therapeutic strategy for glioma treatment.

Read full analysis

Keywords:

ACK1 AKT PDGFR glioma tumorigenesis

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