TY - JOUR
T1 - PINK1-mediated inhibition of EGFR dimerization and activation impedes EGFR-driven lung tumorigenesis
AU - Emily Pei-Ying Lin, Pei-Ying Lin
AU - Huang, Bo Tsang
AU - Lai, Wei Yun
AU - Tseng, Yi Ting
AU - Yang, Shuenn Chen
AU - Kuo, Hao Cheng
AU - Yang, Pan Chyr
N1 - Funding Information:
The authors thank Miss. Siao-Han Wong for TCGA data processing; Dr. Sue Lin- Chao for her opinions; Sue-Ping Lee for technical assistance; theGenomics Core of the Institute of Molecular Biology, the DNA Sequencing Core and Medical Art of the Institute of Biomedical Sciences; and the National RNAi Core Facility, Academia Sinica (Taipei, Taiwan) for technical support. This study was supported by grants from the National Science Council Taiwan (NSC-102-2321-B-002-053 to P.-C. Yang and NSC-103-2321-B-022 to P.-C. Yang), the Ministry of Science and Technology Taiwan (MOST107-2314-B-002-231 to E.P.-Y. Lin and MOST108-2314-B-002-197- MY2 to E.P.-Y. Lin; MOST-108-3114-Y-001-002 to P.-C. Yang, MOST-109-2314-B- 002-254 to P.-C. Yang, MOST-109-2314-B-002-277 to P.-C. Yang, MOST-108-2320- B-001-007-MY2 to P.-C. Yang, MOST-108-2319-B-492-001 to P.-C. Yang, MOST- 109-0210-01-18-02 to P.-C. Yang), and the National Health Research Institute Taiwan (NHRI-EX109-10937BC to E.P.-Y. Lin).
Funding Information:
The authors thank Miss. Siao-Han Wong for TCGA data processing; Dr. Sue Lin-Chao for her opinions; Sue-Ping Lee for technical assistance; the Genomics Core of the Institute of Molecular Biology, the DNA Sequencing Core and Medical Art of the Institute of Biomedical Sciences; and the National RNAi Core Facility, Academia Sinica (Taipei, Taiwan) for technical support. This study was supported by grants from the National Science Council Taiwan (NSC-102-2321-B-002-053 to P.-C. Yang and NSC-103-2321-B-022 to P.-C. Yang), the Ministry of Science and Technology Taiwan (MOST107-2314-B-002-231 to E.P.-Y. Lin and MOST108-2314-B-002-197-MY2 to E.P.-Y. Lin; MOST-108-3114-Y-001-002 to P.-C. Yang, MOST-109-2314-B-002-254 to P.-C. Yang, MOST-109-2314-B-002-277 to P.-C. Yang, MOST-108-2320-B-001-007-MY2 to P.-C. Yang, MOST-108-2319-B-492-001 to P.-C. Yang, MOST-109-0210-01-18-02 to P.-C. Yang), and the National Health Research Institute Taiwan (NHRI-EX109-10937BC to E.P.-Y. Lin).
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/4
Y1 - 2021/4
N2 - EGFR is established as a driver of lung cancer, yet the regulatory machinery underlying its oncogenic activity is not fully understood. PTEN-induced kinase 1 (PINK1) kinase is a key player in mitochondrial quality control, although its role in lung cancer and EGFR regulation is unclear. In this study, we show that PINK1 physically directly interacts with EGFR via the PINK1 C-terminal domain (PINK1-CTD) and the EGFR tyrosine kinase domain. This interaction constituted an endogenous steric hindrance to receptor dimerization and inhibited EGFR-mediated lung carcinogenesis. Depletion of PINK1 from lung cancer cells promoted EGFR dimerization, receptor activation, EGFR downstream signaling, and tumor growth. In contrast, overexpression of PINK1 or PINK1- CTD suppressed EGFR dimerization, activation, downstream signaling, and tumor growth. These findings identify key elements in the EGFR regulatory cascade and illustrate a new direction for the development of anti-EGFR therapeutics, suggesting translational potential of the PINK1-CTD in lung cancer.
AB - EGFR is established as a driver of lung cancer, yet the regulatory machinery underlying its oncogenic activity is not fully understood. PTEN-induced kinase 1 (PINK1) kinase is a key player in mitochondrial quality control, although its role in lung cancer and EGFR regulation is unclear. In this study, we show that PINK1 physically directly interacts with EGFR via the PINK1 C-terminal domain (PINK1-CTD) and the EGFR tyrosine kinase domain. This interaction constituted an endogenous steric hindrance to receptor dimerization and inhibited EGFR-mediated lung carcinogenesis. Depletion of PINK1 from lung cancer cells promoted EGFR dimerization, receptor activation, EGFR downstream signaling, and tumor growth. In contrast, overexpression of PINK1 or PINK1- CTD suppressed EGFR dimerization, activation, downstream signaling, and tumor growth. These findings identify key elements in the EGFR regulatory cascade and illustrate a new direction for the development of anti-EGFR therapeutics, suggesting translational potential of the PINK1-CTD in lung cancer.
UR - http://www.scopus.com/inward/record.url?scp=85104887971&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85104887971&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-20-2582
DO - 10.1158/0008-5472.CAN-20-2582
M3 - Article
C2 - 33574089
AN - SCOPUS:85104887971
SN - 0008-5472
VL - 81
SP - 1745
EP - 1757
JO - Cancer Research
JF - Cancer Research
IS - 7
ER -
