Autophagy negatively regulates tumor cell proliferation through phosphorylation dependent degradation of the Notch1 intracellular domain.
Autophagy is a highly conserved mechanism that degrades long-lived proteins and dysfunctional organelles, and contributes to cell fate. In this study, autophagy attenuates Notch1 signaling by degrading the Notch1 intracellular domain (Notch1-IC). Nutrient-deprivation promotes Notch1-IC phosphorylation by MEKK1 and phosphorylated Notch1-IC is recognized by Fbw7 E3 ligase. The ubiquitination of Notch1-IC by Fbw7 is essential for the interaction between Notch1-IC and p62 and for the formation of aggregates. Inhibition of Notch1 signaling prevents the transformation of breast cancer cells, tumor progression, and metastasis. The expression of Notch1 and p62 is inversely correlated with Beclin1 expression in human breast cancer patients. These results show that autophagy inhibits Notch1 signaling by promoting Notch1-IC degradation and therefore plays a role in tumor suppression.
Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Republic of Korea.
Ji-Seon
JS
Ahn
Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Republic of Korea.
Eun-Jung
EJ
Ann
Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Republic of Korea.
Mi-Yeon
MY
Kim
Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Republic of Korea.
Ji-Hye
JH
Yoon
Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Republic of Korea.
Hye-Jin
HJ
Lee
Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Republic of Korea.
Eun-Hye
EH
Jo
Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Republic of Korea.
Keesook
K
Lee
Department of Pathology, Chonnam National University Medical School and Research Institute of Medical Sciences, Gwangju 61469, Republic of Korea.
Ji Shin
JS
Lee
Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Republic of Korea.
Hee-Sae
HS
Park
D001343:Autophagy; D000071186:Beclin-1 / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D000073979:F-Box-WD Repeat-Containing Protein 7 / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism*; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D016601:RNA-Binding Proteins / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction
C491997:BECN1 protein, human; D000071186:Beclin-1; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C497761:NOTCH1 protein, human; C118585:P62 protein, human; D016601:RNA-Binding Proteins; D051881:Receptor, Notch1; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human
Notch1-IC; autophagy; degradation; phosphorylation; tumorigenesis