Beclin 1 Promotes Endosome Recruitment of Hepatocyte Growth Factor Tyrosine Kinase Substrate to Suppress Tumor Proliferation
Department of Molecular, Cell and Cancer Biology; Medical Scientist Training Program; Program in Systems Biology; Graduate School of Biomedical Sciences, MD/PhD Program; Program in Molecular Medicine
Biochemistry, Biophysics, and Structural Biology | Cell and Developmental Biology
Beclin 1 has nonautophagic functions that include its ability to regulate endocytic receptor trafficking. However, the contribution of this function to tumor suppression is poorly understood. Here, we provide in vivo evidence that Beclin 1 suppresses tumor proliferation by regulating the endocytic trafficking and degradation of the EGFR and transferrin (TFR1) receptors. Beclin 1 promoted endosomal recruitment of hepatocyte growth factor tyrosine kinase substrate (HRS), which was necessary for sorting surface receptors to intraluminal vesicles for signal silencing and lysosomal degradation. In tumors with low Beclin 1 expression, endosomal HRS recruitment was diminished and receptor function was sustained. Collectively, our results demonstrate a novel role for Beclin 1 in impeding tumor growth by coordinating the regulation of key growth factor and nutrient receptors. These data provide an explanation for how low levels of Beclin 1 facilitate tumor proliferation and contribute to poor cancer outcomes. SIGNIFICANCE: Beclin 1 controls the trafficking fate of growth regulatory receptors to suppress tumor proliferation.
DOI of Published Version
Cancer Res. 2020 Jan 15;80(2):249-262. doi: 10.1158/0008-5472.CAN-19-1555. Epub 2019 Nov 19. Link to article on publisher's site
Matthew-Onabanjo AN, Janusis J, Mercado-Matos J, Carlisle AE, Kim D, Levine F, Cruz-Gordillo P, Richards R, Lee MJ, Shaw LM. (2020). Beclin 1 Promotes Endosome Recruitment of Hepatocyte Growth Factor Tyrosine Kinase Substrate to Suppress Tumor Proliferation. Program in Systems Biology Publications. https://doi.org/10.1158/0008-5472.CAN-19-1555. Retrieved from https://escholarship.umassmed.edu/sysbio_pubs/161