Regulation of MET receptor tyrosine kinase signaling by suppressor of cytokine signaling 1 in hepatocellular carcinoma

Oncogene
Y GuiSubburaj Ilangumaran

Abstract

Suppressor of cytokine signaling 1 (SOCS1) is considered as a tumor suppressor protein in hepatocellular carcinoma (HCC), but the underlying mechanisms remain unclear. Previously, we have shown that SOCS1-deficient hepatocytes displayed increased responsiveness to hepatocyte growth factor (HGF) due to enhanced signaling via the MET receptor tyrosine kinase. As aberrant MET activation occurs in many tumors including HCC, here we elucidated the mechanisms of SOCS1-mediated regulation. SOCS1 attenuated HGF-induced proliferation of human and mouse HCC cell lines and their growth as tumors in NOD.scid.gamma mice. Tumors formed by SOCS1 expressing HCC cells showed significantly reduced MET expression, indicating that SOCS1 not only attenuates MET signaling but also regulates MET expression. Mechanistically, SOCS1 interacted with MET via the Src homology 2 domain and this interaction was promoted by MET tyrosine kinase activity. The SOCS1-mediated reduction in MET expression does not require the juxtamembrane Y1003 residue implicated in Cbl-mediated downmodulation. Moreover, the proteasome inhibitor MG-132, but not the inhibitors of lysosomal degradation bafilomycin and chloroquine, reversed the SOCS1-mediated reduction in MET express...Continue Reading

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Citations

Feb 26, 2016·Carcinogenesis·Jack Zhang, Andy Babic
Jan 27, 2016·Cytokine·Claudia BeaurivageCaroline Saucier
Oct 26, 2016·Prostate Cancer and Prostatic Diseases·A Villalobos-HernandezS Ilangumaran
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Sep 9, 2017·Scientific Reports·Carissa Pilling, Jonathan A Cooper
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May 21, 2019·Frontiers in Pharmacology·Jatin Sharma, Joseph Larkin
Mar 3, 2020·Frontiers in Cell and Developmental Biology·Haiyu WangZujiang Yu
Jun 21, 2020·Current Cancer Drug Targets·Yue WangHairui Wang

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