Gui Y, Yeganeh M, Donates Y-C, Tobelaim W-S, Chababi W, Mayhue M, Yoshimura A, Ramanathan S, Saucier C, Ilangumaran S
Immunology Division, Department of Pediatrics, Faculty of Medicine and Health Sciences, University of Sherbrooke, Centre de Recherche Clinique Etienne-Le Bel, Centre Hospitalier de l'Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Department of Anatomy and Cell biology, Faculty of Medicine and Health Sciences, University of Sherbrooke, Centre de Recherche Clinique Etienne-Le Bel, Centre Hospitalier de l'Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Oncogene. 2015 Nov 12;34(46):5718-28. doi: 10.1038/onc.2015.20. Epub 2015 Mar 2.
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 expression, indicating that this process is distinct from Cbl-mediated downmodulation. Accordingly, SOCS1 promoted polyubiquitination of MET via K48-dependent but not K63-mediated ubiquitin chain elongation. Furthermore, siRNA-mediated downmodulation of Cbl did not abolish SOCS1-mediated reduction in MET expression in HCC cells. SOCS1-dependent ubiquitination of endogenous MET receptor occurred rapidly following HGF stimulation in HCC cells, leading to proteasomal degradation of phosphorylated MET receptor. These findings indicate that SOCS1 mediates its tumor suppressor functions, at least partly, by binding to MET and interfering with downstream signaling pathways as well as by promoting the turnover of the activated MET receptor. We propose that loss of this control mechanism due to epigenetic repression of SOCS1 could contribute to oncogenic MET signaling in HCC and other cancers, and that MET inhibitors might be useful in treating these patients.
细胞因子信号转导抑制因子1（SOCS1）被认为是肝细胞癌（HCC）中的一种肿瘤抑制蛋白，但其潜在机制仍不清楚。此前，我们已经表明，由于通过MET受体酪氨酸激酶增强了信号传导，SOCS1缺陷的肝细胞对肝细胞生长因子（HGF）的反应性增加。由于包括HCC在内的许多肿瘤中都会发生MET的异常激活，因此我们在此阐明了SOCS1介导的调控机制。SOCS1减弱了HGF诱导的人和小鼠HCC细胞系的增殖以及它们在NOD.scid.gamma小鼠体内作为肿瘤的生长。由表达SOCS1的HCC细胞形成的肿瘤显示MET表达显著降低，表明SOCS1不仅减弱MET信号传导，还调节MET表达。从机制上讲，SOCS1通过Src同源2结构域与MET相互作用，并且这种相互作用由MET酪氨酸激酶活性促进。SOCS1介导的MET表达降低不需要参与Cbl介导的下调的近膜Y1003残基。此外，蛋白酶体抑制剂MG-132而非溶酶体降解抑制剂巴佛洛霉素和氯喹可逆转SOCS1介导的MET表达降低，表明该过程不同于Cbl介导的下调。因此，SOCS1通过K48依赖性而非K63介导的泛素链延伸促进MET的多聚泛素化。此外，siRNA介导的Cbl下调并未消除SOCS1介导的HCC细胞中MET表达的降低。在HCC细胞中，HGF刺激后内源性MET受体的SOCS1依赖性泛素化迅速发生，导致磷酸化MET受体的蛋白酶体降解。这些发现表明，SOCS1至少部分地通过与MET结合并干扰下游信号通路以及通过促进活化的MET受体的周转来介导其肿瘤抑制功能。我们提出，由于SOCS1的表观遗传抑制导致这种控制机制的丧失可能促成HCC和其他癌症中的致癌MET信号传导，并且MET抑制剂可能对治疗这些患者有用。
