Pro-prion, as a membrane adaptor protein for E3 ligase c-Cbl, facilitates the ubiquitination of IGF-1R, promoting melanoma metastasis
Pro-prion, as a membrane adaptor protein for E3 ligase c-Cbl, facilitates the ubiquitination of IGF-1R, promoting melanoma metastasis
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DOI：
10.1016/j.celrep.2022.111834
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发表时间：
2022-12-20
期刊：
影响因子：
8.8
通讯作者：
Li, Chaoyang
中科院分区：
文献类型：
--
作者：
Li, Huan;Zhang, Jie;Li, Chaoyang
受体酪氨酸激酶（receptor tyrosine kinase，RTK）的异常激活通常是突变的结果，在肿瘤发生中起重要作用。没有突变的RTK如何影响肿瘤发生仍然不完全清楚。在这里，我们表明，在人类黑色素瘤中，朊病毒原（pro-PrP）是E3连接酶c-Cbll的衔接蛋白，使其能够多聚遍在蛋白活化的胰岛素样生长因子-1受体（IGF-1 R）上，从而导致黑色素瘤转移增强。所有人黑色素瘤细胞系研究这里表达前PrP，保留其糖基磷脂酰肌醇肽信号序列（GPI-PSS）。pro-PrP的GPI-PSS中的序列PVILLISFLI结合c-Cbl，将c-Cbl对接到细胞内膜，形成pro-PrP/c-Cbl/IGF-1 R三聚体复合物。随后，IGF-1 R多聚泛素化和降解增强，这增加了自噬和肿瘤转移。重要的是，合成肽PVILLISFLI破坏pro-PrP/c-Cbl/IGF-1 R复合物，减少癌细胞自噬并减轻体外和体内肿瘤侵袭性。靶向与癌症相关的GPI-PSS可以提供用于治疗表达pro-PrP的人类癌症的治疗方法。
Aberrant activation of receptor tyrosine kinase (RTK) is usually a result of mutation and plays important roles in tumorigenesis. How RTK without mutation affects tumorigenesis remains incompletely understood. Here we show that in human melanomas pro-prion (pro-PrP) is an adaptor protein for an E3 ligase c-Cbl, enabling it to polyubiquitinate activated insulin-like growth factor-1 receptor (IGF-1R), leading to enhanced melanoma metastasis. All human melanoma cell lines studied here express pro-PrP, retaining its glycosylphosphatidy-linositol-peptide signal sequence (GPI-PSS). The sequence, PVILLISFLI in the GPI-PSS of pro-PrP, binds c-Cbl, docking c-Cbl to the inner cell membrane, forming a pro-PrP/c-Cbl/IGF-1R trimeric complex. Subse-quently, IGF-1R polyubiquitination and degradation are augmented, which increases autophagy and tumor metastasis. Importantly, the synthetic peptide PVILLISFLI disrupts the pro-PrP/c-Cbl/IGF-1R complex, reducing cancer cell autophagy and mitigating tumor aggressiveness in vitro and in vivo. Targeting cancer-associated GPI-PSS may provide a therapeutic approach for treating human cancers expressing pro-PrP.