Identification of a novel Calpain-2-SRC feed-back loop as necessity for β-Catenin accumulation and signaling activation in hepatocellular carcinoma
Identification of a novel Calpain-2-SRC feed-back loop as necessity for β-Catenin accumulation and signaling activation in hepatocellular carcinoma
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DOI：
10.1038/s41388-022-02367-x
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发表时间：
2022-06-13
期刊：
影响因子：
8
通讯作者：
Lu, Ren-Quan
中科院分区：
文献类型：
--
作者：
Ma, Xiao-Lu;Zhu, Ke-Yu;Lu, Ren-Quan
肝细胞癌（HCC）的快速进展是其预后不良的主要原因，但其潜在机制尚不清楚。在这里，我们发现Calpain-2（CAPN 2），一种在几种恶性肿瘤中加速肿瘤进展的成熟蛋白酶，在HCC中过表达，并作为不良结局的独立预测因子。CAPN 2促进HCC的增殖和侵袭，并与侵袭相关标志物水平呈正相关。从机制上讲，在β-catenin上游发现了一个新的CAPN 2-SRC正调控环，以阻止其泛素化和降解，随后促进HCC进展：CAPN 2可蛋白水解PTP 1B形成约42 kDa的截短体，磷酸酶活性增加，导致SRC Y 530磷酸化减少和SRC激酶活性增加;同时，CAPN 2本身是SRC的真正底物，其主要在Y 625处被SRC磷酸化，并且在磷酸化后表现出增加的蛋白水解活性。有趣的是，CAPN 2-SRC环不仅可以通过抑制GSK 3 β途径来抑制大部分细胞质β-连环蛋白降解，而且即使在β-连环蛋白突变细胞中也可以阻止TRIM 33诱导的细胞核β-连环蛋白降解。目前的研究确定了CAPN 2-SRC正环负责细胞内β-连环蛋白积累和信号激活，靶向CAPN 2蛋白酶活性可能是预防HCC进展的有希望的方法。
Rapid progression is the major cause of the poor prognosis of hepatocellular carcinoma (HCC); however, the underlying mechanism remained unclear. Here, we found Calpain-2 (CAPN2), a well-established protease that accelerates tumor progression in several malignancies, is overexpressed in HCC and acts as an independent predictor for poor outcomes. Furthermore, CAPN2 promoted the proliferation and invasion of HCC, and showed a positive correlation with the levels of invasion-related markers. Mechanistically, a novel CAPN2-SRC positive regulatory loop was identified upstream of beta-catenin to prevent its ubiquitination and degradation, and subsequently promoted HCC progression: CAPN2 could proteolyze PTP1B to form a truncation of approximately 42 kDa with increased phosphatase activity, resulting in reduced SRC Y530 phosphorylation and increased SRC kinase activity; meanwhile, CAPN2 itself was a bone fide substrate of SRC that was primarily phosphorylated at Y625 by SRC and exhibited increased proteolysis activity upon phosphorylation. Interestingly, the CAPN2-SRC loop could not only restrain most of cytoplasmic beta-catenin degradation by inhibiting GSK3 beta pathway, but also prevented TRIM33-induced nuclear beta-catenin degradation even in beta-catenin-mutant cells. Present study identified a CAPN2-SRC positive loop responsible for intracellular beta-catenin accumulation and signaling activation, and targeting CAPN2 protease activity might be a promising approach for preventing HCC progression.