Cysteine Cathepsins: Structure, Physiological Functions, and the Role in Carcinogenesis

IF 0.6 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry Pub Date : 2022-05-17 DOI:10.1134/S1990750822020056

T. A. Gureeva, O. S. Timoshenko, E. V. Kugaevskaya, N. I. Solovyova

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引用次数: 0

Abstract—

Cysteine cathepsins (Cts) also known as thiol proteinases belong to the superfamily of cysteine proteinases. Most Cts are endopeptidases; some of them exhibit exopeptidase activity. All Cts are synthesized as zymogens and activation of most of them occurs autocatalytically. Ct activity depends on pH and it is regulated by endogenous inhibitors. Although the major role of Cts consists in lysosomal degradation of cell proteins these enzymes are also detected in the nucleus, cytoplasm, plasma membrane, and in the extracellular medium. The latter is especially important in the case of certain pathological including cancer. Extracellular Cts not only hydrolyze extracellular matrix (ECM) proteins, but also contribute to ECM remodeling via specific processing of various proteins including cytokines, chemokines, cell adhesion molecules. Normally, expression and activity of Cts are very low and these enzymes are mainly detected inside cells. In cancer, the expression and activity of Cts sharply increase both in cell lysosomes and in the intercellular space and this promotes neoplastic transformation, invasion, metastasis and leads to further tumor progression. It has been shown that Cts expression depends on the cells type, and therefore, their role in the tumor development differs in dependence of their cellular origin. However, the mechanism of Cts action is not limited only by their proteolytic degradation of ECM proteins. Cts play an important role in processing of proteins involved in oncogenic cell signaling. For example, Cts participation in processing of growth factors is mediated through receptor tyrosine kinases (RTK) and various signaling mitogen-activated protein kinases (MAPK), which are involved in regulation of such cell processes as gene transcription, apoptosis, proliferation, and cell migration capacity. In addition, Cts also promote the epithelial-mesenchymal transition (EMT) by activating TGF-β signaling, which is considered as one of the key signaling pathways in this process.

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半胱氨酸组织蛋白酶:结构、生理功能和在癌变中的作用

摘要:半胱氨酸组织蛋白酶(Cts)也被称为巯基蛋白酶，属于半胱氨酸蛋白酶超家族。大多数ct是内肽酶;其中一些具有外肽酶活性。所有的ct都是作为酶原合成的，它们中的大多数都是自催化激活的。Ct活性取决于pH值，并受内源性抑制剂调节。虽然Cts的主要作用在于细胞蛋白的溶酶体降解，但这些酶在细胞核、细胞质、质膜和细胞外介质中也被检测到。后者在某些病理包括癌症的情况下尤为重要。细胞外Cts不仅可以水解细胞外基质(ECM)蛋白，还可以通过对细胞因子、趋化因子、细胞粘附分子等多种蛋白的特异性加工，促进细胞外基质的重塑。正常情况下，Cts的表达和活性都很低，这些酶主要在细胞内检测到。在癌症中，细胞溶酶体和细胞间隙中Cts的表达和活性急剧增加，促进肿瘤转化、侵袭、转移，导致肿瘤进一步进展。研究表明，Cts的表达依赖于细胞类型，因此，它们在肿瘤发展中的作用取决于它们的细胞来源。然而，Cts的作用机制不仅限于它们对ECM蛋白的蛋白水解降解。ct在肿瘤细胞信号传导过程中发挥重要作用。例如，Cts参与生长因子的加工是通过受体酪氨酸激酶(RTK)和各种信号分裂原活化蛋白激酶(MAPK)介导的，它们参与基因转录、凋亡、增殖和细胞迁移能力等细胞过程的调节。此外，Cts还通过激活TGF-β信号通路促进上皮-间质转化(epithelial-mesenchymal transition, EMT)， TGF-β被认为是这一过程中的关键信号通路之一。

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来源期刊

Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry BIOCHEMISTRY & MOLECULAR BIOLOGY-

CiteScore

1.10

自引率

0.00%

发文量

期刊介绍： Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry covers all major aspects of biomedical chemistry and related areas, including proteomics and molecular biology of (patho)physiological processes, biochemistry, neurochemistry, immunochemistry and clinical chemistry, bioinformatics, gene therapy, drug design and delivery, biochemical pharmacology, introduction and advertisement of new (biochemical) methods into experimental and clinical medicine. The journal also publishes review articles. All issues of the journal usually contain solicited reviews.