Abstract:Background
Abnormal proliferation and migration of cells are hallmarks of cancer initiation and malignancy. Asparagine endopeptidase (AEP) has specific substrate cleavage ability and plays a pro-cancer role in a variety of cancers. However, the underlying mechanism of AEP in cancer proliferation and migration still remains unclear.
Methods
Co-immunoprecipitation and following mass spectrometry were used to identify the substrate of AEP. Western blo… Show more
“…Serin/treonin protein kinase 2 (SRPK2) Activation [51] Synaptojanin 1 (SYNJ1) Processing [52] TAR DNA-binding protein 43 (TDP-43) Processing [53] Tau Processing [51,[54][55][56][57] Toll-like receptor 7 (TLR7) Processing [58] Toll-like receptor 9 (TLR9) Processing [59][60][61] Tropomodulin-3 (Tmod-3) Processing [62] Vitamin-D-binding protein (VDBP) Degradation [35] 1.…”
Section: Legumain Substrate Results Of Substrate Cleavage By Legumain...mentioning
confidence: 99%
“…In glioblastoma, legumain has recently been shown to cleave the tumor suppressor p53 (Table 1), mediating p53 inactivation and subsequently cellular and genetic destabilization [48]. Legumain was also demonstrated to cleave tropomodulin-3 (Tmod3; Table 1), a ubiquitously expressed regulatory protein of the cytoskeleton [62]. Tmod3 cleavage by legumain produces functional truncated Tmod3 which is detected in various tumors and associated with poor prognosis of high-grade glioma.…”
The cysteine protease legumain (also known as asparaginyl endopeptidase or δ-secretase) is the only known mammalian asparaginyl endopeptidase and is primarily localized to the endolysosomal system, although it is also found extracellularly as a secreted protein. Legumain is involved in the regulation of diverse biological processes and tissue homeostasis, and in the pathogenesis of various malignant and nonmalignant diseases. In addition to its proteolytic activity that leads to the degradation or activation of different substrates, legumain has also been shown to have a nonproteolytic ligase function. This review summarizes the current knowledge about legumain functions in health and disease, including kidney homeostasis, hematopoietic homeostasis, bone remodeling, cardiovascular and cerebrovascular diseases, fibrosis, aging and senescence, neurodegenerative diseases and cancer. In addition, this review addresses the effects of some marketed drugs on legumain. Expanding our knowledge on legumain will delineate the importance of this enzyme in regulating physiological processes and disease conditions.
“…Serin/treonin protein kinase 2 (SRPK2) Activation [51] Synaptojanin 1 (SYNJ1) Processing [52] TAR DNA-binding protein 43 (TDP-43) Processing [53] Tau Processing [51,[54][55][56][57] Toll-like receptor 7 (TLR7) Processing [58] Toll-like receptor 9 (TLR9) Processing [59][60][61] Tropomodulin-3 (Tmod-3) Processing [62] Vitamin-D-binding protein (VDBP) Degradation [35] 1.…”
Section: Legumain Substrate Results Of Substrate Cleavage By Legumain...mentioning
confidence: 99%
“…In glioblastoma, legumain has recently been shown to cleave the tumor suppressor p53 (Table 1), mediating p53 inactivation and subsequently cellular and genetic destabilization [48]. Legumain was also demonstrated to cleave tropomodulin-3 (Tmod3; Table 1), a ubiquitously expressed regulatory protein of the cytoskeleton [62]. Tmod3 cleavage by legumain produces functional truncated Tmod3 which is detected in various tumors and associated with poor prognosis of high-grade glioma.…”
The cysteine protease legumain (also known as asparaginyl endopeptidase or δ-secretase) is the only known mammalian asparaginyl endopeptidase and is primarily localized to the endolysosomal system, although it is also found extracellularly as a secreted protein. Legumain is involved in the regulation of diverse biological processes and tissue homeostasis, and in the pathogenesis of various malignant and nonmalignant diseases. In addition to its proteolytic activity that leads to the degradation or activation of different substrates, legumain has also been shown to have a nonproteolytic ligase function. This review summarizes the current knowledge about legumain functions in health and disease, including kidney homeostasis, hematopoietic homeostasis, bone remodeling, cardiovascular and cerebrovascular diseases, fibrosis, aging and senescence, neurodegenerative diseases and cancer. In addition, this review addresses the effects of some marketed drugs on legumain. Expanding our knowledge on legumain will delineate the importance of this enzyme in regulating physiological processes and disease conditions.
“…34 TMOD3 is a potential substrate of AEP that is highly expressed in many solid cancers and is associated with poor prognosis of cervical cancer, LUAD, lung squamous cell carcinoma, pancreatic cancer and bladder cancer. 35 Previous reports have shown the feasibility of CD47 blocking immunotherapy as a strategy for the treatment of small-cell lung cancer. 36 PLK1 acts as a shuttle protein in LUAD, and mediated vimentin phosphorylation activates TGF-β signaling pathway, leading to metastasis and immune escape through PD-L1 expression.…”
Section: Discussionmentioning
confidence: 99%
“…Evidence has shown that elevated ALDOA expression is highly associated with metastasis potential and poor prognosis in patients with non‐small cell lung cancer, and has revealed a molecular mechanism that promotes lung cancer metastasis through PhD‐mediated HIF‐1α stabilization and subsequent MMP9 activation 34 . TMOD3 is a potential substrate of AEP that is highly expressed in many solid cancers and is associated with poor prognosis of cervical cancer, LUAD, lung squamous cell carcinoma, pancreatic cancer and bladder cancer 35 . Previous reports have shown the feasibility of CD47 blocking immunotherapy as a strategy for the treatment of small‐cell lung cancer 36 .…”
BackgroundThe involvement of ferroptosis has been found in many pathological conditions of the lung. The genetic engineering of ferroptosis‐related genes may provide a potential target for the treatment of lung adenocarcinoma (LUAD).MethodsNine ferroptosis regulators and markers were collected from FerrDb and their somatic mutations and expressions were analyzed based on The Cancer Genome Atlas (TCGA)‐LUAD cohort data. Least absolute shrinkage and selection operator (LASSO) and Cox regression analysis were performed to screen genes significantly associated with ferroptosis. The ferroptosis‐related gene signature was constructed using TCGA‐LUAD cohort data and was verified using the GSE cohort with pooled data for GSE30219, GSE31210, GSE37745 and GSE50081. Immune microenvironment component and mutation analysis were performed for genes in the ferroptosis‐related gene signature.ResultsAll nine ferroptosis regulators and markers were differentially expressed between normal LUAD tumor tissues and adjacent normal tissues and were related to copy number variation. The expression of 1329 genes were significantly associated with nine ferroptosis regulators and markers in the TCGA‐LUAD dataset, five (ALDOA, PLK1, CD47, CENPC and TMOD3) of which were integrated into a ferroptosis‐related gene signature to calculate the risk score of LUAD samples, showing a significant correlation with the abundance of immune cell infiltration and the immune score. Molecular docking showed the binding activity of natural active compound quercetin to target proteins ALDOA and CD47, as well as the binding activity of aristolochic acid to PLK1 protein and TMOD3 protein.ConclusionsIn the present study, a ferroptosis‐related gene signature with predictive value for LUAD prognosis was constructed, in which the gene was a potential therapeutic target for LUAD. Quercetin and aristolochic acid were potential candidates for inhibiting these targets by directly binding to them and showing high affinity and strong stability.
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