Intracellular signaling by cathepsin X: Molecular mechanisms and diagnostic and therapeutic opportunities in cancer

Kos, Janko; Vizin, Tjasa; Fonović, Urša Pečar; Pišlar, Anja

doi:10.1016/j.semcancer.2014.05.001

Cited by 46 publications

(51 citation statements)

References 79 publications

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“… 7 , 43 , 46 , 67 – 69 Gamma-enolase neurotrophic effect is regulated by cathepsin X, a cysteine carboxymonopeptidase, which is frequently expressed in neuronal and glial cells. 70 , 71 Cathepsin X was shown to sequentially cleave the final two amino acids (433L and 432V) at the C-terminal end of gamma-enolase and to disrupt the PDZ motif, through which gamma-enolase binds to the scaffold protein gamma-1-syntrophin. The latter mediates the translocation of gamma-enolase and its association with plasma membrane, which is a prerequisite for neurotrophic activity.…”

Section: The Pro-survival Function Of Gamma-enolase In Cancermentioning

confidence: 99%

Gamma-enolase: a well-known tumour marker, with a less-known role in cancer

Vizin

Kos

2015

Radiology and Oncology

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BackgroundGamma-enolase, known also as neuron-specific enolase (NSE), is an enzyme of the glycolytic pathway, which is expressed predominantly in neurons and cells of the neuroendocrine system. As a tumour marker it is used in diagnosis and prognosis of cancer; however, the mechanisms enrolling it in malignant progression remain elusive. As a cytoplasmic enzyme gamma-enolase is involved in increased aerobic glycolysis, the main source of energy in cancer cells, supporting cell proliferation. However, different cellular localisation at pathophysiological conditions, proposes other cellular engagements.ConclusionsThe C-terminal part of the molecule, which is not related to glycolytic pathway, was shown to promote survival of neuronal cells by regulating neuronal growth factor receptor dependent signalling pathways, resulting also in extensive actin cytoskeleton remodelling. This additional function could be important also in cancer cells either to protect cells from stressful conditions and therapeutic agents or to promote tumour cell migration and invasion. Gamma-enolase might therefore have a multifunctional role in cancer progression: it supports increased tumour cell metabolic demands, protects tumour cells from stressful conditions and promotes their invasion and migration.

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Section: The Pro-survival Function Of Gamma-enolase In Cancermentioning

confidence: 99%

Gamma-enolase: a well-known tumour marker, with a less-known role in cancer

Vizin

Kos

2015

Radiology and Oncology

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“…Cathepsin X in particular seems to interact with many different potential partners (Kos et al 2014) that are however yet to be verified with regards to their in vivo significance, because many of these belong, e.g., to the cytoskeleton and are therefore not supposed to meet this cysteine cathepsin under physiological conditions. In addition, procathepsin X is well known to interact with integrins, to regulate other cellular processes such as cell-cell adhesion and lymphocyte activation but in a non-proteolytic fashion (Lechner et al 2006;Lines et al 2012).…”

Section: Endo-lysosomal Cysteine Peptidases: Myths and Common Questionsmentioning

confidence: 99%

Proteolysis mediated by cysteine cathepsins and legumain—recent advances and cell biological challenges

et al. 2014

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Proteases play essential roles in protein degradation, protein processing, and extracellular matrix remodeling in all cell types and tissues. They are also involved in protein turnover for maintenance of homeostasis and protein activation or inactivation for cell signaling. Proteases range in function and specificity, with some performing distinct substrate cleavages, while others accomplish proteolysis of a wide range of substrates. As such, different cell types use specialized molecular mechanisms to regulate the localization of proteases and their function within the compartments to which they are destined. Here, we focus on the cysteine family of cathepsin proteases and legumain, which act predominately within the endo-lysosomal pathway. In particular, recent knowledge on cysteine cathepsins and their primary regulator legumain is scrutinized in terms of their trafficking to endo-lysosomal compartments and other less recognized cellular locations. We further explore the mechanisms that regulate these processes and point to pathological cases which arise from detours taken by these proteases. Moreover, the emerging biological roles of specific forms and variants of cysteine cathepsins and legumain are discussed. These may be decisive, pathogenic, or even deadly when localizing to unusual cellular compartments in their enzymatically active form, because they may exert unexpected effects by alternative substrate cleavage. Hence, we propose future perspectives for addressing the actions of cysteine cathepsins and legumain as well as their specific forms and variants. The increasing knowledge in non-canonical aspects of cysteine cathepsin- and legumain-mediated proteolysis may prove valuable for developing new strategies to utilize these versatile proteases in therapeutic approaches.

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“…Human cysteine cathepsins comprise an 11-member family: cathepsins B, C, F, H, K, L/V, O, S, Z, X and W (Kos et al, 2015;Rawlings et al, 2016). Although initially associated with increased metabolism and lysosomal protein degradation in cancer cells, diverse and distinct other functions of cathepsins have later been revealed, for example, their involvement in resistance development to therapeutics (Olson and Joyce, 2015).…”

Section: The Role Of Various Protease Classes In Cancermentioning

confidence: 99%

“…Finally, inefficacy of protease inhibitors may be due to non-proteolytic roles of proteases such as their interaction with other proteins (Kessenbrock et al, 2015). For example, TAM-derived and cancer cell-derived pro-form of cathepsin X promotes cancer cell adhesion and migration through binding to the RGD domain of integrins on cancer cell membranes (Kos et al, 2015). Furthermore, inhibitors that target the hemopexin domain (HPX) in MMPs, which is located at the C-terminal of most MMP members and is crucial for protein-protein interactions, block tumour growth (Kessenbrock et al, 2015).…”

Section: Proteases In Stromal Cellsmentioning

confidence: 99%

Proteases and cytokines as mediators of interactions between cancer and stromal cells in tumours

Breznik

Motaln

Turnšek

2017

Biological Chemistry

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Proteolytic enzymes are highly relevant in different processes of cancer progression. Their interplay with other signalling molecules such as cytokines represents important regulation of multicellular cross-talk. In this review, we discuss protease regulation mechanisms of cytokine signalling in various types of cancer. Additionally, we highlight the reverse whereby cytokines have an impact on protease expression in an autocrine and paracrine manner, representing complex feedback mechanisms among multiple members of these two protein families. The relevance of the protease-cytokine axis is illustrated in glioblastoma, where interactions between normal mesenchymal stem cells and cancer cells play an important role in this very malignant form of brain cancer.

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Intracellular signaling by cathepsin X: Molecular mechanisms and diagnostic and therapeutic opportunities in cancer

Cited by 46 publications

References 79 publications

Gamma-enolase: a well-known tumour marker, with a less-known role in cancer

Gamma-enolase: a well-known tumour marker, with a less-known role in cancer

Proteolysis mediated by cysteine cathepsins and legumain—recent advances and cell biological challenges

Proteases and cytokines as mediators of interactions between cancer and stromal cells in tumours

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