Cysteine cathepsins and extracellular matrix degradation

Fonović, Marko; Turk, Boris

doi:10.1016/j.bbagen.2014.03.017

Cited by 286 publications

(251 citation statements)

References 213 publications

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“…We show here that CtsZ promotes invasion and migration via a noncatalytic mechanism, which contrasts with the proteolytic roles of other proinvasive cathepsin family members (Fonovic and Turk 2014;Sevenich and Joyce 2014), including those previously analyzed in the RT2 model (Gocheva et al 2006(Gocheva et al , 2010b. This suggests that multiple modes of cell invasion may be important in PanNET malignancy and likely other tumor types.…”

Section: Discussioncontrasting

confidence: 38%

Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix

et al. 2014

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During the process of tumor progression, cancer cells can produce the requisite growth-and invasion-promoting factors and can also rely on noncancerous cells in the tumor microenvironment as an alternative, cell-extrinsic source. However, whether the cellular source influences the function of such tumor-promoting factors remains an open question. Here, we examined the roles of the cathepsin Z (CtsZ) protease, which is provided by both cancer cells and macrophages in pancreatic neuroendocrine tumors in humans and mice. We found that tumor proliferation was exclusively regulated by cancer cell-intrinsic functions of CtsZ, whereas tumor invasion required contributions from both macrophages and cancer cells. Interestingly, several of the tumor-promoting functions of CtsZ were not dependent on its described catalytic activity but instead were mediated via the Arg-Gly-Asp (RGD) motif in the enzyme prodomain, which regulated interactions with integrins and the extracellular matrix. Together, these results underscore the complexity of interactions within the tumor microenvironment and indicate that cellular source can indeed impact molecular function.[Keywords: cell invasion; cell migration; tumor microenvironment; protease] Supplemental material is available for this article. Received July 26, 2014; revised version accepted August 29, 2014. Tumors arise in complex tissue microenvironments in which a multitude of different noncancerous cell types can potently regulate disease initiation and progression (Hanahan and Coussens 2012;Quail and Joyce 2013). In addition, interactions with the extracellular matrix (ECM) are critical for modulating cell behavior, including enhancing cell survival and promoting invasion via ECM turnover and proteolysis (Lu et al. 2012;Sevenich and Joyce 2014). The ECM is a heterogeneous mix of proteins and polysaccharides, including different collagens, laminins, fibronectin, and heparan sulfate proteoglycans, which form an intricate network that confers tissue structure and regulates growth factor availability (Hynes and Naba 2012;Lu et al. 2012). Integrins are central in mediating interactions between cells and the surrounding ECM, and integrin engagement at the cell surface results in activation of downstream signaling nodes, including focal adhesion kinase (FAK) and Src kinase, to promote cancer cell proliferation, survival, migration, and invasion (Desgrosellier and Cheresh 2010;Huttenlocher and Horwitz 2011;Moreno-Layseca and Streuli 2014).Among the noncancerous cell types that modulate tumorigenesis, tumor-associated macrophages (TAMs) have emerged as critical regulators of tumor progression (Biswas et al. 2013;Noy and Pollard 2014). This is particularly evident in tumor invasion, as TAMs provide a major source of proteases that modulate the ECM (Joyce and Pollard 2009). In determining the mechanisms by which TAMs promote different tumorigenic processes, the focus to date has been predominantly centered on identifying factors that are TAM-specific or TAM-enriched, which are not necessa...

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Section: Discussioncontrasting

confidence: 38%

Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix

et al. 2014

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“…Cathepsins are synthesized as precursor proteins called zymogens and many function in the lysosome, where the protease function becomes activated at low pH (Fonovićand Turk, 2014;Mohamed and Sloane, 2006;Turk et al, 2000). Ctsba is a cysteine type cathepsin and the nucleophile is the sulphydryl group of a cysteine residue, which forms an acyl intermediate.…”

Section: Discussion Ctsba Endopeptidase Function In Developmentmentioning

confidence: 99%

Split top: A maternal cathepsin B that regulates dorsoventral patterning and morphogenesis

et al. 2016

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The vertebrate embryonic dorsoventral axis is established and patterned by Wnt and bone morphogenetic protein (BMP) signaling pathways, respectively. Whereas Wnt signaling establishes the dorsal side of the embryo and induces the dorsal organizer, a BMP signaling gradient patterns tissues along the dorsoventral axis. Early Wnt signaling is provided maternally, whereas BMP ligand expression in the zebrafish is zygotic, but regulated by maternal factors. Concomitant with BMP activity patterning dorsoventral axial tissues, the embryo also undergoes dramatic morphogenetic processes, including the cell movements of gastrulation, epiboly and dorsal convergence. Although the zygotic regulation of these cell migration processes is increasingly understood, far less is known of the maternal regulators of these processes. Similarly, the maternal regulation of dorsoventral patterning, and in particular the maternal control of ventral tissue specification, is poorly understood. We identified split top, a recessive maternal-effect zebrafish mutant that disrupts embryonic patterning upstream of endogenous BMP signaling. Embryos from split top mutant females exhibit a dorsalized embryonic axis, which can be rescued by BMP misexpression or by derepressing endogenous BMP signaling. In addition to dorsoventral patterning defects, split top mutants display morphogenesis defects that are both BMP dependent and independent. These morphogenesis defects include incomplete dorsal convergence, delayed epiboly progression and an early lysis phenotype during gastrula stages. The latter two morphogenesis defects are associated with disruption of the actin and microtubule cytoskeleton within the yolk cell and defects in the outer enveloping cell layer, which are both known mediators of epiboly movements. Through chromosomal mapping and RNA sequencing analysis, we identified the lysosomal endopeptidase cathepsin Ba (ctsba) as the gene deficient in split top embryos. Our results identify a novel role for Ctsba in morphogenesis and expand our understanding of the maternal regulation of dorsoventral patterning.

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“…Importantly, stromelysin, MMP-3, has a broad spectrum and can degrade other components of the extracellular matrix as well, including proteoglycans and elastin (Libby 2013a). Cathepsins are another group of enzymes capable of effectively degrading the various components of the fibrous cap (Fonovic and Turk 2014). Thus, the presence of inflammatory cells in the caps of advanced plaques tends to render the plaque unstable and prone to rupture by both decreasing the production and increasing the degradation of the extracellular matrix of the fibrous cap.…”

Section: Atherothrombosismentioning

confidence: 99%

HDL and Atherothrombotic Vascular Disease

Annema

Eckardstein

Kovanen

2014

High Density Lipoproteins

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High-density lipoproteins (HDLs) exert many beneficial effects which may help to protect against the development or progression of atherosclerosis or even facilitate lesion regression. These activities include promoting cellular cholesterol efflux, protecting low-density lipoproteins (LDLs) from modification, preserving endothelial function, as well as anti-inflammatory and antithrombotic effects. However, questions remain about the relative importance of these activities for atheroprotection. Furthermore, the many molecules (both lipids and proteins) associated with HDLs exert both distinct and overlapping activities, which may be compromised by inflammatory conditions, resulting in either loss of function or even gain of dysfunction. This complexity of HDL functionality has so far precluded elucidation of distinct structure-function relationships for HDL or its components. A better understanding of HDL metabolism and structure-function relationships is therefore crucial to exploit HDLs and its associated components and cellular pathways as potential targets for anti-atherosclerotic therapies and diagnostic markers.

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Cysteine cathepsins and extracellular matrix degradation

Cited by 286 publications

References 213 publications

Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix

Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix

Split top: A maternal cathepsin B that regulates dorsoventral patterning and morphogenesis

HDL and Atherothrombotic Vascular Disease

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