Cathepsin X cleaves the β2 cytoplasmic tail of LFA‐1 inducing the intermediate affinity form of LFA‐1 and α‐actinin‐1 binding

Jevnikar, Zala; Obermajer, Nataša; Pečar-Fonović, Urša; Carmona, Adriana K.; Kos, Janko

doi:10.1002/eji.200939562

Cited by 20 publications

(19 citation statements)

References 41 publications

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“…Cathepsin X degrades various molecular targets involved in signal transduction, growth, maturation, adhesion, cell-cell communication, proliferation and migration of immune and neuronal cells [9], [12], [21], [22]. Its important role was also suggested in tumor cells and results of our study clearly demonstrate the association of its carboxypeptidase activity with the invasiveness of prostate PC-3 cells and breast cancer MDA-MB-231 and MCF-7 cells.…”

Section: Discussionsupporting

confidence: 61%

Profilin 1 as a Target for Cathepsin X Activity in Tumor Cells

et al. 2013

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Cathepsin X has been reported to be a tumor promotion factor in various types of cancer; however, the molecular mechanisms linking its activity with malignant processes are not understood. Here we present profilin 1, a known tumor suppressor, as a target for cathepsin X carboxypeptidase activity in prostate cancer PC-3 cells. Profilin 1 co-localizes strongly with cathepsin X intracellularly in the perinuclear area as well as at the plasma membrane. Selective cleavage of C-terminal amino acids was demonstrated on a synthetic octapeptide representing the profilin C-terminal region, and on recombinant profilin 1. Further, intact profilin 1 binds its poly-L-proline ligand clathrin significantly better than it does the truncated one, as shown using cathepsin X specific inhibitor AMS-36 and immunoprecipitation of the profilin 1/clathrin complex. Moreover, the polymerization of actin, which depends also on the binding of poly-L-proline ligands to profilin 1, was promoted by AMS-36 treatment of cells and by siRNA cathepsin X silencing. Our results demonstrate that increased adhesion, migration and invasiveness of tumor cells depend on the inactivation of the tumor suppressive function of profilin 1 by cathepsin X. The latter is thus designated as a target for development of new antitumor strategies.

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Section: Discussionsupporting

confidence: 61%

Profilin 1 as a Target for Cathepsin X Activity in Tumor Cells

et al. 2013

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“…Similarly, a-actinin is a prominent actin-binding protein that interacts with many partners to regulate cell-cell adhesion among several other cellular processes. a-Actinin is localized to the cytoplasmic face of many sites of cell-cell and cell-extracellular matrix adhesion, including leukocyte-endothelial contact sites, where it binds to the cytoplasmic tails of the classical, as well as nonclassical, adhesion molecules to link them to actin and microtubules (40)(41)(42)(43)(44)(45). At these sites, a-actinin serves to strengthen the site, maintain cell shape, bind and organize signaling molecules at adhesion sites, increase avidity by clustering adhesion molecules, and control the activity of independent receptors.…”

Section: Discussionmentioning

confidence: 99%

Tyrosine Phosphorylation of CD13 Regulates Inflammatory Cell–Cell Adhesion and Monocyte Trafficking

Subramani

Ghosh

Rahman

et al. 2013

The Journal of Immunology

101

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CD13 is a large cell surface peptidase expressed on the monocytes and activated endothelial cells important for homing to and resolving the damaged tissue at sites of injury. We have previously shown that crosslinking of human monocytic CD13 with activating antibodies induces strong adhesion to endothelial cells in a tyrosine kinase- and microtubule-dependent manner. In the current study we examined the molecular mechanisms underlying these observations in vitro and in vivo. We found that crosslinking of CD13 on U937 monocytic cells induced phosphorylation of a number of proteins, including Src, FAK and ERK and inhibition of these abrogated CD13-dependent adhesion. We found that CD13 itself was phosphorylated in a Src dependent manner, an unexpected finding as its 7 amino acid cytoplasmic tail was assumed to be inert. Furthermore, CD13 was constitutively associated with the scaffolding protein IQGAP1 and CD13 crosslinkinginduced complex formation with the actin-binding protein α-actinin, linking membrane-bound CD13 to the cytoskeleton, further supporting CD13 as an inflammatory adhesion molecule. Mechanistically, mutation of the conserved CD13 cytoplasmic tyrosine to phenylalanine abrogated adhesion, Src, FAK and ERK phosphorylation and cytoskeletal alterations upon antibody crosslinking. Finally, CD13 was phosphorylated in isolated murine inflammatory peritoneal exudate cells and adoptive transfer of monocytic cell lines engineered to express the mutant CD13 were severely impaired in their ability to migrate into the inflamed peritoneum, confirming that CD13 phosphorylation is relevant to inflammatory cell trafficking in vivo. Therefore, this study identifies CD13 as a novel, direct activator of intracellular signaling pathways in pathophysiological conditions.

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“…Moreover, cathepsin X was found to cleave β 2 integrin, thereby demonstrating another way of regulating T-cell migration [150]. There are indications that cathepsin X removes the C-terminal residues of LFA-1, a β 2 integrin, thereby increasing its affinity for the adaptor protein talin [151,152]. The subsequent cleavages result in the intermediate as well as the high-affinity LFA-1.…”

Section: Protein Substrate Hydrolysismentioning

confidence: 99%

Cysteine cathepsins: From structure, function and regulation to new frontiers

Türk

Stoka

Vasiljeva

et al. 2012

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

1,117

1,054

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It is more than 50 years since the lysosome was discovered. Since then its hydrolytic machinery, including proteases and other hydrolases, has been fairly well identified and characterized. Among these are the cysteine cathepsins, members of the family of papain-like cysteine proteases. They have unique reactive-site properties and an uneven tissue-specific expression pattern. In living organisms their activity is a delicate balance of expression, targeting, zymogen activation, inhibition by protein inhibitors and degradation. The specificity of their substrate binding sites, small-molecule inhibitor repertoire and crystal structures are providing new tools for research and development. Their unique reactive-site properties have made it possible to confine the targets simply by the use of appropriate reactive groups. The epoxysuccinyls still dominate the field, but now nitriles seem to be the most appropriate "warhead". The view of cysteine cathepsins as lysosomal proteases is changing as there is now clear evidence of their localization in other cellular compartments. Besides being involved in protein turnover, they build an important part of the endosomal antigen presentation. Together with the growing number of non-endosomal roles of cysteine cathepsins is growing also the knowledge of their involvement in diseases such as cancer and rheumatoid arthritis, among others. Finally, cysteine cathepsins are important regulators and signaling molecules of an unimaginable number of biological processes. The current challenge is to identify their endogenous substrates, in order to gain an insight into the mechanisms of substrate degradation and processing. In this review, some of the remarkable advances that have taken place in the past decade are presented. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.

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Cathepsin X cleaves the β2 cytoplasmic tail of LFA‐1 inducing the intermediate affinity form of LFA‐1 and α‐actinin‐1 binding

Cited by 20 publications

References 41 publications

Profilin 1 as a Target for Cathepsin X Activity in Tumor Cells

Profilin 1 as a Target for Cathepsin X Activity in Tumor Cells

Tyrosine Phosphorylation of CD13 Regulates Inflammatory Cell–Cell Adhesion and Monocyte Trafficking

Cysteine cathepsins: From structure, function and regulation to new frontiers

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