Degradome of soluble ADAM10 and ADAM17 metalloproteases

Scharfenberg, Franka; Helbig, Andreas O.; Sammel, Martin; Benzel, Julia; Schlomann, Uwe; Peters, Florian; Wichert, Rielana; Bettendorff, Maximilian; Schmidt-Arras, Dirk; Rose–John, Stefan; Moali, Catherine; Lichtenthaler, Stefan F.; Pietrzik, Claus U.; Bartsch, Jörg W.; Tholey, Andreas; Becker‐Pauly, Christoph

doi:10.1007/s00018-019-03184-4

Cited by 53 publications

(60 citation statements)

References 95 publications

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“…This mutant was used as a model mimicking the physiological situation in tumours, in which shedding of CA IX might be hampered due to the absence of ADAM17, its inactivation by TIMPs-mediated inhibition, its aberrant maturation and activation, or due to somatic mutations affecting the CA IX folding and interaction with the proteinase. 46,47 The impairment of CA IX shedding was accomplished by deletion of 10 amino acids from the stalk region linking the catalytic CA domain to the transmembrane region. The CA IX stalk consists of 22 amino acids and thus fulfils the size requirement formulated in the study on IL-6R shedding.…”

Section: Discussionmentioning

confidence: 99%

“…This idea is in accord with previous observations that the cell-surface availability of ADAM17 can be controlled through multilevel regulation including maturation, trafficking, activation, endocytosis-recycling-exocytosis mechanisms, or by shedding of its ectodomain via other ADAMs. 46,47,51,52 It is quite conceivable that ADAM17 remains sequestered by the substrate and dissociates only after the execution of cleavage. However, the CA IX cleavage actually cannot happen in the absence of the cleavage site presumably causing that the NS-CA IX variant keeps ADAM17 in the long-term assembly and thereby prevents its degradation and/or shedding.…”

Section: Discussionmentioning

confidence: 99%

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Impairment of carbonic anhydrase IX ectodomain cleavage reinforces tumorigenic and metastatic phenotype of cancer cells

et al. 2020

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BACKGROUND: Carbonic anhydrase IX (CA IX) is a hypoxia-induced enzyme regulating tumour pH and facilitating cell migration/ invasion. It is primarily expressed as a transmembrane cell-surface protein, but its ectodomain can be shed by ADAM17 to extracellular space. This study aims to elucidate the impact of CA IX shedding on cancer cells. METHODS: We generated a non-shed CA IX mutant by deletion of amino acids 393-402 from the stalk region and studied its phenotypic effects compared to full-length, shedding-competent CA IX using a range of assays based on immunodetection, confocal microscopy, in vitro real-time cell monitoring and in vivo tumour cell inoculation using xenografted NMRI and C57BL/6J female mice. RESULTS: We demonstrated that the impairment of shedding does not alter the ability of CA IX to bind ADAM17, internalise, form oligomers and regulate pH, but induces cancer-promoting changes in extracellular proteome. Moreover, it affects intrinsic properties of cells expressing the non-shed variant, in terms of their increased ability to migrate, generate primary tumours and form metastatic lesions in lungs. CONCLUSIONS: Our results show that the ectodomain shedding controls pro-tumorigenic and pro-metastatic roles of the cellassociated CA IX and suggest that this phenomenon should be considered when developing CA IX-targeted therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Impairment of carbonic anhydrase IX ectodomain cleavage reinforces tumorigenic and metastatic phenotype of cancer cells

et al. 2020

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“…ADAM10 and 17 are membrane-anchored and their ectodomains can be released by ADAM8. The soluble ectodomains show different target specificity 98 .…”

Section: Changes In Ecm Modification and Organisation In Cancermentioning

confidence: 99%

Concepts of extracellular matrix remodelling in tumour progression and metastasis

et al. 2020

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Tissues are dynamically shaped by bidirectional communication between resident cells and the extracellular matrix (ECM) through cell-matrix interactions and ECM remodelling. Tumours leverage ECM remodelling to create a microenvironment that promotes tumourigenesis and metastasis. In this review, we focus on how tumour and tumour-associated stromal cells deposit, biochemically and biophysically modify, and degrade tumour-associated ECM. These tumour-driven changes support tumour growth, increase migration of tumour cells, and remodel the ECM in distant organs to allow for metastatic progression. A better understanding of the underlying mechanisms of tumourigenic ECM remodelling is crucial for developing therapeutic treatments for patients.

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“…While MMPs/ADAMs are commonly thought to lack clear consensus sequences for cleavage 39 , recent comprehensive surveys have identified motifs that may be preferred by one MMP/ADAM over the other (for example 40,41 ). Based on these studies, GPR37L1 may have a weak consensus sequence for ADAM10 or ADAM17 40 , but not MMPs 41 ; these motifs should have been disrupted in the 112 Ala 114 , 118 Ala 120 , and 121 Ala 123 GPR37L1-eYFP triple mutants because they contain either the preferred P1′ lysine or valine 40 , yet GPR37L1 proteolysis was unchanged. A similar study of N-terminal proteolysis at the closely related GPR37 yielded the same result 38 .…”

Section: Discussionmentioning

confidence: 99%

The N-terminus of GPR37L1 is proteolytically processed by matrix metalloproteases

Coleman

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Smythe

et al. 2020

Sci Rep

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GPR37L1 is an orphan G protein-coupled receptor expressed exclusively in the brain and linked to seizures, neuroprotection and cardiovascular disease. Based upon the observation that fragments of the GPR37L1 N-terminus are found in human cerebrospinal fluid, we hypothesized that GPR37L1 was subject to post-translational modification. Heterologous expression of GPR37L1-eYFP in either HEK293 or U87 glioblastoma cells yielded two cell surface species of approximately equivalent abundance, the larger of which is N-glycosylated at Asn105. The smaller species is produced by matrix metalloprotease/ADAM-mediated proteolysis (shown by the use of pharmacological inhibitors) and has a molecular weight identical to that of a mutant lacking the entire N-terminus, Δ122 GPR37L1. Serial truncation of the N-terminus prevented GPR37L1 expression except when the entire N-terminus was removed, narrowing the predicted site of N-terminal proteolysis to residues 105–122. Using yeast expressing different G protein chimeras, we found that wild type GPR37L1, but not Δ122 GPR37L1, coupled constitutively to Gpa1/Gαs and Gpa1/Gα16 chimeras, in contrast to previous studies. We tested the peptides identified in cerebrospinal fluid as well as their putative newly-generated N-terminal ‘tethered’ counterparts in both wild type and Δ122 GPR37L1 Gpa1/Gαs strains but saw no effect, suggesting that GPR37L1 does not signal in a manner akin to the protease-activated receptor family. We also saw no evidence of receptor activation or regulation by the reported GPR37L1 ligand, prosaptide/TX14A. Finally, the proteolytically processed species predominated both in vivo and ex vivo in organotypic cerebellar slice preparations, suggesting that GPR37L1 is rapidly processed to a signaling-inactive form. Our data indicate that the function of GPR37L1 in vivo is tightly regulated by metalloprotease-dependent N-terminal cleavage.

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Degradome of soluble ADAM10 and ADAM17 metalloproteases

Cited by 53 publications

References 95 publications

Impairment of carbonic anhydrase IX ectodomain cleavage reinforces tumorigenic and metastatic phenotype of cancer cells

Impairment of carbonic anhydrase IX ectodomain cleavage reinforces tumorigenic and metastatic phenotype of cancer cells

Concepts of extracellular matrix remodelling in tumour progression and metastasis

The N-terminus of GPR37L1 is proteolytically processed by matrix metalloproteases

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