Evidence for Restricted Reactivity of ADAMDEC1 with Protein Substrates and Endogenous Inhibitors

Lund, J.; Troeberg, Linda; Kjeldal, Henrik; Olsen, Ole H.; Nagase, Hideaki; Sørensen, Esben S.; Stennicke, Henning R.; Petersen, H; Overgaard, Michael Toft

doi:10.1074/jbc.m114.601724

Cited by 11 publications

(17 citation statements)

References 37 publications

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“…The P1 substituent allows for interaction with different zinc binding groups (amino carboxylate, phosphinate, and phosphonic acid) (Johnson et al, ). Batimastat (Lund et al, ) and marimastat (Wallace et al, ) are two broad spectrum succinyl hydroxamates with P1 substituents, with an additional thienylthiomethylene alpha‐substituent (Clements et al, ) and hydroxyl alpha‐substituent (Betz et al, ) respectively. Due to non‐specific inhibition, specificity can be conferred by modifying the P1 substituent.…”

Section: Matrix Metalloproteinase Inhibitorsmentioning

confidence: 99%

“…The P2′ group only confers a modest increase in potency but has a greater effect on the pharmacokinetic properties. The larger and sterically bulky the group, the higher the aqueous solubility (Tonn et al, ) and, therefore, bioavailability is increased (Lund et al, ). Furthermore, a P3′ substituent may be added to further adjunct the pharmacokinetics and increase inhibition of various MMPs and sheddases (Broadhurst et al, ; Beckett et al, ,).…”

Section: Matrix Metalloproteinase Inhibitorsmentioning

confidence: 99%

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Intricate Functions of Matrix Metalloproteinases in Physiological and Pathological Conditions

Mittal

Patel

Debs

et al. 2016

Journal Cellular Physiology

147

115

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Matrix metalloproteinases (MMPs) are a diverse group of proteolytic enzymes and play an important role in the degradation and remodeling of the extracellular matrix (ECM). In normal physiological conditions, MMPs are usually minimally expressed. Despite their low expression, MMPs have been implicated in many cellular processes ranging from embryological development to apoptosis. The activity of MMPs is controlled at three different stages: (1) transcription; (2) zymogen activation; and (3) inhibition of active forms by tissue inhibitor metalloproteinases (TIMPs). They can collectively degrade any component of ECM and basement membrane, and their excessive activity has been linked to numerous pathologies mainly including, but not limited to, tumor invasion and metastasis. The lack of information about several MMPs and the steady stream of new discoveries suggest that there is much more to be studied in this field. In particular, there is a need for controlling their expression in disease states. Various studies over the past 30 years have found that each MMP has a specific mode of activation, action, and inhibition. Drugs specifically targeting individual MMPs could revolutionize the treatment of a great number of health conditions and tremendously reduce their burden. In this review article, we have summarized the recent advances in understanding the role of MMPs in physiological and pathological conditions. J. Cell. Physiol. 231: 2599-2621, 2016. © 2016 Wiley Periodicals, Inc.

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Section: Matrix Metalloproteinase Inhibitorsmentioning

confidence: 99%

Section: Matrix Metalloproteinase Inhibitorsmentioning

confidence: 99%

Intricate Functions of Matrix Metalloproteinases in Physiological and Pathological Conditions

Mittal

Patel

Debs

et al. 2016

Journal Cellular Physiology

147

115

View full text Add to dashboard Cite

show abstract

“…14 Recently it has been demonstrated that the unique nature of the active site in ADAMDEC1 allows it to escape inhibition by the tissue inhibitors of metalloproteases 1–3 [TIMP1-3]. 15 ADAMDEC1 seems to have evolved to function independently from the normal intrinsic inhibitory mechanisms that regulate other metalloproteases.…”

Section: Introductionmentioning

confidence: 99%

Critical Role of the Disintegrin Metalloprotease ADAM-like Decysin-1 [ADAMDEC1] for Intestinal Immunity and Inflammation

O’Shea

Chew

Dunne

et al. 2016

ECCOJC

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Background and Aims:ADAM [A Disintegrin And Metalloproteinase] is a family of peptidase proteins which have diverse roles in tissue homeostasis and immunity. Here, we study ADAM-like DECysin-1 [ADAMDEC1] a unique member of the ADAM family. ADAMDEC1 expression is restricted to the macrophage/dendritic cell populations of the gastrointestinal tract and secondary lymphoid tissue. The biological function of ADAMDEC1 is unknown but it has been hypothesised to play a role in immunity. The identification of reduced ADAMDEC1 expression in Crohn’s disease patients has provided evidence of a potential role in bowel inflammation.Methods:Adamdec1-/- mice were exposed to dextran sodium sulphate or infected orally with Citrobacter rodentium or Salmonella typhimurium. The clinical response was monitored.Results:The loss of Adamdec1 rendered mice more susceptible to the induction of bacterial and chemical induced colitis, as evidenced by increased neutrophil infiltration, greater IL-6 and IL-1β secretion, more weight loss and increased mortality. In the absence of Adamdec1, greater numbers of Citrobacter rodentium were found in the spleen, suggestive of a breakdown in mucosal immunity which resulted in bacteraemia.Conclusion:In summary, ADAMDEC1 protects the bowel from chemical and bacterial insults, failure of which may predispose to Crohn’s disease.

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“…Our study identifies a new feedback loop that enables GSCs to access FGF2 in the tumor microenvironment through secretion of the ADAMDEC1. ADAMDEC1 is a novel member of the ADAM family of metalloproteinases due to the absence of a transmembrane domain and altered catalytic domain, features shared by no other ADAM family member (20,30,31), which result in a unique secreted, soluble protease with distinct ligand specificity (20,21). Additionally, ADAMDEC1 was shown to modulate apical membrane extrusion of epithelial cells (32).…”

Section: Discussionmentioning

confidence: 99%

“…ADAMDEC1 is a soluble member of this family that is novel in mammals. It has restricted hydrolytic capacity due to a substitution in an active site residue (20) and selectively solubilizes growth factors from immobile precursor forms (21). Whether ADAMDEC1 solubilizes additional ligands, and whether this contributes to GBM growth and progression, has yet to be determined.…”

Section: Introductionmentioning

confidence: 99%

ADAMDEC1 maintains a novel growth factor signaling loop in cancer stem cells

Hale

Jimenez-Pascual

Kordowski

et al. 2019

Preprint

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Glioblastomas (GBM) are lethal brain tumors where poor outcome is attributed to cellular heterogeneity, therapeutic resistance, and a highly infiltrative nature. These characteristics are preferentially linked to GBM cancer stem cells (GSCs), but how GSCs maintain their stemness is incompletely understood and the subject of intense investigation. Here, we identify a novel signaling loop that induces and maintains GSCs. This loop consists of an atypical metalloproteinase, a disintegrin and metalloproteinase domain-like protein decysin 1 (ADAMDEC1), secreted by GSCs. ADAMDEC1 rapidly solubilizes fibroblast growth factor-2 (FGF2) to stimulate FGF receptor 1 (FGFR1) expressed on GSCs. This signaling axis induces upregulation of Zinc finger E-box-binding homeobox 1 (ZEB1) that regulates ADAMDEC1 expression, creating a positive feedback loop. Genetic or pharmacological targeting of components of this axis attenuates self-renewal and tumor growth. These findings reveal a new signaling axis for GSC maintenance and highlight ADAMDEC1 and FGFR1 as potential therapeutic targets in GBM. Statement of SignificanceCancer stem cells (CSC) drive tumor growth in many cancers including glioblastoma. We identified a novel sheddase, a disintegrin and metalloproteinase domain-like protein decysin 1, that initiates a fibroblast growth factor autocrine loop to promote stemness in CSCs. This loop can be targeted to reduce glioblastoma growth.

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Evidence for Restricted Reactivity of ADAMDEC1 with Protein Substrates and Endogenous Inhibitors

Cited by 11 publications

References 37 publications

Intricate Functions of Matrix Metalloproteinases in Physiological and Pathological Conditions

Intricate Functions of Matrix Metalloproteinases in Physiological and Pathological Conditions

Critical Role of the Disintegrin Metalloprotease ADAM-like Decysin-1 [ADAMDEC1] for Intestinal Immunity and Inflammation

ADAMDEC1 maintains a novel growth factor signaling loop in cancer stem cells

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