ADAM10 | M12: Astacin/Adamalysin | IUPHAR/BPS Guide to PHARMACOLOGY

ADAM10

Target id: 1658

Nomenclature: ADAM10

Family: M12: Astacin/Adamalysin

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

   GtoImmuPdb view: OFF :     ADAM10 has curated GtoImmuPdb data

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 748 15q2 ADAM10 ADAM metallopeptidase domain 10
Mouse - 749 9 D Adam10 a disintegrin and metallopeptidase domain 10
Rat - 544 8q24 Adam10 ADAM metallopeptidase domain 10
Previous and Unofficial Names
Kuzbanian protein homolog | Mammalian disintegrin-metalloprotease | CD156c | kuz | MADM | a disintegrin and metallopeptidase domain 10 | ADAM metallopeptidase domain 10 | HER-2 sheddase
Database Links
Specialist databases
MEROPS M12.210 (Hs)
Other databases
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Enzyme Reaction
EC Number: 3.4.24.81

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
ilomastat Hs Inhibition 8.1 pIC50 5
pIC50 8.1 (IC50 8.1x10-9 M) [5]
Description: Measured in an in vitro assay.
compound 25 [PMID: 18068976] Hs Inhibition 7.8 pIC50 1
pIC50 7.8 (IC50 1.6x10-8 M) [1]
GI254023X Hs Inhibition 5.3 pIC50 3
pIC50 5.3 (IC50 5.3x10-6 M) [3]
Immunopharmacology Comments
ADAM10 has been identified as the primary physiologically relevant sheddase responsible for cleavage of ICOS ligand, and regulation of ICOS/ICOSL-dependent immune responses [4]. B cell ADAM10 inhibition represents a novel mechanism to modulate the ICOS/ICOSL pathway and alter the humoral immune response. Experimental evidence using patient-derived cells has identified ADAM10 as important for the shedding of soluble semaphorin 4D (Sema4D) from CD15+ granulocytes, a pathway implicated in the promotion of autoreactive antibody secretion by B cells that leads to the development of the autoimmune skin condition bullous pemphigoid [6].
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 3 GO processes
GO:0010820 positive regulation of T cell chemotaxis IMP
GO:0042117 monocyte activation IMP
GO:0043312 neutrophil degranulation TAS
Immuno Process:  Immune regulation
GO Annotations:  Associated to 1 GO processes
GO:0010820 positive regulation of T cell chemotaxis IMP
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 1 GO processes
GO:0034612 response to tumor necrosis factor IDA
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 1 GO processes
GO:0010820 positive regulation of T cell chemotaxis IMP
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 2 GO processes
GO:0042117 monocyte activation IMP
GO:0043312 neutrophil degranulation TAS
Clinically-Relevant Mutations and Pathophysiology
Disease:  Reticulate acropigmentation of Kitamura; RAK
OMIM: 615537
Orphanet: ORPHA178307
General Comments
The proteolytic domains of ADAM10 and ADAM17 exhibit a high degree of homology, which explains their ability to cleave overlapping substrates. ADAM10 is responsible for cleaving a variety of substrates, including Notch receptors, delta-like 1, IL-6R, CXCL16, CD23 and ICOS ligand [2,4,7].

References

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1. Burns DM, He C, Li Y, Scherle P, Liu X, Marando CA, Covington MB, Yang G, Pan M, Turner S et al.. (2008) Conversion of an MMP-potent scaffold to an MMP-selective HER-2 sheddase inhibitor via scaffold hybridization and subtle P1' permutations. Bioorg. Med. Chem. Lett., 18 (2): 560-4. [PMID:18068976]

2. Gibb DR, El Shikh M, Kang DJ, Rowe WJ, El Sayed R, Cichy J, Yagita H, Tew JG, Dempsey PJ, Crawford HC et al.. (2010) ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo. J. Exp. Med., 207 (3): 623-35. [PMID:20156974]

3. Hoettecke N, Ludwig A, Foro S, Schmidt B. (2010) Improved synthesis of ADAM10 inhibitor GI254023X. Neurodegener Dis, 7 (4): 232-8. [PMID:20197648]

4. Lownik JC, Luker AJ, Damle SR, Cooley LF, El Sayed R, Hutloff A, Pitzalis C, Martin RK, El Shikh MEM, Conrad DH. (2017) ADAM10-Mediated ICOS Ligand Shedding on B Cells Is Necessary for Proper T Cell ICOS Regulation and T Follicular Helper Responses. J. Immunol., 199 (7): 2305-2315. [PMID:28814605]

5. Oh M, Im I, Lee YJ, Kim YH, Yoon JH, Park HG, Higashiyama S, Kim YC, Park WJ. (2004) Structure-based virtual screening and biological evaluation of potent and selective ADAM12 inhibitors. Bioorg. Med. Chem. Lett., 14 (24): 6071-4. [PMID:15546732]

6. Shen S, Ke Y, Dang E, Fang H, Chang Y, Zhang J, Zhu Z, Shao S, Qiao P, Zhang T et al.. (2018) Semaphorin 4D from CD15+ Granulocytes via ADAM10-Induced Cleavage Contributes to Antibody Production in Bullous Pemphigoid. J. Invest. Dermatol., 138 (3): 588-597. [PMID:29054606]

7. Weskamp G, Ford JW, Sturgill J, Martin S, Docherty AJ, Swendeman S, Broadway N, Hartmann D, Saftig P, Umland S et al.. (2006) ADAM10 is a principal 'sheddase' of the low-affinity immunoglobulin E receptor CD23. Nat. Immunol., 7 (12): 1293-8. [PMID:17072319]

How to cite this page

M12: Astacin/Adamalysin: ADAM10. Last modified on 25/10/2017. Accessed on 26/09/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1658.