ADAM10

Immunopharmacology Ligand Target has curated data in GtoImmuPdb

Target id: 1658

Nomenclature: ADAM10

Gene and Protein Information
Species	TM	AA	Chromosomal Location	Gene Symbol	Gene Name	Reference
Human	1	748	15q21.3	ADAM10	ADAM metallopeptidase domain 10
Mouse	1	749	9 39.53 cM	Adam10	a disintegrin and metallopeptidase domain 10
Rat	1	749	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
Alphafold	O14672 (Hs), O35598 (Mm), Q10743 (Rn)
BRENDA	3.4.24.81
CATH/Gene3D	3.40.390.10, 4.10.70.10
ChEMBL Target	CHEMBL5028 (Hs)
Ensembl Gene	ENSG00000137845 (Hs), ENSMUSG00000054693 (Mm), ENSRNOG00000054257 (Rn)
Entrez Gene	102 (Hs), 11487 (Mm), 29650 (Rn)
Human Protein Atlas	ENSG00000137845 (Hs)
KEGG Enzyme	3.4.24.81
KEGG Gene	hsa:102 (Hs), mmu:11487 (Mm), rno:29650 (Rn)
OMIM	602192 (Hs)
Orphanet	ORPHA358659 (Hs)
Pharos	O14672 (Hs)
RefSeq Nucleotide	NM_001110 (Hs), NM_007399 (Mm), NM_019254 (Rn)
RefSeq Protein	NP_001101 (Hs), NP_031425 (Mm), NP_062127 (Rn)
UniProtKB	O14672 (Hs), O35598 (Mm), Q10743 (Rn)
Wikipedia	ADAM10 (Hs)

Enzyme Reaction

EC Number: 3.4.24.81

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Inhibitors

Key to terms and symbols

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Ligand		Sp.	Action	Value	Parameter	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].

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

Immuno Process:

Immune regulation

Immuno Process:

Cytokine production & signalling

Immuno Process:

Chemotaxis & migration

Immuno Process:

Cellular signalling

Immuno Process:

Immune system development

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]