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FLASH GENE

Symbol

ADAM10

contributors: mct - updated : 14-10-2018

HGNC name	ADAM metallopeptidase domain 10
HGNC id	188

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

RNA

TRANSCRIPTS	type	messenger

text	with a shorter alternatively spliced form

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001110 16 - 3927 NP_001101 84 748 - 1998 9618175 precursor

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive mouth tongue     highly Lymphoid/Immune thymus       highly Nervous brain       highly Homo sapiens Respiratory respiratory tract trachea     highly Skin/Tegument skin         Homo sapiens Urinary kidney

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / hematopoietic bone marrow     highly Homo sapiens Epithelial barrier lining epidermis   highly Homo sapiens Muscular striatum skeletal   highly Homo sapiens Nervous peripherous     highly Homo sapiens

cells

System Cell Pubmed Species Stage Rna symbol Blood/Hematopoietic progenitor cell Homo sapiens Digestive ameloblast Homo sapiens Lymphoid/Immune T cell Homo sapiens Muscular myoblast Homo sapiens Nervous neuron Skin/Tegument keratinocyte Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

embryo, fetal

Text	somitic dermatome and myotome, fetal liver

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	domains similar to hemorrhagic snake venom proteins (HSVP) with a prodomain
	a Zn-binding site metalloproteinase
	a disintegrin-like domain
	a cysteine rich domain
	an EGF-like repeat
	the cytoplasmic domain of ADAM10 negatively regulates its constitutive activity through an ER retention motif but is dispensable for its stimulated activity
	four potential N-glycosylation sites (N267, N278, N439 and N551), that cleaves several plasma membrane proteins
	a transmembrane domain
	a cytoplasmic tail

conjugated

GlycoP , MetalloP

isoforms

Precursor

cleaved by a furin endopeptidase

HOMOLOGY

interspecies	homolog to Drosophila Kuzbanian
	homolog to rattus Adam10 (96.4pc)
	homolog to murine Adam10 (96.0pc)

Homologene

FAMILY

ADAM (a disintegrin and metalloprotease domain) family

CATEGORY

adaptor , enzyme

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,Golgi
	intracellular,nucleus
text	localized in the plasma membrane but predominantly expressed in the Golgi apparatus and in released membrane vesicles derived likely from the Golgi

basic FUNCTION	may be presenting alpha secretase activity
	involved in cell-cell and cell-matrix interactions, regulating sympatoadrenal cell fate in development and neoplasia
	involved in the proteolytic processing of APP and in early vertebrate embryogenesis (through notch signaling pathway)
	vesicle-based protease, involved in direct cleavage at the cell surface, or release and cleavage in secretory vesicles most likely derived from the Golgi apparatus
	involved in the constitutive cleavage of CX3CL1 and thereby may regulate the recruitment of monocytic cells to CX3CL1-expressing cell layers
	playing an essential role during neuronal development
	cleaving many proteins including TNF-alpha and E-cadherin
	playing a crucial role on beta-catenin signaling, and constitutes a central switch in the signaling pathway from N-cadherin at the cell surface to beta-catenin/LEF-1-regulated gene expression in the nucleus
	may contribute to allergic reactions by shedding the low-affinity IgE receptor CD23
	being responsible with ADAM17 for the cytokine-induced shedding of CXCL16
	may be critical in muscle fiber differentiation (
	critically involved in the shedding of FASLG
	represents an important molecular modulator of FASLG-mediated cell death
	initiating the regulated intramembrane proteolysis
	metalloprotease when it is membrane-bound and potential signaling protein once cleaved by ADAM9/15 and the gamma secretase complex
	is required for NOTCH1 signaling induced by ligands, cleaving NOTCH1
	contributes to the normal cleavage of the cellular prion protein
	essential alpha-secretase in neurons, and the control of neuronal ADAM10 activity has crucial importance in the etiology of Alzheimer disease
	may be involved in the motility of breast cancer cells via its activation by mesenchymal stem cells
	physiologically relevant, constitutive alpha-secretase of APP
	ADAM10, but not ADAM9 or 17, is essential for the constitutive alpha-secretase cleavage of APP
	might not only be important for cleavage of FCER2, but also for sorting FCER into exosomes
	required for alpha-secretase cleavage in primary neurons
	key role in the complex sequence of events through which CDH2 affects spine maturation and controls structure and function of glutamatergic synapses
	involved in the cleavage of PCDH12
	although ADAM10 is expressed in high abundance in the peripheral nerve, it is not critical for normal myelination
	involved in the cleavage od CDH1 that mediates epithelial cell sorting downstream of EPHB signalling
	nonredundant roles of cell-autonomous and non-cell-autonomous ADAM10 activity in the maintenance of hematopoiesis
	negatively regulates neuronal differentiation, possibly via its proteolytic effect on the NOTCH1 signaling during development of the spinal cord
	ADAM10 protease is an important factor in mast cell migration and tissue distribution
	acts in a cell autonomous manner within the intestinal crypt compartment to regulate NOTCH1 signaling
	ADAM10 and ADAM17 have opposite effects on sprouting angiogenesis that may be unrelated to Notch signalling and involves differentially expressed anti-angiogenic proteins such as TSP1
	major alpha-secretase that catalyzes the amyloid precursor protein (APP) ectodomain shedding in the brain and prevents amyloid formation
	both ADAM10 and ADAM17 are associated with FASLG-containing secretory lysosomes
	is essential for development because it cleaves Notch proteins to induce Notch signaling and regulate cell fate decisions
	is essential for embryonic development through activation of Notch proteins

CELLULAR PROCESS

protein, degradation

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

ADAM10/DLL4 signaling is a major signaling pathway in ECs driving inflammatory events involved in inflammation and immune cell recruitment

a component

INTERACTION

DNA

RNA

small molecule	metal binding,
	Zn2+

protein	interacting with YWHAZ
	interacting with CX3CL1 (fractalkine) and regulating CX3CL1-mediated cell-cell adhesion
	interacting with CDH1 (proteolytic processing of CDH1 for regulating cell-cell adhesion, motility, and proliferation of epithelial cells)
	interacting with BTC (mediates ectodomain shedding of the betacellulin precursor)
	cleaving specifically CDH2
	interaction with FASLG may be of critical importance for the tight regulation of induced cell death in health and disease
	with RECK (regulates the ectodomain shedding of Notch ligands by directly inhibiting the proteolytic activity of ADAM10)
	interacting with EFNA2
	partner for TSPAN12
	ADAM10 is a sheddase capable of releasing the GPNMB ectodomain from the surface of breast cancer cells, which induces endothelial cell migration
	binds FCER2 in a protease-independent manner
	its activity is regulated by inhibition of ADAM9, and this regulation may be used to control shedding of amyloid precursor protein by enhancing &
	945;-secretase activity, a key regulatory step in the etiology of Alzheimer disease
	required for the hypoxia-induced shedding of MICA, a ligand that triggers the cytolytic action of immune effectors, from the surface of tumor cells
	mediates endogenous CADM1 shedding
	SIGMAR1 overexpression diminished ADAM17- and ADAM10-dependent shedding
	TSPAN15 specifically associate with ADAM10 (TSPAN15 accelerates the ER-exit of the ADAM10-TSPAN15 complex and stabilizes the active form of ADAM10 at the cell surface)
	ADAM10 and/or MMP9 are playing important roles in constitutive and PACAP-induced RAGE shedding
	TSPAN5 and TSPAN14 positively regulated ligand-induced ADAM10-dependent NOTCH1 signaling
	P2RX7 activation induces the rapid shedding of CXCL16 and this process involves ADAM10
	ADAM10-dependent regulation of DLL1 and DLL4 expression in association with changes in HES1 and HEY1 expression
	in hippocampal neurons, DLG1 an excitatory synapse scaffolding element, governs ADAM10 trafficking from dendritic Golgi outposts to synaptic membranes
	CDH1/CTNNB1 signaling pathway is regulated by PKD1 and GNA12 via ADAM10
	TNFRSF13B is released by ADAM10 and reflects B cell activation in autoimmunity
	is required for shedding of membrane proteins such as EGF, betacellulin, the amyloid precursor protein, and CD23 from cells
	CTF1 activates NOTCH1 signaling through the up-regulation of ADAM10, a rate-limiting factor of NOTCH1 signaling activation
	MAZ plays an important role in ADAM10 transcription in response to CTF1 in neural progenitor cells
	ADAM10 releases NEGR1 from neuronal membrane
	TSPAN3 acts in concert with other tetraspanins as a stabilizing factor of active ADAM10, APP and the gamma-secretase complex at the plasma membrane and within the endocytic pathway
	role for ADAM10-dependent shedding of cell surface LSAMP in promoting outgrowth from dorsal root ganglion cells (DRGs) neurons
	endothelial TSPAN5- and TSPAN17-ADAM10 complexes may regulate inflammation by maintaining normal CDH5 expression and promoting T lymphocyte transmigration
	TSPANC8s are required for ADAM10 trafficking from the endoplasmic reticulum and its enzymatic maturation
	ADAM10 associates directly with all members (TSPAN5, TSPAN10, TSPAN14, TSPAN15, TSPAN17 and TSPAN33) of a subgroup of tetraspanins having eight cysteines in the large extracellular domain and referred to as TSPANC8
	NRCAM-dependent function for ADAM10 in neurite outgrowth
	ADAM10 is expressed by ameloblasts, cleaves the RELT TNF receptor extracellular domain and facilitates enamel development
	TACSTD2 cleavage by ADAM10 is an activator switch for cancer growth and metastasis

cell & other

REGULATION

inhibited by	binding of Zn2+
	TIMP1, TIMP3 (but N-terminal domains of TIMPs alone are insufficient for the inhibition of ADAM10)
	SFRP1, SFRP2 (inhibit the ADAM10 metalloprotease, which might have important implications in pathological events, including cancer and Alzheimer disease)

Other	is subject to regulated intramembrane proteolysis by ADAM9/15 and the gamma secretase complex
	induced in osteoarthritis affected-cartilage
	TSPAN12 promotes ADAM10 maturation and thereby facilitates ADAM10-dependent proteolysis of APP
	regulated by N-glycosylation (is crucial for ADAM10 processing and resistance to proteolysis)
	TSPANC8 tetraspanins have a conserved function in the regulation of ADAM10 trafficking and activity, thereby positively regulating NOTCH1 receptor activation

ASSOCIATED DISORDERS

corresponding disease(s)

RAK

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --over   in atrial fibrillation constitutional     --low   in platelet of Alzheimer disease tumoral       gain of function by RAR and acitretin, resulting in an increase of the ratio between alpha- and beta-secretase activity in neuroblastoma cells constitutional       gain of function constitutive activation of ADAM10 contributes to the growth of mantle cell lymphoma constitutional     --other   in FRA X fibroblasts, a dual dysregulation of APP and ADAM10 leads to the production of an excess of soluble APPalpha and to synaptic and behavioral deficits

Susceptibility

Variant & Polymorphism

Candidate gene	participating in signaling intrinsic to NOTCH1 mutations associated with leukemia
	candidate gene for Alzeihmer's disease with two potentially pathogenic mutations (Q170H, R181G) with incomplete penetrance
Marker
Therapy target
	System Type Disorder Pubmed neurology neurodegenerative alzheimer pharmacological activation of alpha-secretase (ADAM10) may be a therapeutic approach to Alzheimer disease cancer digestive liver antidrug cancer can modulate expression of ADAM10, epirubicin therapy may have an effect on antitumor immunity in hepatocellular carcinoma patients neurology neurodegenerative alzheimer activation of ADAM10 by epigallocatechin-3-gallate (EGCG), and promotion of non-amyloidogenic APP processing is warranted to support the use of this compound as a safe alternative to estrogen replacement therapy in the prevention and treatment of Alzheime cancer hemopathy   may be a useful strategy to enhance the response of mantle cell lymphoma to other therapeutic agents mental retardation fragile X   downregulation of ADAM10 activity at synapses may be an effective strategy for ameliorating Fragile X phenotypes neurology neurodegenerative alzheimer increasing ADAM10 activity is suggested as a therapy to prevent the production of the neurotoxic APP peptide in Alzheimer disease

ANIMAL & CELL MODELS

ADAM10-null mice display no obvious alteration of myelination