ADAM10

Official Full Name

ADAM metallopeptidase domain 10

Organism

Homo sapiens

GeneID

102

Background

Members of the ADAM family are cell surface proteins with a unique structure possessing both potential adhesion and protease domains. This gene encodes and ADAM family member that cleaves many proteins including TNF-alpha and E-cadherin. Alternate splicing results in multiple transcript variants encoding different proteins that may undergo similar processing. [provided by RefSeq, Feb 2016]

Synonyms

RAK; kuz; AD10; AD18; MADM; CD156c; CDw156; HsT18717;

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Detailed Information

ADAM10, a member of the disintegrin and metalloprotease (ADAM) family, was isolated and purified from the brain myelin of cattle. It was called mammalian integrin metalloprotein, and it was later found to be Cytoplasmic myelin alkaline protease.

ADAM10 belongs to the zinc protease family and is a 750 amino acid type I integrated transmembrane protein composed of multiple functional domains, including prodomain, metalloproteinase domain, de-integration domain, cysteine-rich region, epidermal growth factor like domain, transmembrane domain, and cytoplasmic tail. After excision of the signal sequence, the process by which ADAM10 is activated by two precursor protein invertases, Flyin or Proprotein convertase (PC) 7. This process is called prodomain structural processing.

ADAM10 Figure 1. ADAM10 involvement in Alzheimer disease. (Saftig, et al. 2015)

ADAM10 and Alzheimer's Disease (AD)

The metalloproteinase domain of ADAM10 contains a typical zinc-binding co-recognition motif (HEXGHXXGXXHD). After introducing a point mutation (E384A) in this motif, it was found that APPsα secretion was significantly reduced in HEK cells and mice.

Subsequent studies showed that ADAM10 was expressed in both human brain and peripheral tissues; whereas in ADK293 cells overexpressing ADAM10 cDNA, ADAM10 was first confirmed to have APP-cleaving alpha-secretase activity. Postina et al. crossed Alzheimer disease (AD) mice with ADAM10 transgenic mice and found that the amyloid plaques in the brain of mice were significantly reduced, while the soluble fragment APPsα produced by α-secretase cleavage amyloid precursor protein (APP) increased, and the learning and memory ability of hybrid mice increased. In contrast, ADAM10 mutant mice had reduced APPsα, increased amyloid plaques, and reduced learning ability. The above results indicate that ADAM10 is a functional secretase that inhibits the formation of amyloid plaques by processing APP.

Current studies have shown that activation or overexpression of ADAM10 in the brain is helpful in the treatment of neurodegenerative diseases, especially AD. Studies have found that ADAM10 can significantly improve the emotional activity and exercise capacity of AD mice, reducing learning and cognitive impairment; while ADAM10 overexpressing mice have increased cortical synapse formation. Another study showed that ADAM10 overexpression reduced the symptoms of long-term augmentation disorders in AD model mice and enhanced its learning and memory ability.

Studies have shown that inhibition of ADAM10 expression in mouse neural progenitor cells can lead to perinatal fatal injury, as well as abnormalities in the notch signaling pathway, resulting in immature neuronal differentiation and leading to destruction of the mouse cortex. This suggests that ADAM10 plays an important role in the formation of the cerebral cortex. Notch is a cell surface receptor involved in cell differentiation and is essential for cell growth and development. Studies have shown that ADAM10 plays an important role in the development of B cells by activating the notch signaling pathway.

ADAM10 and Diabetic Encephalopathy (DE)

Diabetic encephalopathy (DE) is a central nervous system damage caused by diabetes and can cause cognitive dysfunction. AD-like changes such as Aβ aggregation caused by DE may be the mechanism for the development of DE.

ADAM10 mediates synaptic development and is closely related to the morphology of synapses. ADAM10 participates in the regulation of cognitive function through regulation of synapses. ADAM10 controls different exfoliated cell adhesion molecules (CAMS) at the postsynaptic site to promote synaptic development and progression. The soluble fragment sAPPα produced by ADAM10 cleavage APP can also participate in synapse formation. In ADAM10 knockout neurons, N-Cadherin and neuroligin-1 are impaired and Aβ produces a large number of damaging synapses, producing short, thick spinous processes that degrade synaptic function and causing cognitive decline. Therefore, how to enhance the hydrolysis activity of ADAM10 in the body, let ADAM10 cleave more APP and produce more sAPPα, and inhibit the formation of amyloid plaque, has become a new direction of research DE.

ADAM10 and Cancer

ADAM10 is overexpressed in oral squamous cell carcinoma and gastric cancer, and antisense oligonucleotides or anti-ADAM10 antibodies reduce its overexpression in cancer cells. It has been reported that ADAM10-mediated human papillomavirus L1 protein can increase cell invasion and metastasis of uterine and ovarian tumors. Human papillomavirus L1 protein also has invasion and metastasis activity in lymphoma, lung cancer and melanoma, and ADAM10 appears to be a major factor in the release of human papillomavirus L1 protein in these tumors. ADAM10 is also expressed in prostate cancer and leukemia.

Abdominal aortic aneurysm (AAA) is a degenerative disease characterized by destruction of the abdominal aortic wall structure and progressive expansion into a pulsatile mass. The study found that ADAM10 can catalyze the release of TNF-α, a key enzyme that promotes chronic inflammation. Not only that, ADAM10 can activate IL-6R, chemokine-like ligand 1 (CX3CL1), CXCL16, VEGFR2, E-cadherin and other membrane-protein molecules that are widely expressed on the surface of vascular system cells participate in the inflammatory response of the arterial wall, and chronic inflammation is exactly one of the important mechanisms of AAA formation.

In addition, ADAM10 is able to separate components between the extracellular matrix and the cell wall, such as collagen IV and colloid, thereby degrading the extracellular matrix component. Studies have shown that ADAM10 may also act on several other extracellular matrix proteins such as cadherin and collagen XVII. The ADAM10 found in human AAA tissue membrane microvesicles has the function of hydrolyzing proteins, which also confirms its involvement in the pathogenesis of AAA.

References:

Saftig, P., & Lichtenthaler, S. F. (2015). The alpha secretase adam10: a metalloprotease with multiple functions in the brain. Progress in Neurobiology, 135, 1-20.
Vincent B. (2016). Regulation of the α-secretase adam10 at transcriptional, translational and post-translational levels. Brain Research Bulletin, 126(Pt 2), 154.
Prox, J., Bernreuther, C., Altmeppen, H., Grendel, J., Glatzel, M., & D'Hooge, R., et al. (2013). Postnatal disruption of the disintegrin/metalloproteinase adam10 in brain causes epileptic seizures, learning deficits, altered spine morphology, and defective synaptic functions. Journal of Neuroscience, 33(32), 12915-12928.
Folkesson, M., Li, C., Frebelius, S., Swedenborg, J., Wågsäter, D., & Williams, K. J., et al. (2015). Proteolytically active adam10 and adam17 carried on membrane microvesicles in human abdominal aortic aneurysms. Thrombosis & Haemostasis, 114(6), 1165-74.

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