The ADAM gene family: surface proteins with adhesion and protease activity

doi:10.1016/S0168-9525(99)01926-5

Trends in Genetics

Volume 16, Issue 2, 1 February 2000, Pages 83-87

https://doi.org/10.1016/S0168-9525(99)01926-5 Get rights and content

Abstract

An ADAM is a transmembrane protein that contains a disintegrin and metalloprotease domain and, therefore, it potentially has both cell adhesion and protease activities. Currently, the ADAM gene family has 29 members, although the function of most ADAM gene products is unknown. We discuss the ADAM gene products with known functions that act in a highly diverse set of biological processes, including fertilization, neurogenesis, myogenesis, embryonic TGF-α release and the inflammatory response.

Section snippets

Some ADAM proteases are sheddases

During development and in the adult, cells have the ability to modify their surface to regulate various kinds of functions. For example, the extracellular domain of >40 plasma membrane-anchored cytokines, growth factors, receptors, adhesion molecules and enzymes can be cleaved and thereby released (shed) from the plasma membrane by various proteases (called sheddases or secretases)¹⁸. These sheddases are themselves transmembrane proteins and, in several cases, are ADAMs.

One of the best-studied

ADAMTS

In 1999, several reports made it clear that the ADAM proteins with a thrombospondin motif (ADAMTS) represent an important class of proteases that are closely related to ADAMs (31, 32, 33, 34). The ADAMTS proteins for which biological functions have been characterized include gon-1 (involved in gonad formation), ADAMTS-4 (aggrecanase-1) and, the most recently described, ADAMTS-11 (aggrecanase-2). Metalloprotease activity of the gon-1 protein is required for achieving correct organ shape during

Adhesion role of ADAMs in fertilization

Among the 29 ADAMs, there is no basis for predicting how many will be active in cell adhesion because the required active-site residues in the disintegrin domain have not been defined as yet. The best studied ADAM that has adhesion activity is the sperm surface protein, fertilin, which is a heterodimer that contains two subunits, ADAM 1 and 2, also known as fertilin α and β (Fig. 3).

Interest in fertilin arose originally from the finding that an anti-fertilin β monoclonal antibody (mAb) blocks

Conclusions

In the last decade, we have gained many important insights into the ADAM protein family, yet it is easy to feel that there are many questions still to address. Even well-studied ADAMs are surrounded by unanswered questions that concern their regulation, signaling ability and function of each domain. As these many unknowns are analyzed, the area should remain active, dynamic and of broad biological significance.

Acknowledgements

This research was supported by NICHD grants U54-HD29125 and HD 16580.

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Is there a relationship between infertility and fertilin β protein distribution?
2022, Revista Internacional de Andrologia
Fertilin β is a sperm surface protein that can mediate sperm-egg membrane interaction. This study was conducted to determine whether the expression of fertilin β after intrauterine insemination (IUI) in donors with normal parameters after standard semen analysis is related to low success rate or failure of fertilization.
We examined the sperm of 30 male donors who have normal as controls, oligozoospermia, and unexplained infertility as the clinically indication for IUI. Fertilin β has been labeled with the ADAM2 antibody by indirect immunofluorescence (IF) assay. To evaluate the reproducibility of the test, we selected four sperm samples scale of 0 to +++ according to the distribution of fluorescence label.
The results were highly correlated with the corrected total cell fluorescence (CTCF) (R_p = 0.9972, P < 0.05). We suggest that the relationship between infertility and fertilin β may be due to the distribution of this protein on the sperm surface. Male partners of couples with unexplained infertility showed a low distribution of fertilin β by a decrease of the fluorescence signal in the IF labeling (scale of +++ by 7.4 ± 10.32%, P < 0.0001, ±SD).
Abnormal fertilin β function may be a potential mechanism that could lead to fertilization failure.
La fertilin β es una proteína de la superficie del esperma que puede mediar entre la interacción del espermatozoide y la membrana del óvulo. Este estudio se realizó para determinar si la expresión de fertilin β después de la inseminación intrauterina (IIU) en donantes con parámetros normales después del análisis estándar de semen está relacionada con una baja tasa de éxito o fracaso de la fertilización.
Examinamos los espermatozoides de 30 donantes masculinos que tenían controles normales, oligozoospermia e infertilidad inexplicable como indicación clínica de IIU. La fertilin β ha sido etiquetada con el anticuerpo ADAM2 mediante un ensayo de inmunofluorescencia indirecta (IF). Para evaluar la reproducibilidad de la prueba, seleccionamos cuatro muestras de esperma en una escala de 0 a +++ según la distribución de la etiqueta de fluorescencia.
Los resultados estuvieron altamente correlacionados con la fluorescencia celular total corregida (Rp = 0,9972, p < 0,05). Sugerimos que la relación entre la infertilidad y la fertilin β puede deberse a la distribución de esta proteína en la superficie del esperma. Los compañeros masculinos de parejas con infertilidad inexplicable mostraron una baja distribución de fertilin β por una disminución de la señal de fluorescencia en el etiquetado IF (escala de +++ en 7,4 ±10,32%, p < 0,0001, ±DE).
La función anormal de la fertilin β puede ser un mecanismo potencial que podría conducir al fracaso de la fertilización.
Inhibitory monoclonal antibody targeting ADAM17 expressed on cancer cells
2022, Translational Oncology
ADAM17 is upregulated in many cancers and in turn activates signaling pathways, including EGFR/ErbB, as well as those underlying resistance to targeted anti-EGFR therapies. Due to its central role in oncogenic pathways and drug resistance mechanisms, specific and efficacious monoclonal antibodies against ADAM17 could be useful for a broad patient population with solid tumors. Hence, we describe here an inhibitory anti-ADAM17 monoclonal antibody, named D8P1C1, that preferentially recognizes ADAM17 on cancer cells. D8P1C1 inhibits the catalytic activity of ADAM17 in a fluorescence-based peptide cleavage assay, as well as the proliferation of a range of cancer cell lines, including breast, ovarian, glioma, colon and the lung adenocarcinoma. In mouse models of triple-negative breast cancer and ovarian cancer, treatment with the mAb results in 78% and 45% tumor growth inhibition, respectively. Negative staining electron microscopy analysis of the ADAM17 ectodomain in complex with D8P1C1 reveals that the mAb binds the ADAM17 protease domain, consistent with its ability to inhibit the ADAM17 catalytic activity. Collectively, our results demonstrate the therapeutic potential of the D8P1C1 mAb to treat solid tumors.
ADAMs family in kidney physiology and pathology
2021, EBioMedicine
A disintegrin and metalloproteinases (ADAMs) family are proteolytic transmembrane proteases that modulate diverse cell functions and coordinate intercellular communication. ADAMs are responsible for regulating cell proliferation, differentiation, migration, and organ morphogenesis in kidney development. Abnormally activated ADAMs drive inflammation and fibrosis in response to kidney diseases such as acute kidney injury, diabetic kidney disease, polycystic kidney disease, and chronic allograft nephropathy. ADAM10 and ADAM17, known as the most characterized members of ADAMs, are extensively investigated in kidney diseases. Notably, ADAM proteases have the potential to be targets for developing novel treatment approaches in kidney diseases.
Sperm morphology and its disorders in the context of infertility
2021, F and S Reviews
Citation Excerpt :
This is followed by zona penetration and fusion with the oolemma, followed by egg penetration. The interaction of sperm and the zona pellucida, and sperm and the oolemma, are intrinsically related to specific receptor-ligand interactions located at the zona pellucida and the plasma membranes of the male and female gametes (23–31). A brief analysis of the relationships between mature sperm morphology and functional capacities depicts a high degree of cellular compartmentalization.
This manuscript reviews sperm morphology and its disorders in the context of infertility. A new look into an old challenge is delivered, based on contemporary scientific and clinical evidence. We highlight the functional repercussions of sperm morphology aberrations and dissect the cause and effect of a variety of insults and pathogenic mechanisms focusing on the relationships among sperm shape, function, and compartmental analysis of cellular and subcellular structures. Different types of teratozoospermia are identified as a sequela of aberrant spermiogenesis, and their proven or speculated origins are discussed. In addition to known and suspected genetic causes, oxidative damage is highlighted as a major plausible pathogenic factor. The examination of sperm morphology with the use of strict criteria provides valuable information to guide the clinician to direct therapeutic management. We emphasize that sperm morphology is probably the most relevant parameter of the traditional semen evaluation and can be used as a valid biomarker of functional deficiencies, providing information about chances of conception. The information provided by the examination of sperm morphology as part of a complete semen analysis becomes more and more significant from a clinical point of view for infertility and perhaps men’s health.
The evolution of ADAM gene family in eukaryotes
2020, Genomics
The ADAM (A Disintegrin And Metalloprotease) gene family encodes proteins with adhesion and proteolytic functions. ADAM proteins are associated with diseases like cancers. Twenty ADAM genes have been identified in humans. However, little is known about the evolution of the family. We analyzed the repertoire of ADAM genes in a vast number of eukaryotic genomes to clarify the main gene copy number expansions. For the first time, we provide compelling evidence that early-branching green algae (Mamiellophyceae) have ADAM genes, suggesting that they originated in the last common ancestor of eukaryotes, before the split of plants, fungi and animals. The ADAM family expanded in early metazoans, with the most significative gene expansion happening during the first steps of vertebrate evolution. We concluded that most of mammal ADAM diversity can be explained by gene duplications in early bone fish. Our data suggest that ADAM genes were lost early in green plant evolution.
ADAM proteases: Emerging role and targeting of the non-catalytic domains
2019, Cancer Letters
Citation Excerpt :
It is known that ADAM-mediated cleavage is essential for G-protein-coupled [20,21] or stress-induced [22] EGF receptor transactivation, and it is modulated by intracellular signaling in response to growth factors, phorbol esters, and changes in tyrosine kinase activity [8]. Interestingly, while ADAM family members harbor cytoplasmic protein-docking motifs [8], cytoplasmically-truncated ADAM10 and ADAM17 are fully functional [23], suggesting only a minor role for the cytoplasmic domains in controlling downstream signaling. ADAM17 is suggested to be regulated by cysteine oxidation that modulates the conformation of its extracellular domain [24,25].
ADAM proteases are multi domain transmembrane metalloproteases that cleave a range of cell surface proteins and activate signaling pathways implicated in tumor progression, including those mediated by Notch, EFGR, and the Eph receptors. Consequently, they have emerged as key therapeutic targets in the efforts to inhibit tumor initiation and progression. To that end, two main approaches have been taken to develop ADAM antagonists: (i) small molecule inhibitors, and (ii) monoclonal antibodies. In this mini-review we describe the distinct features of ADAM proteases, particularly of ADAM10 and ADAM17, their domain organization, conformational rearrangements, regulation, as well as their emerging importance as therapeutic targets in cancer. Further, we highlight an anti-ADAM10 monoclonal antibody that we have recently developed, which has shown significant promise in inhibiting Notch signaling and deterring growth of solid tumors in pre-clinical settings.

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Trends in Genetics

ReviewThe ADAM gene family: surface proteins with adhesion and protease activity

Abstract

Section snippets

Some ADAM proteases are sheddases

ADAMTS

Adhesion role of ADAMs in fertilization

Conclusions

Acknowledgements

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Am. J. Pathol.

Trends Cell Biol.

Cell

Adv. Dev. Biochem.

Curr. Opin. Cell Biol.

J. Biol. Chem.

Cell

J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

Dev. Biol.

J. Biol. Chem.

Cell

Chem. Biol.

Dev. Biol.

A potential fusion peptide and an integrin ligand domain in a protein active in sperm–egg fusion

Nature

Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha

Nature

Fertilization defects in sperm from mice lacking fertilin beta

Science

A role for the disintegrin domain of cyritestin, a sperm surface protein belonging to the ADAM family, in mouse sperm–egg plasma membrane adhesion and fusion

J. Cell. Biol.

Review
The ADAM gene family: surface proteins with adhesion and protease activity