A Disintegrin And Metalloproteinase 9, commonly known as ADAM9, is an enzyme that resides on the surface of cells. It belongs to the ADAM family of membrane-anchored enzymes. ADAM9 participates in various cellular processes by modifying other proteins, playing a role in how cells interact with their environment and communicate.
Understanding ADAM9
ADAM9 is structured with several distinct regions that enable its diverse functions. It possesses a metalloprotease domain, which acts like molecular scissors, allowing it to cleave or “shed” other proteins from the cell surface. This shedding process releases the extracellular portions of membrane-bound molecules, including growth factors, cytokines, and receptors, into the surrounding environment. The protein also includes a disintegrin domain, which is involved in cell adhesion by interacting with other cell surface molecules like integrins.
Located primarily on cell membranes, ADAM9 is widely expressed across various human tissues, including the lung, colon, kidney, and nervous system. It is initially produced in an inactive form with a prodomain, which is later removed during transport to the cell membrane by enzymes like furin, activating the protein. There are also two isoforms of ADAM9, a full-length membrane-bound form (ADAM9-L) and a shorter, soluble form (ADAM9-S) which lacks transmembrane and cytoplasmic domains due to alternative splicing. Both forms contribute to its overall activity in the body.
ADAM9’s Role in Biological Processes
ADAM9 participates in biological functions supporting healthy tissue development and maintenance. Its ability to cleave proteins from cell surfaces, known as ectodomain shedding, influences various cellular signals. For instance, ADAM9 can shed growth factors, which stimulate cell growth, proliferation, and differentiation, modulating their availability to other cells. This action helps regulate the precise signaling needed for proper tissue formation and repair.
Beyond its shedding activity, ADAM9 plays a part in cell adhesion and migration, processes fundamental to development and wound healing. Through its disintegrin domain, ADAM9 interacts with integrins, which are cell surface receptors that connect cells to the extracellular matrix. This interaction can influence how cells attach to surfaces and move within tissues, a mechanism that is utilized in processes like the formation of multinucleated giant cells from monocytes and the migration of keratinocytes during skin repair.
The protein also influences signaling pathways by modifying receptors and other cell surface molecules. For example, it can affect the signaling of Ephrin receptor B4 (EphB4) and Epidermal Growth Factor (EGF), which are involved in cell-cell communication and growth regulation. Its involvement in various cell types and tissues helps maintain physiological balance.
ADAM9 and Disease Development
Dysregulation of ADAM9 activity, either too much or too little, can contribute significantly to the progression of various diseases. In certain types of cancer, ADAM9 is frequently found in elevated levels and is associated with increased tumor aggressiveness and poorer patient outcomes. Its metalloprotease activity can degrade components of the extracellular matrix, which is the network of molecules supporting cells, thereby facilitating tumor cell invasion and metastasis. ADAM9 also promotes cancer cell migration and contributes to tumor growth through mechanisms that involve both its proteolytic and non-proteolytic functions.
For instance, in prostate cancer, ADAM9 can cleave and release growth factors like Epidermal Growth Factor (EGF) and Fibroblast Growth Factor Receptor 2iiib (FGFR2iiib), which drive cancer progression. In lung cancer, ADAM9 overexpression promotes tumor cell adhesion to vascular endothelial cells, enhances cell migration, and increases resistance to cell death. Similarly, in gastric cancer, hypoxic stress can increase ADAM9 expression and activity, promoting tumor invasion and spread.
In neurodegenerative conditions like Alzheimer’s disease, ADAM9 has a complex and debated role related to amyloid-beta processing. Amyloid-beta peptides accumulate to form plaques in the brains of Alzheimer’s patients, and their formation involves the processing of a larger protein called amyloid precursor protein (APP). ADAM9 is considered an alpha-secretase, an enzyme that can cleave APP within the amyloid-beta domain, which theoretically prevents the formation of the problematic amyloid-beta peptides. However, ADAM9 can also cleave another alpha-secretase, ADAM10, and inhibiting ADAM9 might actually increase the membrane-bound ADAM10, leading to higher levels of soluble APP-alpha and reduced amyloid-beta levels.
ADAM9 as a Therapeutic Target
Given its involvement in various disease processes, ADAM9 has emerged as a potential target for new drug therapies. Researchers are interested in modulating its activity to intervene in disease progression, particularly in cancers where it is overexpressed. Inhibiting ADAM9’s proteolytic activity could potentially reduce tumor growth, invasion, and metastasis by preventing the shedding of pro-tumorigenic molecules and disrupting cell-matrix interactions. Preclinical studies have shown that ADAM9 inhibitors can decrease tumor cell proliferation and improve the effectiveness of certain chemotherapy agents.
Developing therapies that specifically target ADAM9 presents both opportunities and challenges. The goal is to design molecules that can either inhibit or, in some cases, enhance ADAM9’s function without causing widespread off-target effects due to its broad physiological roles. Researchers are exploring small molecule inhibitors that can selectively block ADAM9’s catalytic activity. Understanding the precise mechanisms by which ADAM9 contributes to specific diseases, as well as its interactions with other proteins, is crucial for developing safe and effective therapeutic strategies.