ADAMTS2, a member of the ADAMTS zinc metalloproteinase family, is widely recognized for its pivotal role as a procollagen I N-proteinase. This enzyme plays a crucial part in the maturation of fibrillar collagens, which are essential for maintaining the structural integrity of connective tissues. Beyond its traditional role, recent discoveries have revealed that ADAMTS2 is involved in a diverse range of biological processes that extend well beyond collagen maturation.
One of the most significant findings about ADAMTS2 is its association with the Ehlers-Danlos syndrome dermatosparaxis type (dEDS). This rare genetic disorder is marked by extreme skin fragility due to defective collagen processing. The loss of ADAMTS2 enzyme activity leads to the retention of N-propeptides in type I procollagen molecules, resulting in weakened and disorganized collagen fibrils. This discovery has shed light on the molecular basis of dEDS and has highlighted the critical role of ADAMTS2 in collagen homeostasis.
However, ADAMTS2's functions are not confined to collagen processing. The enzyme has emerged as a key player in angiogenesis, where it exhibits anti-angiogenic and anti-tumorigenic activities. By interacting with nucleolin on endothelial cell surfaces, ADAMTS2 can suppress cell proliferation, induce morphological changes, and promote anoikis-induced apoptosis. This anti-angiogenic function positions ADAMTS2 as a potential therapeutic target for controlling tumor growth and metastasis.
Furthermore, ADAMTS2 has been implicated in lymphangiogenesis through its ability to process pro-VEGFC into its active form, thereby promoting VEGFR3 signaling. This function highlights the enzyme's contribution to maintaining lymphatic homeostasis and its potential relevance in pathological conditions where lymphangiogenesis plays a role.
Intriguingly, ADAMTS2 also plays a role in neurodevelopment by modulating the activity of Reelin, a glycoprotein essential for neuronal migration and synaptic plasticity. In the central nervous system, ADAMTS2-mediated cleavage of Reelin can lead to impaired neuronal function, which is linked to neurodegenerative diseases such as Alzheimer's and schizophrenia. This suggests that ADAMTS2 may be a crucial factor in the pathophysiology of neuropsychiatric disorders.
ADAMTS2 also contributes to the regulation of the immune system. It influences the activity of several immune components, including immunoglobulins, complement proteins, and macrophage inhibitory factors. These interactions underscore the enzyme's potential role in immune modulation and inflammatory responses.
Research has also highlighted the involvement of ADAMTS2 in cardiovascular diseases, where it appears to modulate cardiac hypertrophy and heart failure through interactions with the PI3K/AKT signaling pathway. This regulatory capacity points to its cardioprotective role under conditions of cardiac stress.
The multifunctional nature of ADAMTS2 suggests its potential as both a biomarker and a therapeutic target in a range of diseases. As research continues to unravel the complexities of this enzyme's role, the potential to develop targeted therapies aimed at modulating ADAMTS2 activity offers promising prospects for treating conditions ranging from genetic disorders to cancer and cardiovascular diseases.
