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ANXA6
ANXA6 Full Name
annexin A6
ANXA6 Introduction
Annexin A6 (ANXA6) is a member of the annexin family, a group of proteins characterized by their calcium ion-dependent phospholipid-binding capacity. Structurally, ANXA6 stands out as one of the most unique members of the family, composed of two repetitive core domains—each containing four characteristic annexin repeats—which endow it with complex regulatory functions. Its core molecular role is to act as an intracellular calcium sensor and scaffold protein. When intracellular calcium levels rise due to cellular stimulation or injury, ANXA6 rapidly translocates from the cytoplasm to bind to the plasma membrane or intracellular vesicle membranes, initiating or modulating downstream events. As a scaffold, ANXA6 organizes specific membrane compartments and interacts with various proteins—such as EGFR, Ras, and PKCα—and lipids, thereby regulating cholesterol homeostasis, cytoskeletal rearrangement, and signaling pathways. Experimental evidence indicates that ANXA6 directly modulates calcium influx; its stable expression at the plasma membrane can attenuate store-operated calcium entry, subsequently influencing processes such as cell proliferation.
Figure 1. Annexin A6 protein structure. (Source: Enrich C, et al. 2011)
Leveraging its calcium-dependent membrane-binding properties, ANXA6 plays vital roles in several key cellular processes, particularly in plasma membrane repair and vesicular trafficking. Upon membrane injury, local transient calcium influx recruits ANXA6 to the damaged site. Research shows that, in the presence of calcium, ANXA6 is recruited to multivesicular bodies (MVBs) and anchors them near the plasma membrane, facilitating their fusion. This process not only releases contents via exosomes but, more critically, acts as a "patch" that repairs the damaged membrane, preserving cellular integrity. Consequently, loss of ANXA6 significantly impairs the cell's membrane repair capacity. Additionally, ANXA6 is broadly involved in intracellular trafficking, endocytosis, exocytosis, and the regulation of lipid metabolism. For instance, it contributes to fatty acid-induced lipid droplet formation and mitochondrial morphogenesis, and helps maintain cellular cholesterol homeostasis. Through interactions with diverse signaling proteins, ANXA6 influences cell migration, invasion, and adhesion—functions central to its physiological and pathological roles.
Dysregulation of ANXA6 is closely linked to the development of various human diseases, especially cancer, cardiovascular disorders, and metabolic syndromes, where its functions exhibit high complexity and context dependence. In oncology, ANXA6 acts as a "double-edged sword." In head and neck squamous cell carcinoma (HNSCC), its upregulation is significantly associated with lymph node metastasis and poor prognosis, potentially mediated by the induction of autophagy that promotes cancer cell survival and migration. Conversely, in triple-negative breast cancer (TNBC), ANXA6 appears to function as a tumor suppressor, with low expression linked to tumor progression. This duality underscores that the role of ANXA6 is highly dependent on cancer type and microenvironment. In metabolic diseases, ANXA6 has been shown to be highly enriched in monocytes of individuals with obesity and type 2 diabetes. It also participates in pathological processes involving mineralization, such as osteoporosis and osteoarthritis.
Alternate Names for ANXA6
ANXA6; annexin A6; ANX6; CBP68; p68; p70; CPB-II; annexin-6; calelectrin; lipocortin VI; calphobindin II; calphobindin-II; chromobindin-20; annexin VI (p68); 67 kDa calelectrin; calcium-binding protein p68;
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