Annexins are a family of membrane- and calcium-binding proteins involved in several functions, including regulation of cell growth, cell division and apoptosis. The Annexin protein family is divided into five subclasses, named A through E for human and vertebrate, non-vertebrate metazoans, fungi and molds, plants and protists orthologs, respectively. Each subclass in turn comprises multiple protein members identified by numbers (1-11 and 13 in humans). The presence of Annexins in almost every species indicates that these proteins have are highly conserved. The existence of a variety of structurally homologous Annexin proteins also implies functional redundancy.
Annexins have two structural domains: a conserved carboxyl terminus and a variable amino-terminus. The carboxyl terminus core domain, made of four Annexin repeats, mediates the interaction with calcium and negatively charged phospholipids in the membranes. Together, the four Annexin repeats form a structure with a central hydrophilic hollow core that might be involved in voltage-dependent calcium channel activity. The short amino terminus contains the ligand interaction domain. The N-terminus ranges from a few up to 200 amino acids and shows very little homology. This low homology makes the N-terminus the essential part differentiating the family members. It is essential in several processes, including association with other proteins and overall structural stability.
Fig. 1 Structural domains of the Annexin protein.
Annexins are involved in a range of intra- and extra-cellular biological processes. Many of the Annexins functions are related to their membrane- and calcium-binding properties: calcium signaling, vesicle traffic, interaction with membrane scaffolds, ion channeling, membrane repair. Since the Annexin-membrane interaction is reversible, the Annexin functions can be modulated in response to different cellular stimuli. Besides their function on membranes, Annexins are also found in extracellular compartments, where they play a role in virus interaction, inflammation and anticoagulants. Each individual Annexin reacts in a unique way to a specific stimulus or set of stimuli, only under specific conditions.
ANXA2 is one of the most studied members of the ANXA protein family. ANXA2 is expressed in most tissues and in each tissue it can have different functions. ANXA2 has a wide variety of functions; most of them are associated with ANXA2’s ability to bind membranes. ANXA2 often interacts with S100A10 and forms a hetero-tetrameric complex with a very high affinity for calcium and membranes. There is evidence that ANXA2, in the vicinity of dynamic membranes, is involved in actin remodeling. Partially through this function, ANXA2 plays an important role in apicobasal polarity of epithelial cells. Cell polarity is fundamental for the architecture and function of epithelial tissues. Cell polarization is governed by the Epithelial Polarity Program (EPP), which adapts the cytoskeleton in polarized cells to sort and deliver membrane proteins to apical or basolateral membranes. ANXA2 is an integral component of the EPP. One of its key functions is to bind and recruit to the membrane CDC42, a master regulator of polarity. Indeed, ANXA2 knock down disrupts cell polarity and ultimately inhibits lumen formation, in a 3-dimensional model of epithelial morphogenesis.
In many epithelial cancers the EPP is altered. Consistently, alterations in ANXA2 levels have been found in many types of tumours. ANXA2 was found upregulated in colon cancer, pancreatic cancer, liver cancer, gliomas and renal carcinomas, while it seems downregulated in prostate cancer. In breast cancer, there is controversial evidence. In some breast cancer studies ANXA2 was found upregulated while in other studies it was downregulated. Recently, it was reported that Annexin A2 downregulation enhances EGFR signaling and metastasis formation. In conclusion, evidence from the literature indicates that interference with Annexin A2 levels may play an active role in tumorigenesis and cancer progression, likely by disrupting polarization programs, lumen formation and actin dynamics.
ANXA8 is one of the least studied proteins form the Annexin superfamily. ANXA8 was first described as an anti-coagulation factor. More recently, it was reported that ANXA8 has specific phospholipid and F-actin binding properties, suggesting a role in the organization of certain actin-associated membrane domains. In addition, depletion of ANXA8 reduces the association of late endosomal membranes with actin filaments, indicating a specific function in late endosome organization and function. ANXA8 is overexpressed in different types of cancers, including promyelocytic leukemia, pancreatic cancer and breast cancer. Gene ex