Translational implications of targeting annexin A2: From membrane repair to muscular dystrophy, cardiovascular disease and cancer

Abstract

Annexin A2 (A2) contributes to several key cellular functions and processes, including membrane repair. Effective repair prevents cell death and degeneration, especially in skeletal or cardiac muscle, epithelia, and endothelial cells. To maintain cell integrity after damage, mammalian cells activate multiple membrane repair mechanisms. One protein family that facilitates membrane repair processes are the Ca²⁺-regulated phospholipid-binding annexins. Annexin A2 facilitates repair in association with S100A10 and related S100 proteins by forming a plug and linking repair to other physiologic functions. Deficiency of annexin A2 enhances cellular degeneration, exacerbating muscular dystrophy and degeneration. Downstream of repair, annexin A2 links membrane with the cytoskeleton, calcium-dependent endocytosis, exocytosis, cell proliferation, transcription, and apoptosis to extracellular roles, including vascular fibrinolysis, and angiogenesis. These roles regulate cardiovascular disease progression. Finally, annexin A2 protects cancer cells from membrane damage due to immune cells or chemotherapy. Since these functions are regulated by post-translational modifications, they represent a therapeutic target for reducing the negative consequences of annexin A2 expression. Thus, connecting the roles of annexin A2 in repair to its other physiologic functions represents a new translational approach to treating muscular dystrophy and cardiovascular diseases without enhancing its pro-tumorigenic activities.

Keywords: annexin; cancer; cardiovascular disease; membrane repair; muscular dystrophy.

Figure 1.. Annexin A2 promotes membrane repair.

During membrane perforation, annexin A2 senses Ca²⁺ flux. Annexin A2-S100A10 tetramers can be recruited to the membrane. Once recruited, annexin A2 tetramers complex with actin and facilitate recruitment of other repairs proteins, such as annexins (A1, A4, A5 or A6), and dysferlin to promote physical blockade of the pore by proteins (clogging), internal vesicles (patch repair), or sequestration and shedding of the damaged membrane (microvesicular shedding) using lipid and/or ESCRT-III mediated mechanisms. The figure was created using BioRender.

Figure 2.. Annexin A2 protects organisms from muscular dystrophy and cardiovascular diseases.

(1a or 1b) Upon membrane injury and Ca²⁺ influx, (2a and 2b) intracellular annexin A2 binds and stabilizes S100A10 to form annexin A2/S100A10 tetramers (A2tet) via Ser1 acetylation. A2tet facilitates repair in (3a) skeletal and (3b) cardiac muscles. Two alternative pathways may occur, described for peripheral muscles or cardiomyocytes. (4a) In muscle cells, extracellular annexin A2 can activate TLR4 signaling to trigger inflammation by via pro-inflammatory cytokines. Active TLR4 activates protein kinase C (PKC). (5a) Activated PKC phosphorylates annexin A2 at Ser25, exposing Ser11 to phosphorylation. Ser11 is phosphorylated by cyclic AMP/protein kinase A (cAMP/PKA) or calcium/calmodulin-dependent protein kinase (CaMK). Ser11/Ser25 phosphorylation dissociates intracellular A2tet, allowing (6a) ubiquitination of S100A10 and/or (7a) SUMOylation of annexin A2. These post-translational modifications target S100A10 for degradation, and reduce annexin A2 function. (4b) Another intracellular pathway occurs from Src activation. (5b) Activated Src can phosphorylate annexin A2 at Tyr23 and release A2tet into the extracellular matrix. (6b) A2tet then binds to tPA and plasminogen, generating plasmin, leading to vascular fibrinolysis and angiogenesis. These functions promote cardiovascular health, while mineralization of arteries is detrimental to cardiovascular health. The figure was created using BioRender.

Figure 3.. Annexin A2 promotes cancer.

Overexpression of annexin A2 confers resistance to membrane stress caused by pore forming toxins, radiation, and reactive oxidative species by phosphorylating annexin A2. Phosphorylation of annexin A2 by a tyrosine kinase may allow for recruitment to the membrane for repair. This enables annexin A2 to detoxify oxidative damage and prevent chemotoxic agent penetration into the cancer cell. Annexin A2 further promotes survival in cancer cells by neutralizing p53, blocking the p53-dependent arrest of the cell cycle at stage G2. This permits rapid division, proliferation and failure of apoptosis in cancer cells. Finally, elevated extracellular annexin A2 cleaves plasminogen, promotes extracellular matrix degradation, giving cancer cells both blood supply and escape from the primary tumor. These functions promote tumor metastasis. The figure was created using BioRender.

Figure 4.. Annexin A2 connects repair to many downstream signaling pathways.

Annexin A2 is a key membrane repair protein that works with S100A10 and other S100 proteins to execute its membrane repair and extracellular roles. Annexin A2 is a therapeutic target because loss of annexin A2 function enhances cellular degeneration, which exacerbates muscular dystrophy and cardiovascular disease. Annexin A2-mediated protection is hijacked by cancer cells to enhance survival and metastasis. The figure was created using BioRender.