The ANXA2/S100A10 Complex—Regulation of the Oncogenic Plasminogen Receptor

Abstract

The generation of the serine protease plasmin is initiated by the binding of its zymogenic precursor, plasminogen, to cell surface receptors. The proteolytic activity of plasmin, generated at the cell surface, plays a crucial role in several physiological processes, including fibrinolysis, angiogenesis, wound healing, and the invasion of cells through both the basement membrane and extracellular matrix. The seminal observation by Albert Fischer that cancer cells, but not normal cells in culture, produce large amounts of plasmin formed the basis of current-day observations that plasmin generation can be hijacked by cancer cells to allow tumor development, progression, and metastasis. Thus, the cell surface plasminogen-binding receptor proteins are critical to generating plasmin proteolytic activity at the cell surface. This review focuses on one of the twelve well-described plasminogen receptors, S100A10, which, when in complex with its regulatory partner, annexin A2 (ANXA2), forms the ANXA2/S100A10 heterotetrameric complex referred to as AIIt. We present the theme that AIIt is the quintessential cellular plasminogen receptor since it regulates the formation and the destruction of plasmin. We also introduce the term oncogenic plasminogen receptor to define those plasminogen receptors directly activated during cancer progression. We then discuss the research establishing AIIt as an oncogenic plasminogen receptor-regulated during EMT and activated by oncogenes such as SRC, RAS, HIF1α, and PML-RAR and epigenetically by DNA methylation. We further discuss the evidence derived from animal models supporting the role of S100A10 in tumor progression and oncogenesis. Lastly, we describe the potential of S100A10 as a biomarker for cancer diagnosis and prognosis.

The invasion phenotypes of glioblastoma depend on plastic and reprogrammable cell states

“…In epithelial cancers, epithelial-to-mesenchymal transition (EMT) has been linked to growth along blood vessels [48]. In accordance, we found intriguing overlaps between previously described regulators of EMT and genes detected in ANXA1-positive cells, including TCF4 [45, 46], and S100A10 [49]. Future research endeavors include delineating regulatory dependencies and exploring the efficacy of targeting ANXA1 with small peptides [50] or exploiting it as a surface antigen for perivascular invading GBM cells.…”

S100A10 Promotes Pancreatic Ductal Adenocarcinoma Cells Proliferation, Migration and Adhesion through JNK/LAMB3-LAMC2 Axis

“…S100A10 has been reported to promote tumor progression and metastasis by regulating multiple signaling pathways related to cell migration, invasion, metastasis, and angiogenesis [22]. S100A10 is known for its role in interacting with ANXA2 to form the ANXA2/S100A10 heterotetrameric complex (AIIt), which is identified as one of the oncogenic plasminogen receptors [23]. The activation of plasminogen by AIIt not only activates pro-matrix metalloproteinases (pro-MMPs) but also induces the angiogenesis of cancer stroma via ECM-associated proangiogenic growth factors, which both play an important role in the invasion and metastasis of cancer [7].…”

Pseudorabies Virus Regulates the Extracellular Translocation of Annexin A2 To Promote Its Proliferation

“…Previous studies have shown that phosphorylation at Tyr23 of ANXA2 is important for its extracellular translocation, and ANXA2 is a substrate of Src kinase ( 34 , 35 ). Therefore, we next wanted to know whether PRV infection can modify the phosphorylation of ANXA2 and Src kinase activity.…”