The Biochemistry and Regulation of S100A10: A Multifunctional Plasminogen Receptor Involved in Oncogenesis

Figure 5

Regulation of the expression of extracellular S100A10. Many physiological agents (EGF, interferon-γ, transforming growth factor-α) and pathophysiological agents (PML-RARα and KRas oncogenes) stimulate the upregulation of S100A10 protein levels. Annexin A2 is thought to play two important roles in the export of S100A10. First, the association of annexin A2 with S100A10 protects S100A10 from ubiquitin-mediated proteasomal degradation as S100A10 is rapidly degraded in the absence of annexin A2. Secondly, the binding of annexin A2 with S100A10 is thought to promote the capture of the complex by the exosomes. Exosomes are small vesicles, approximately 30–100 nM in diameter, that are formed by the inward budding of large intracellular compartments called multivesicular endosomes (MVE). Proteins and RNA that are present in the cytoplasm are trapped within the lumen of the exosomes during this inward budding process and proteins that associate with the MVE lumenal membrane during MVE budding are localized to the outer surface of the exosomes. The exosomes, sequestered as intact vesicles within the MVE, are released from cells when the membrane of the MVE fuses with the plasma membrane. The association of annexin A2 with exosomes has been reported but it is unclear at this time if the S100A10/annexin A2 complex is present on the surface or in the lumen of the exosomes. In our speculative model, we show that S100A10 protein that is synthesized in response to oncogenic agents such as oncogenic Ras or the PML-RAR oncogene forms a complex with annexin A2. The S100A10/annexin A2 complex is then sequestered with the lumen of the exosomes during the inward budding of the MVE (A). These MVEs fuse with the plasma membrane resulting in the release of the exosomes into the extracellular space. These exosomes rupture and release the S100A10/annexin A2 complex from their lumen which then allows the association of the complex with the plasma membrane. Alternately, the S100A10/annexin A2 complex may be present on the lumenal surface of the MVE (B). The inward budding of the MVE results in the association of the S100A10/annexin A2 complex with the outer surface of the newly formed exosomes. The exosomes released by the fusion of the MVE with the plasma membrane fuse with the plasma membrane resulting in the incorporation of the S100A10/annexin A2 complex at the plasma membrane.