Figure 1.

Direct and indirect effects of thrombospondin-1 (TSP1) on CD47 signaling. TSP1 is secreted under stress conditions and binds with high affinity to CD47, which is expressed on all cells. TSP1 binding induces CD47 signaling that alters cell metabolism, gene expression, and responses to stress. CD47 also interacts with signal regulatory protein-α (SIRPα) on different cells (trans interaction) and induces SIRPα signaling by altering the activity of phosphatases SHP1 and SHP2. Functional cis interactions between CD47 and SIRPα on the surface of a single cell have been reported but require further verification. TSP1 can also prevent cis and trans SIRPα signaling by inhibiting its binding to CD47. Conversely, therapeutic agents that target CD47 or SIRPα may also alter TSP1 interactions with CD47 to alter metabolism of glucose, fatty acids, and reactive oxygen species (ROS).