Figure 1. RANK/RANKL signalling in cancer cells: a very complex molecular network.

RANKL is a trimeric complex produced in a membrane or soluble form. Secreted RANKL can be produced from a specific transcript or by proteolysis of its membrane form. Trimeric RANKL interacts with a trimeric receptor named RANK and triggers a signalling cascade controlling the transcription of numerous effector genes. Additional protagonists intervene to regulate the binding of RANKL to RANK. In this way, OPG acts as a decoy receptor interacting with RANKL, and complex VIII (FVIII-vWF) showed a similar capacity. However, OPG is itself controlled by many ligands, including TRAIL, vWF and glycoaminoglycans (GAGs), and the final inhibitory effect of OPG on RANKL is dependent on its binding to these ligands. Very recently, it has been demonstrated that LGR4 is a new receptor for RANKL which can counterbalance the RANKL activities transmitted by RANK signalling.