Fig. 2. A model of inside-out signalling from agonist to integrin. For integrins to become activated, they need to be triggered by the inside-out signalling cascade. The key target of this pathway is the GTPase Rap1. Agonist signalling leads to an increase in Ca²⁺ and DAG that activates the Rap1 GEF CalDAG-GEF1, which is a major Rap1 activator in haematopoietic cells. The relocalization of Rap1 to the membrane is regulated by the adaptor protein RIAM. A next step is the recruitment of talin to the β-subunit of the integrin, bringing about the conversion of integrin conformation to one of higher affinity. Kindlin-3 also binds to the β-subunit and aids talin binding.