Fig. 4. A speculative model for how Rap1 governs the functional activation of integrins. In resting blood cells, most integrins are kept inactive, possibly owing to conformational constraints in the cytoplasmic tails (bottom left). A small proportion of the integrin dimers display the thermodynamically unfavourable, active conformation and can bind their ligand (top left). However, if Rap1-GTP levels remain low, structural constraints (blue arrows) force the equilibrium towards the inactive form. Upon agonist stimulation, Rap1 is transiently converted to the active GTP-bound form (red arrows), exposing the effector-binding region(s), and one of its downstream targets (depicted in orange) directly or indirectly (through the yellow rod-shaped molecule) maintains the integrin in its active conformation. By contrast, Mn²⁺ treatment (grey arrow) does not activate Rap1, although endogenous levels of active Rap1 still control Mn²⁺-induced integrin activation. Rap1 activity is therefore required in all cases for ligand binding and outside-in signalling to take place, as suggested in this figure by the anchoring of the ligand-bound integrin to the actin cytoskeleton.