Scheme for PEAR1 signaling pathway. In resting platelets, low amounts of PEAR1 are found on the platelet surface. During platelet activation with various platelet agonists, the expression of both PEAR1 and its ligand increase at the surface. Interactions between PEAR1 and its ligand on adjacent platelets induces formation of a complex comprising at least 2 PEAR1 receptors. Dimeric (or oligomeric) PEAR1 complexes are rapidly tyrosine-phosphorylated in a SFK-dependent manner (inhibited by the SFK inhibitor PP1), transiently recruiting additional c-Src and Fyn. PEAR1-P avidly binds p85 PI3K, leading to strong and sustained activation of Akt at Ser⁴⁷³ (inhibited by the PI3K inhibitor LY294002 and by PP1). PI3K activation amplifies αIIbβ3 activation, sustaining platelet aggregation. Because c-Src is already strongly bound to PEAR1 in resting platelets, c-Src may be the SFK rapidly activated and responsible for PEAR1 phosphorylation, on ligand binding, but this was not formally shown. (Fg, fibrinogen; Y, tyrosine; P, phosphorylation). The EMI domain in PEAR1 is depicted in black.