SFKs in GPVI-FcR γ-chain proximal signaling. (A) The SFKs Lyn and Fyn constitutively associate with the proline-rich juxtamembrane region of GPVI via their SH3 domains. This interaction unclamps and activates the SFKs. The receptor-like PTP CD148 maintains the SFKs in an activated state by dephosphorylating their C-terminal inhibitory tyrosine residues. Collagen-mediated clustering of the receptor induces trans-autophosphorylation of the activation loop tyrosine residue and maximal SFK activation. SFKs phosphorylate tandem tyrosine residues in the ITAM-containing FcR γ-chain, which provides a high-affinity docking site for the tandem SH2 domain–containing protein-tyrosine kinase Syk. SFKs also phosphorylate and active Syk. SFKs and Syk phosphorylate downstream effectors and propagate the signal. (B) The ITIM/ITSM-containing inhibitory receptors PECAM-1 and G6b-B inhibit GPVI-FcR γ-chain signaling. Lyn phosphorylates tandem tyrosine residues in the ITIM/ITSM in the cytoplasmic tails of PECAM-1 and G6b-B that provides a high-affinity binding site for the SH2 domain–containing nontransmembrane PTPs Shp1 and Shp2. Lyn associated with the cytoplasmic tail of PECAM-1 facilitates phosphorylation. Lyn also phosphorylates and activates SH2 domain–containing SHIP-1 and PKCδ that form a complex and inhibit dense granule secretion.