Proposed contact-dependent role of Sema4D in GPVI signaling. (1) Based on work by others, clustering of GPVI leads to Src family kinase (SFK)–mediated phosphorylation of FcRγ resulting in the recruitment and (2) subsequent phosphorylation of Syk. Subsequent signaling through phospholipase Cγ leads to integrin activation and (3) the formation of stable, integrin-dependent contacts between platelets. (4) The data presented here suggest that this allows Sema4D to engage in trans with its receptors, amplifying Syk activation. It also allows outside-in signaling by the integrin to promote Syk phosphorylation, in part by increasing FcRγ phosphorylation (5).