PH motifs in PAR_1&2 endow breast cancer growth

Although emerging roles of protease-activated receptor_1&2 (PAR_1&2) in cancer are recognized, their underlying signalling events are poorly understood. Here we show signal-binding motifs in PAR_1&2 that are critical for breast cancer growth. This occurs via the association of the pleckstrin homology (PH) domain with Akt/PKB as a key signalling event of PARs. Other PH-domain signal-proteins such as Etk/Bmx and Vav₃ also associate with PAR₁ and PAR₂ through their PH domains. PAR₁ and PAR₂ bind with priority to Etk/Bmx. A point mutation in PAR₂, H349A, but not in R352A, abrogates PH-protein association and is sufficient to markedly reduce PAR₂-instigated breast tumour growth in vivo and placental extravillous trophoblast (EVT) invasion in vitro. Similarly, the PAR₁ mutant hPar1-7A, which is unable to bind the PH domain, reduces mammary tumours and EVT invasion, endowing these motifs with physiological significance and underscoring the importance of these previously unknown PAR₁ and PAR₂ PH-domain-binding motifs in both pathological and physiological invasion processes.