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 Vav(3) also associate with PAR(1) and PAR(2) through their PH domains. PAR(1) and PAR(2) bind with priority to Etk/Bmx. A point mutation in PAR(2), H349A, but not in R352A, abrogates PH-protein association and is sufficient to markedly reduce PAR(2)-instigated breast tumour growth in vivo and placental extravillous trophoblast (EVT) invasion in vitro. Similarly, the PAR(1) 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 PAR(1) and PAR(2) PH-domain-binding motifs in both pathological and physiological invasion processes.