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Here we show signal-binding motifs in PAR<jats:sub>1&amp;2<\/jats:sub> 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<jats:sub>3<\/jats:sub> also associate with PAR<jats:sub>1<\/jats:sub> and PAR<jats:sub>2<\/jats:sub> through their PH domains. PAR<jats:sub>1<\/jats:sub> and PAR<jats:sub>2<\/jats:sub> bind with priority to Etk\/Bmx. A point mutation in PAR<jats:sub>2<\/jats:sub>, H349A, but not in R352A, abrogates PH-protein association and is sufficient to markedly reduce PAR<jats:sub>2<\/jats:sub>-instigated breast tumour growth <jats:italic>in vivo<\/jats:italic> and placental extravillous trophoblast (EVT) invasion <jats:italic>in vitro<\/jats:italic>. Similarly, the PAR<jats:sub>1<\/jats:sub> mutant <jats:italic>hPar1-7A,<\/jats:italic> 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<jats:sub>1<\/jats:sub> and PAR<jats:sub>2<\/jats:sub> PH-domain-binding motifs in both pathological and physiological invasion processes.<\/jats:p>","DOI":"10.1038\/ncomms9853","type":"journal-article","created":{"date-parts":[[2015,11,24]],"date-time":"2015-11-24T10:03:20Z","timestamp":1448359400000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["PH motifs in PAR1&amp;2 endow breast cancer growth"],"prefix":"10.1038","volume":"6","author":[{"given":"A.","family":"Kancharla","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Maoz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Jaber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D.","family":"Agranovich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"Peretz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Grisaru-Granovsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Uziely","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Bar-Shavit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,11,24]]},"reference":[{"key":"BFncomms9853_CR1","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1038\/nrc2069","volume":"7","author":"RT Dorsam","year":"2007","unstructured":"Dorsam, R. 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