title: PH motifs in PAR1&2 endow breast cancer growth.
abstract: Although emerging roles of protease-activated receptor1&2 (PAR1&2) in cancer are recognized, their underlying signalling events are poorly understood. Here we show signal-binding motifs in PAR1&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.
authors.affiliation: Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center Jerusalem, Jerusalem 91120, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Kancharla
authors.affiliation: Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center Jerusalem, Jerusalem 91120, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Maoz
authors.affiliation: Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center Jerusalem, Jerusalem 91120, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Jaber
authors.affiliation: Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center Jerusalem, Jerusalem 91120, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Agranovich
authors.affiliation: Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center Jerusalem, Jerusalem 91120, Israel.
authors.forename: T
authors.initials: T
authors.lastname: Peretz
authors.affiliation: Department of Obstetrics and Gynecology, Hebrew-University, Shaare Zedek Jerusalem 91031, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Grisaru-Granovsky
authors.affiliation: Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center Jerusalem, Jerusalem 91120, Israel.
authors.forename: B
authors.initials: B
authors.lastname: Uziely
authors.affiliation: Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center Jerusalem, Jerusalem 91120, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Bar-Shavit
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D055786:Gene Knockout Techniques; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D061986:MCF-7 Cells; D008321:Mammary Glands, Animal / Q000473:pathology; D009154:Mutation; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010920:Placenta / Q000378:metabolism* / Q000502:physiology; D011247:Pregnancy; D017434:Protein Structure, Tertiary; D044463:Receptor, PAR-1 / Q000235:genetics* / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000235:genetics* / Q000378:metabolism; D014327:Trophoblasts / Q000378:metabolism* / Q000502:physiology
chemical_list: D044463:Receptor, PAR-1; D044464:Receptor, PAR-2