G-Protein Coupled Receptors; GPCRs in Epithelial Cancers and Novel Targeted PH-Domain Dinding Motifs

Despite the fact that GPCRs emerge as oncogenes that regulate cancer-associated signaling networks, their role in tumor biology is not well understood. Indeed, several cancer “driver” GPCR-genes are becoming now recognized as playing a central role in tumor biology. Among these are protease-activated receptors; PARs, members of chemokine receptors such as CXCR4 and in bone metastasis, the parathyroid hormone receptor; PTHR. We demonstrate novel signal-binding motifs in PAR_1&2 C-tails that are critical for breast cancer growth. This is manifested via the association of Akt/PKB pleckstrin-homology (PH)-domain as a key-signaling event of PARs. Other PH-domain signal-proteins such as Etk/Bmx and Vav₃ also associate with PAR₁ and PAR₂ through their PH-domains. Priority however, is allocated to Etk/Bmx. A point mutation in PAR₂, H349A, but not mutant R352A, abrogated PH-protein association and was sufficient to markedly reduce PAR₂-instigated breast tumor growth in vivo and placental extravillous trophoblast (EVT) time-limited invasion in vitro. Similarly, PAR₁ mutant hPar1-7A, devoid of PH domain binding, markedly reduced mammary gland tumors and EVT invasion, endowing these motifs with physiological significance and underscoring the importance of novel PAR₁ and PAR₂ PH-domain binding motifs in both pathological and physiological invasion process. In the PTHR but not in CXCR4 we find similarly, a PH-domain binding motif located in its C-tail that is critical for PTHR instigated invasion. This novel approach broadens our prospect for identifying translational means and suitable platform in cancer models.

Reference: Kancharla A, Maoz M, Jaber M, Agranovich D, Peretz T, ^*Grisaru-Granovsky S, Uziely B, and Rachel Bar-Shavit . Nature Commun, in revision, June 2015