PCP pathway

The Wnt signaling pathway is highly conserved in eukaryotes and is one of the most important signaling pathways. It is used extensively during animal development to regulate diverse processes including cell proliferation, differentiation, polarity, and migration, which are fundamental to embryogenesis. Wnt signals are transduced by at least two distinct pathways: the well-established canonical Wnt/β-catenin pathway and the β-catenin independent noncanonical Wnt pathway. Noncanonical Wnt signaling is very diverse and is still evolving into more and more branches. Two non-canonical signaling pathways have been well studied, the Wnt/PCP and Wnt/Ca2+. Wnt/PCP signaling is the first described and most extensively studied among the Wnt noncanonical pathways. Taken together, PCP pathway components transduce extracellular polarity cues and integrate a myriad of extracellular and intracellular inputs to induce intracellular cytoskeleton rearrangements and impact cell behaviors.In the Wnt/PCP pathway Wnt binds the 7-transmembrane Frizzled (FZD) receptor and activates the recruitment of cytoplasmic scaffold protein Disheveled (DVL) to the plasma membrane. Downstream of DVL, diverse pathways regulate different aspects of cytoskeleton reorganization in cell movements and polarity. DAAM1 binds DVL by its carboxyl terminus and RHOA by its amino terminus, leading to the formation of DV-RHOA complex. Profilin1 is a new interacting partner of DAAM1 and localized with DAAM1 to actin stress fibers in response to Wnt signal. DVL -Rac1 complex activates JNK. PCP signaling is regulated at multiple levels. 7-transmembrane protocadherin CELSR regulates the asymmetrical localization of FZD and 4-transmembrane protein VANGL, contributing to the maintenance of planar polarity. The cytoplasmic tail of VANGL binds and recruits Prickle to plasma membrane, where PRICKLE binds DVL and antagonizes DVL recruitment by FZD, thus inhibiting PCP signaling. Cthrc1, a secreted glycoprotein, stabilizes the Wnt- FZD complex to promote PCP signaling. EphrinB1 also positively regulates PCP signaling. The cytoplasmic tail of EphrinB1 binds DVL and activates RhoA.