PAQR family members in cell signaling and development

【摘要】：正Ras plays a pivotal role in many cellular activities and subcellular compartmentation of Ras as well as its downstream signaling components controls the information flow and output in the context of stimulus and cell type.However,how Ras signaling is modulated by subcellular compartmentation at the Golgi apparatus as well as its physiological significance are largely unknown.Here we report a mode of spatial regulation of Ras signaling by two highly homologous proteins RasTG1 and RasTG2(Ras Trapping to Golgi 1 and 2) of the PAQR family.Both RasTGs are membrane proteins specifically localized at the Golgi apparatus.RasTG interacts with HRas and NRas and mobilizes them onto the Golgi apparatus,in which Ras is activated in situ,leading to activation of MEK,ERK,and other downstream targets. RasTG also engages a guanine nucleotide exchange protein RasGRP1 onto the Golgi, contributing to the activation of Ras at the Golgi.In zebrafish,knockdown of RasTG2 leads to defects in the development of atrioventricular canal and formation of heart valves.Furthermore,MEK inhibitors and a dominant negative HRas can mimic RasTG2 knockdown in inducing cardiac developmental defects.Constitutive active HRas is able to rescue the cardiac defects caused by RasTG2 knockdown.Taken together,these data uncover a new paradigm of Ras signaling,whereby RasTG serves as an organelle-restricted protein that tethers Ras to the Golgi apparatus and such spatial regulation of Ras plays an important role in cardiac valve development.