Background:Sorting nexins are a large family of proteins that are associated with various components of the endosome system and they play many roles in processes such as endocytosis,intracellular protein trafficking a...Background:Sorting nexins are a large family of proteins that are associated with various components of the endosome system and they play many roles in processes such as endocytosis,intracellular protein trafficking and cell signaling.The subcellular distribution patterns of many of them remain controversial and their in vivo functions have not been characterized yet.Results:We investigated the subcellular distribution and function of SNX16 in this study.SNX16 is detected on Rab5-positive endosomes localized adjacent to focal adhesions at cell cortex.Inhibition of SNX23,polymerization of microtubule filaments as well as the PI3-kinase all disrupt the cell cortex distribution of SNX16.Ectopic expression of SNX16 reduces the migration and the tumor formation activity of MCF-7 cells.Conclusion:Our results indicate that,in addition to the PI3P,there is a SNX23-and microtubule-dependent cargo transport pathway required for the proper subcellular distribution of SNX16.SNX16 plays a negative regulatory role during cell migration and tumorigenesis.展开更多
Background:Notch is one of the most important signaling pathways involved in cell fate determination.Activation of the Notch pathway requires the binding of a membrane-bound ligand to the Notch receptor in the adjacen...Background:Notch is one of the most important signaling pathways involved in cell fate determination.Activation of the Notch pathway requires the binding of a membrane-bound ligand to the Notch receptor in the adjacent cell which induces proteolytic cleavages and the activation of the receptor.A unique feature of the Notch signaling is that processes such as modification,endocytosis or recycling of the ligand have been reported to play critical roles during Notch signaling,however,the underlying molecular mechanism appears context-dependent and often controversial.Results:Here we identified SNX17 as a novel regulator of the Notch pathway.SNX17 is a sorting nexin family protein implicated in vesicular trafficking and we find it is specifically required in the ligand-expressing cells for Notch signaling.Mechanistically,SNX17 regulates the protein level of Jag1a on plasma membrane by binding to Jag1a and facilitating the retromer-dependent recycling of the ligand.In zebrafish,inhibition of this SNX17-mediated Notch signaling pathway results in defects in neurogenesis as well as pancreas development.Conclusions:Our results reveal that SNX17,by acting as a cargo-specific adaptor,promotes the retromer dependent recycling of Jag1a and Notch signaling and this pathway is involved in cell fate determination during zebrafish neurogenesis and pancreas development.展开更多
基金We thank members of the lab for technical assistance and helpful discussions.This work was supported by grants from the"Strategic Priority Research Program"of the Chinese Academy of Sciences(XDA01020401,XDA01020307)National Natural Science Foundation of China(31271502)Science and Technology Planning Project of Guangdong Province(2011A060901019).
文摘Background:Sorting nexins are a large family of proteins that are associated with various components of the endosome system and they play many roles in processes such as endocytosis,intracellular protein trafficking and cell signaling.The subcellular distribution patterns of many of them remain controversial and their in vivo functions have not been characterized yet.Results:We investigated the subcellular distribution and function of SNX16 in this study.SNX16 is detected on Rab5-positive endosomes localized adjacent to focal adhesions at cell cortex.Inhibition of SNX23,polymerization of microtubule filaments as well as the PI3-kinase all disrupt the cell cortex distribution of SNX16.Ectopic expression of SNX16 reduces the migration and the tumor formation activity of MCF-7 cells.Conclusion:Our results indicate that,in addition to the PI3P,there is a SNX23-and microtubule-dependent cargo transport pathway required for the proper subcellular distribution of SNX16.SNX16 plays a negative regulatory role during cell migration and tumorigenesis.
基金We thank M.Itoh,M.M.Chiu,G.Weinmaster,J.Hald,Z.Li and D.Yao for reagents and other members of our lab for technical support.This work was supported by grants from the“Strategic Priority Research Program”of the Chinese Academy of Sciences(XDA01020401,XDA01020307)Ministry of Science and Technology 973 program(2009CB941102)CAS 100-talent project(X.S.).
文摘Background:Notch is one of the most important signaling pathways involved in cell fate determination.Activation of the Notch pathway requires the binding of a membrane-bound ligand to the Notch receptor in the adjacent cell which induces proteolytic cleavages and the activation of the receptor.A unique feature of the Notch signaling is that processes such as modification,endocytosis or recycling of the ligand have been reported to play critical roles during Notch signaling,however,the underlying molecular mechanism appears context-dependent and often controversial.Results:Here we identified SNX17 as a novel regulator of the Notch pathway.SNX17 is a sorting nexin family protein implicated in vesicular trafficking and we find it is specifically required in the ligand-expressing cells for Notch signaling.Mechanistically,SNX17 regulates the protein level of Jag1a on plasma membrane by binding to Jag1a and facilitating the retromer-dependent recycling of the ligand.In zebrafish,inhibition of this SNX17-mediated Notch signaling pathway results in defects in neurogenesis as well as pancreas development.Conclusions:Our results reveal that SNX17,by acting as a cargo-specific adaptor,promotes the retromer dependent recycling of Jag1a and Notch signaling and this pathway is involved in cell fate determination during zebrafish neurogenesis and pancreas development.
