Endosomal localization and function of sorting nexin 1.
There are 17 human members of the sorting nexin (SNX) family of proteins that contain Phox (PX) domains. Yeast orthologs function in vesicular trafficking and mammalian proteins have been implicated in endocytic trafficking of cell surface receptors. The first member of this family, SNX1, was identified via interaction with the epidermal growth factor receptor. The present studies indicate that SNX1 and SNX2 are colocalized to tubulovesicular endosomal membranes and this localization depends on PI 3-kinase activity. Point mutations in the PX domain that abolish recognition of phosphorylated phosphatidylinositol (PtdIns) in vitro abolish vesicle localization in vivo indicating that lipid binding by the PX domain is necessary for localization to vesicle membranes. Deletion of a predicted coiled-coil region in the COOH terminus of SNX1 also abolished vesicle localization, indicating that this helical domain, too, is necessary for SNX1 localization. Thus, both PX domain recognition of PtdIns and COOH terminal helical domains are necessary for localization of SNX1 with neither alone being sufficient. Regulated overexpression of the NH(2) terminus of SNX1 containing the PX domain decreased the rate of ligand-induced epidermal growth factor receptor degradation, an effect consistent with inhibition of endogenous SNX1 function in the endosome compartment. SNX1 thus functions in regulating trafficking in the endosome compartment via PX domain recognition of phosphorylated PtdIns and via interaction with other protein components.
Zhong
Qi
Q
Department of Medicine, University of California at San Diego School of Medicine, La Jolla, CA 92093-0650, USA.
Lazar
Cheri S
CS
Tronchère
Hélène
H
Sato
Trey
T
Meerloo
Timo
T
Yeo
Michele
M
Songyang
Zhou
Z
Emr
Scott D
SD
Gill
Gordon N
GN
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D015536:Down-Regulation; D011992:Endosomes / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D015870:Gene Expression; D008969:Molecular Sequence Data; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D011817:Rabbits; D013347:Subcellular Fractions; D033921:Vesicular Transport Proteins
D002352:Carrier Proteins; D018129:Phosphatidylinositol Phosphates; D033921:Vesicular Transport Proteins; C060974:phosphatidylinositol 3,4,5-triphosphate; D066246:ErbB Receptors