Other entities represented in this entry:
HGNC Approved Gene Symbol: SNX1
Cytogenetic location: 15q22.31 Genomic coordinates (GRCh38): 15:64,095,982-64,144,231 (from NCBI)
SNX1 is a member of the sorting nexin family of molecules that contain an approximately 100-amino acid region termed the phox homology (PX) domain (Haft et al., 1998).
Kurten et al. (1996) described a protein, designated sorting nexin-1, that plays a role in targeting ligand-activated EGFR (131550) to the lysosomes for degradation after endocytosis from the cell surface and release from the Golgi. Kurten et al. (1996) isolated a cDNA encoding the COOH-terminal 58 amino acids of SNX1 from a HeLa cDNA library in a yeast 2-hybrid system, using the core tyrosine kinase domain of EGFR. A 1,974-bp SNX1 cDNA was then assembled from full-length and partial cDNA clones from a HeLa cell cDNA library. They identified a human EST that was 70% identical to SNX1, suggesting that SNX1 defines a family of molecules.
By EST database searching with the human SNX1 sequence, Haft et al. (1998) isolated a putative splice variant isoform of SNX1, which they designated SNX1A. The major difference between SNX1 and SNX1A is a deletion of 195 nucleotides that results in an in-frame deletion of 65 amino acids; thus, SNX1A cDNA is predicted to encode a 457-amino acid hydrophilic protein. By PCR, the authors confirmed the presence of both SNX1 and SNX1A mRNAs in multiple tissues. Northern blot analysis showed that human SNX1/1A mRNAs are ubiquitously expressed, with highest levels in the medulla oblongata, prostate, spinal cord, spleen, pancreas, and pituitary gland.
The International Radiation Hybrid Mapping Consortium mapped the SNX1 gene to chromosome 15 (stSG27380).
Kurten et al. (1996) demonstrated that overexpression of SNX1 downregulated endogenous EGFR in CV-1 cells that were stably transfected with SNX1. They also demonstrated that the turnover of cell surface receptors in these SNX1 overexpressing cells was enhanced by EGF (131530) treatment and required an active kinase.
By Western blot analysis, Haft et al. (1998) showed that SNX1, SNX1A, SNX2 (605929), and SNX4 (605931) are associated predominantly with membranes, whereas SNX3 (605930) is found mainly in the cytosol. SNX2 forms heteromeric complexes with SNX1, SNX1A, and SNX4, but not with SNX3. When expressed in COS-7 cells, epitope-tagged SNX1, SNX1A, SNX2, and SNX4 coimmunoprecipitated with receptor tyrosine kinases for EGF, platelet-derived growth factor (see 173490), and insulin (147670). They also associated with the long isoform of the leptin receptor (601007) but not with the short and medium isoforms. Only SNX1 and SNX1A coimmunoprecipitated with endogenous transferrin receptors (see 190010). Based on the functions of their yeast homologs, Haft et al. (1998) suggested that mammalian sorting nexins function in intracellular trafficking of proteins to various organelles.
Zhong et al. (2002) demonstrated that SNX1 and SNX2 are colocalized to tubulovesicular endosomal membranes and that this localization depends on PI3K (see 171834). Point mutations in the PX domain that abolish recognition of phosphorylated phosphatidylinositol in vitro abolished vesicle localization in vivo, indicating that lipid binding by the PX domain is necessary for localization to vesicle membranes.
The cell surface receptor CED1 (107770) mediates apoptotic cell recognition by phagocytic cells, enabling cell corpse clearance in C. elegans. Chen et al. (2010) found that the C. elegans intracellular protein sorting complex, retromer, was required for cell corpse clearance by mediating the recycling of CED1. The mammalian retromer complex contains sorting nexins 1 and 2 (C. elegans homolog snx1) and 5/6 (605937, 606098) (C. elegans homolog snx6). Retromer was recruited to the surfaces of phagosomes containing cell corpses, and its loss of function caused defective cell corpse removal. The retromer probably acted through direct interaction with CED1 in the cell corpse recognition pathway. In the absence of retromer function, CED1 associated with lysosomes and failed to recycle from phagosomes and cytosol to the plasma membrane. Thus, Chen et al. (2010) concluded that retromer is an essential mediator of apoptotic cell clearance by regulating phagocytic receptor(s) during cell corpse engulfment.
Chen, D., Xiao, H., Zhang, K., Wang, B., Gao, Z., Jian, Y., Qi, X., Sun, J., Miao, L., Yang, C. Retromer is required for apoptotic cell clearance by phagocytic receptor recycling. Science 327: 1261-1264, 2010. [PubMed: 20133524] [Full Text: https://doi.org/10.1126/science.1184840]
Haft, C. R., de la Luz Sierra, M., Barr, V. A., Haft, D. H., Taylor, S. I. Identification of a family of sorting nexin molecules and characterization of their association with receptors. Molec. Cell. Biol. 18: 7278-7287, 1998. [PubMed: 9819414] [Full Text: https://doi.org/10.1128/MCB.18.12.7278]
Kurten, R. C., Cadena, D. L., Gill, G. N. Enhanced degradation of EGF receptors by a sorting nexin, SNX1. Science 272: 1008-1010, 1996. [PubMed: 8638121] [Full Text: https://doi.org/10.1126/science.272.5264.1008]
Zhong, Q., Lazar, C. S., Tronchere, H., Sato, T., Meerloo, T., Yeo, M., Songyang, Z., Emr, S. D., Gill, G. N. Endosomal localization and function of sorting nexin 1. Proc. Nat. Acad. Sci. 99: 6767-6772, 2002. [PubMed: 11997453] [Full Text: https://doi.org/10.1073/pnas.092142699]