Premium
Different Motifs Regulate Trafficking of SorCS1 Isoforms
Author(s) -
Nielsen Morten S.,
Keat Sady J.,
Hamati Jida W.,
Madsen Peder,
Gutzmann Jakob J.,
Engelsberg Arne,
Pedersen Karen M.,
Gustafsen Camilla,
Nykjær Anders,
Gliemann Jørgen,
HermansBorgmeyer Irm,
Kuhl Dietmar,
Petersen Claus M.,
Hermey Guido
Publication year - 2008
Publication title -
traffic
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.677
H-Index - 130
eISSN - 1600-0854
pISSN - 1398-9219
DOI - 10.1111/j.1600-0854.2008.00731.x
Subject(s) - biology , internalization , gene isoform , endosome , microbiology and biotechnology , endocytic cycle , signal transducing adaptor protein , cytoplasm , golgi apparatus , transmembrane protein , transport protein , endocytosis , transmembrane domain , signal transduction , intracellular , receptor , genetics , gene , endoplasmic reticulum
The type I transmembrane protein SorCS1 is a member of the Vps10p‐domain receptor family comprised of Sortilin, SorLA and SorCS1, ‐2 and ‐3. Current information indicates that Sortilin and SorLA mediate intracellular protein trafficking and sorting, but little is known about the cellular functions of the SorCS subgroup. SorCS1 binds platelet‐derived growth factor‐BB (PDGF‐BB) and is expressed in isoforms differing only in their cytoplasmic domains. Here, we identify two novel isoforms of mouse SorCS1 designated m‐SorCS1c and ‐d. In situ hybridization revealed a combinatorial expression pattern of the variants in brain and embryonic tissues. We demonstrate that among the mouse variants, only SorCS1c mediates internalization and that the highly conserved SorCS1c is internalized through a canonical tyrosine‐based motif. In contrast, human SorCS1a, whose cytoplasmic domain is completely different from mouse SorCS1a, is internalized through a DXXLL motif. We report that the human SorCS1a cytoplasmic domain interacts with the αC/σ2 subunits of the adaptor protein (AP)‐2 complex, and internalization of human SorCS1a and ‐c is mediated by AP‐2. Our results suggest that the endocytic isoforms target internalized cargo to lysosomes but are not engaged in Golgi–endosomal transport to a significant degree.