Different motifs regulate trafficking of SorCS1 isoforms.
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 alphaC/sigma2 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.
Nielsen
Morten S
MS
MIND center, Department of Medical Biochemistry, University of Aarhus, Aarhus, Denmark.
Keat
Sady J
SJ
Hamati
Jida W
JW
Madsen
Peder
P
Gutzmann
Jakob J
JJ
Engelsberg
Arne
A
Pedersen
Karen M
KM
Gustafsen
Camilla
C
Nykjaer
Anders
A
Gliemann
Jørgen
J
Hermans-Borgmeyer
Irm
I
Kuhl
Dietmar
D
Petersen
Claus M
CM
Hermey
Guido
G
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D020033:Protein Isoforms / Q000737:chemistry; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D020539:Sequence Analysis, Protein; D014018:Tissue Distribution
D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D020033:Protein Isoforms; D011956:Receptors, Cell Surface; C472780:SORCS1 protein, human; C402822:SorCS protein, mouse