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J Biol Chem. 2013 May 17;288(20):13988-99. doi: 10.1074/jbc.M112.444737. Epub 2013 Mar 22.

Molecular mediators for raft-dependent endocytosis of syndecan-1, a highly conserved, multifunctional receptor.

Author information

1
Division of Endocrinology, Department of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.

Abstract

Endocytosis via rafts has attracted considerable recent interest, but the molecular mediators remain incompletely characterized. Here, we focused on the syndecan-1 heparan sulfate proteoglycan, a highly conserved, multifunctional receptor that we previously showed to undergo raft-dependent endocytosis upon clustering. Alanine scanning mutagenesis of three to five consecutive cytoplasmic residues at a time revealed that a conserved juxtamembrane motif, MKKK, was the only region required for efficient endocytosis after clustering. Endocytosis of clustered syndecan-1 occurs in two phases, each requiring a kinase and a corresponding cytoskeletal partner. In the initial phase, ligands trigger rapid MKKK-dependent activation of ERK and the localization of syndecan-1 into rafts. Activation of ERK drives the dissociation of syndecan-1 from α-tubulin, a molecule that may act as an anchor for syndecan-1 at the plasma membrane in the basal state. In the second phase, Src family kinases phosphorylate tyrosyl residues within the transmembrane and cytoplasmic regions of syndecan-1, a process that also requires MKKK. Tyrosine phosphorylation of syndecan-1 triggers the robust recruitment of cortactin, which we found to be an essential mediator of efficient actin-dependent endocytosis. These findings represent the first detailed characterization of the molecular events that drive endocytosis of a raft-dependent receptor and identify a novel endocytic motif, MKKK. Moreover, the results provide new tools to study syndecan function and regulation during uptake of its biologically and medically important ligands, such as HIV-1, atherogenic postprandial remnant lipoproteins, and molecules implicated in Alzheimer disease.

KEYWORDS:

ERK; Lipid Raft; Lipoprotein Receptor; Proteoglycan; Receptor Endocytosis; Src

PMID:
23525115
PMCID:
PMC3656258
DOI:
10.1074/jbc.M112.444737
[Indexed for MEDLINE]
Free PMC Article
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