Intracellular trafficking of LRP9 is dependent on two acidic cluster/dileucine motifs

Boucher, Rémi; Larkin, Heidi; Brodeur, Jean‐Marc; Gagnon, Hugo; Thériault, Catherine; Lavoie, Christine

doi:10.1007/s00418-008-0436-5

Cited by 35 publications

(63 citation statements)

References 46 publications

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“…Thus, we established that cooperative action of both the DDSLL and the EDDADDD GGA-binding site is necessary for efficient stabilin-1-mediated intracellular sorting. This finding is consistent with the cooperative function of both DXXLL motifs in the TGN retention of LRP9 (2). The identification of EDDADDD as a GGA-binding sorting motif is the first example of a leucine-free acidic cluster that mediates interaction of this cargo receptor with GGAs.…”

Section: Discussionsupporting

confidence: 76%

A Novel GGA-Binding Site Is Required for Intracellular Sorting Mediated by Stabilin-1

Zhang

Gratchev

Riabov

et al. 2009

Molecular and Cellular Biology

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Stabilin-1 is a unique scavenger receptor that combines endocytic and intracellular sorting functions in macrophages. Stabilin-1 mediates the endocytosis of acetylated low-density lipoprotein (acLDL), SPARC, and growth hormone family member placental lactogen (PL). At the same time, stabilin-1 is involved in trans-Golgi network-to-endosome routing of the endogenous chitinase-like protein SI-CLP (stabilin-interacting chitinaselike protein). A DDSLL motif in the cytoplasmic tail of stabilin-1 interacts with GGA adaptors; however, the deletion of DDSLL reduces but does not abrogate this interaction. Here, we identified a novel GGA-binding site, EDDADDD, in the cytoplasmic tail of stabilin-1. The deletion of EDDADDD impaired and the deletion of both the DDSLL and EDDADDD sites abrogated the interaction of stabilin-1 with GGAs. The surface exposure of stabilin-1 and stabilin-1-mediated endocytosis of acLDL, SPARC, and PL were not affected by the deletion either of DDSLL or EDDADDD or both. At the same time, both GGA-binding sites were necessary for the intracellular sorting of SI-CLP performed by stabilin-1. Our data indicate that the novel GGA-binding site EDDADDD is essential for stabilin-1-mediated intracellular sorting but is not required for endocytosis.Stabilin-1 is a type 1 transmembrane receptor selectively expressed on tissue macrophages and sinusoidal endothelial cells in healthy organisms. It is expressed on both macrophages and different subtypes of endothelial cells and is induced during chronic inflammation and tumorigenesis (6,7,14). The major activities of stabilin-1-positive cells include control of tissue remodeling and angiogenesis and tolerogenic clearance of non-self and unwanted self products. Our most recent study revealed that stabilin-1 is induced on the CD14 ϩ CD16 ϩ monocyte subset in the blood circulation of patients with proatherosclerotic conditions (20). Our intracellular localization studies demonstrated that stabilin-1 is involved in two intracellular trafficking pathways, receptor-mediated endocytosis and shuttling between the endosomal compartment and trans-Golgi network (TGN) (16). The first function identified for stabilin-1 was endocytic clearance and targeting for the lysosomal degradation of several extracellular ligands: acetylated low-density lipoprotein (acLDL), the matricellular protein SPARC, and the growth hormone family member placental lactogen (PL) (13,17,19,21). The spectrum of stabilin-1 ligands indicates its functional significance for tissue homeostasis and remodeling during healing, carcinogenesis, and development. The second function of stabilin-1 identified by us is intracellular sorting of the novel chitinase-like protein SI-CLP (stabilin-interacting chitinase-like protein) (18). SI-CLP is the last identified member of the mammalian family of Glyco_18 domain-containing proteins, comprising true enzymes, as well as secreted chitinase-like proteins lacking enzymatic activity. The closest homologues of SI-CLP are enzymatically inactive Glyco_18 domain-containing c...

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Section: Discussionsupporting

confidence: 76%

A Novel GGA-Binding Site Is Required for Intracellular Sorting Mediated by Stabilin-1

Zhang

Gratchev

Riabov

et al. 2009

Molecular and Cellular Biology

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“…These cargo proteins include cationdependent and cation-independent mannose 6-phosphate receptors (9,11,14,15,17), sortilin (13,16), sorting-protein-related receptor (12,43), low-density lipoprotein receptor-related proteins, and ␤-secretase (8,10,16). We have demonstrated that GGA3 and ␣ 2B -AR physically associated in co-IP and GST fusion protein pulldown assays.…”

Section: Discussionmentioning

confidence: 97%

“…It has been well defined that the trafficking function of GGA proteins is mediated through their direct interactions with cargo proteins (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). To elucidate the possible molecular mechanisms underlying the function of GGA3 in ␣ 2B -AR export, we determined if GGA3 and ␣ 2B -AR could physically associate to form a complex in co-IP assays using ␣ 2B -AR antibodies.…”

Section: Resultsmentioning

confidence: 99%

“…Each domain of the GGAs has been shown to interact with specific proteins to coordinate their trafficking functions. Specifically, the N-terminal VHS domain interacts with the DXXLL-type sorting motifs of cargo proteins that cycle between the TGN and the endosomal compartment (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). These highly coordinated VHS-DXXLL signal interactions specifically dictate cargo proteins into the TGN-to-endosome pathway.…”

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confidence: 99%

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GGA3 Interacts with a G Protein-Coupled Receptor and Modulates Its Cell Surface Export

Zhang

Davis

et al. 2016

Molecular and Cellular Biology

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Molecular mechanisms governing the anterograde trafficking of nascent G protein-coupled receptors (GPCRs) are poorly understood. Here, we have studied the regulation of cell surface transport of ␣ 2 -adrenergic receptors (␣ 2 -ARs) by GGA3 (Golgi-localized, ␥-adaptin ear domain homology, ADP ribosylation factor-binding protein 3), a multidomain clathrin adaptor protein that sorts cargo proteins at the trans-Golgi network (TGN) to the endosome/lysosome pathway. By using an inducible system, we demonstrated that GGA3 knockdown significantly inhibited the cell surface expression of newly synthesized ␣ 2B -AR without altering overall receptor synthesis and internalization. The receptors were arrested in the TGN. Furthermore, GGA3 knockdown attenuated ␣ 2B -AR-mediated signaling, including extracellular signal-regulated kinase 1/2 (ERK1/2) activation and cyclic AMP (cAMP) inhibition. More interestingly, GGA3 physically interacted with ␣ 2B -AR, and the interaction sites were identified as the triple Arg motif in the third intracellular loop of the receptor and the acidic motif EDWE in the VHS domain of GGA3. In contrast, ␣ 2A -AR did not interact with GGA3 and its cell surface export and signaling were not affected by GGA3 knockdown. These data reveal a novel function of GGA3 in export trafficking of a GPCR that is mediated via a specific interaction with the receptor.

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“…IdentiWcation of motifs involved in intracellular sorting of proteins was the subject also of a recent original paper. Thus, essential molecular determinants for the traYcking of LDL receptorrelated protein 9 (LRP9), a distant member of the low-density lipoprotein receptor superfamily, between the TGN, endosomes and the plasma membrane were identiWed by Boucher et al (2008). They succeeded in showing that two acidic cluster/dileucine motifs (DXXLL) in the cytoplasmic tail of LRP9 were needed for interaction with Golgi localized, -ear-containing, ADP ribosylation factor-binding proteins, monomeric adaptor proteins that mediate the transport of cargo proteins between the TGN and endosomes (reviewed by Bonifacino 2004;Ghosh and Kornfeld 2004), and suggested that this as yet uncharacterized receptor may have a function in protein sorting and transport.…”

Section: Secretory Pathwaysmentioning

confidence: 99%

State-of-the-art technologies, current opinions and developments, and novel findings: news from the field of histochemistry and cell biology

Asan

Drenckhahn

2008

Histochem Cell Biol

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Investigations of cell and tissue structure and function using innovative methods and approaches have again yielded numerous exciting findings in recent months and have added important data to current knowledge, inspiring new ideas and hypotheses in various fields of modern life sciences. Topics and contents of comprehensive expert reviews covering different aspects in methodological advances, cell biology, tissue function and morphology, and novel findings reported in original papers are summarized in the present review.

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Intracellular trafficking of LRP9 is dependent on two acidic cluster/dileucine motifs

Cited by 35 publications

References 46 publications

A Novel GGA-Binding Site Is Required for Intracellular Sorting Mediated by Stabilin-1

A Novel GGA-Binding Site Is Required for Intracellular Sorting Mediated by Stabilin-1

GGA3 Interacts with a G Protein-Coupled Receptor and Modulates Its Cell Surface Export

State-of-the-art technologies, current opinions and developments, and novel findings: news from the field of histochemistry and cell biology

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