The Novel Drosophila Lysosomal Enzyme Receptor Protein Mediates Lysosomal Sorting in Mammalian Cells and Binds Mammalian and Drosophila GGA Adaptors

Dennes, André; Cromme, C; Suresh, K.; Kumar, Neeraj; Eble, Johannes A.; Hahnenkamp, Anke; Pohlmann, R

doi:10.1074/jbc.m410626200

Cited by 52 publications

(52 citation statements)

References 37 publications

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“…Acidic LEs or lysosomes marked by Lysotracker were also enlarged (Fig. 6C,D), as were LEs containing GFP fused to Lysosomal enzyme receptor protein (Lerp), which is the Drosophila homolog of the mannose 6-phosphate receptor (Dennes et al, 2005;Hirst et al, 2009) (Fig. 6E,F).…”

Section: Pi4kii Mutants Missort Granule Proteins To Enlarged Lesmentioning

confidence: 97%

Type II phosphatidylinositol 4-kinase regulates trafficking of secretory granule proteins inDrosophila

et al. 2012

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SUMMARYType II phosphatidylinositol 4-kinase (PI4KII) produces the lipid phosphatidylinositol 4-phosphate (PI4P), a key regulator of membrane trafficking. Here, we generated genetic models of the sole Drosophila melanogaster PI4KII gene. A specific requirement for PI4KII emerged in larval salivary glands. In PI4KII mutants, mucin-containing glue granules failed to reach normal size, with glue protein aberrantly accumulating in enlarged Rab7-positive late endosomes. Presence of PI4KII at the Golgi and on dynamic tubular endosomes indicated two distinct foci for its function. First, consistent with the established role of PI4P in the Golgi, PI4KII is required for sorting of glue granule cargo and the granule-associated SNARE Snap24. Second, PI4KII also has an unforeseen function in late endosomes, where it is required for normal retromer dynamics and for formation of tubular endosomes that are likely to be involved in retrieving Snap24 and Lysosomal enzyme receptor protein (Lerp) from late endosomes to the trans-Golgi network. Our genetic analysis of PI4KII in flies thus reveals a novel role for PI4KII in regulating the fidelity of granule protein trafficking in secretory tissues.

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Section: Pi4kii Mutants Missort Granule Proteins To Enlarged Lesmentioning

confidence: 97%

Type II phosphatidylinositol 4-kinase regulates trafficking of secretory granule proteins inDrosophila

et al. 2012

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“…Lerp localizes to the trans-Golgi together with dGGA Recently, Lerp was identified as a Drosophila ortholog of the mammalian CI-MPR and was shown to function as a sorting receptor for lysosomal cathepsins when ectopically expressed in MPR-deficient mouse fibroblasts (Dennes et al, 2005). However, its properties and physiological function in Drosophila have not been elucidated.…”

Section: Acts In Lerp Traffic In Drosophilamentioning

confidence: 99%

“…These fly cells offer several advantages over mammalian cells, the most important of which is the existence in their genome of single genes encoding GGA, each of the subunits of AP-1 complex, and Lerp (lysosomal enzyme receptor protein), an ortholog of mammalian CI-MPR (Boehm and Bonifacino, 2001;Dennes et al, 2005). Moreover, most mammalian proteins that are involved in cargo sorting and transport-carrier formation are also conserved in the fly genome, most often as single proteins (Boehm and Bonifacino, 2001), indicating that this organism possesses similar mechanisms of intracellular protein trafficking.…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of protein-sorting machineries at the trans-Golgi network in Drosophila melanogaster

Kametaka

Sawada

Bonifacino

et al. 2010

Journal of Cell Science

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SummaryTargeting of proteins to their final destination is a prerequisite for living cells to maintain their homeostasis. Clathrin functions as a coat that forms transport carriers called clathrin-coated vesicles (CCVs) at the plasma membrane and post-Golgi compartments. In this study, we established an experimental system using Schneider S2 cells derived from the fruit fly, Drosophila melanogaster, as a model system to study the physiological roles of clathrin adaptors, and to dissect the processes of CCV formation. We found that a clathrin adaptor Drosophila GGA (dGGA), a homolog of mammalian GGA proteins, localizes to the trans-Golgi network (TGN) and is capable of recruiting clathrin from the cytosol onto TGN membranes. dGGA itself is recruited from the cytosol to the TGN in an ARF1 small GTPase (dARF79F)-dependent manner. dGGA recognizes the cytoplasmic acidic-cluster-dileucine (ACLL) sorting signal of Lerp (lysosomal enzyme receptor protein), a homolog of mammalian mannose 6-phosphate receptors. Moreover, both dGGA and another type of TGN-localized clathrin adaptor, AP-1 (adaptor protein-1 complex), are shown to be involved in the trafficking of Lerp from the TGN to endosomes and/or lysosomes. Taken together, our findings indicate that the protein-sorting machinery in fly cells is well conserved relative to that in mammals, enabling the use of fly cells to dissect CCV biogenesis and clathrin-dependent protein trafficking at the TGN of higher eukaryotes.

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“…32 Rabbit antisera against mouse cathepsin D and the cytoplasmic tail of human M6P/IGF2R were kindly provided by Dr. Regina Pohlmann (Westf€ alische Wilhelms-Universit€ at M€ unster, Germany). 33 Rabbit antiserum against recombinant mouse procathepsin L was generously donated by Dr. Ann H. Erickson (University of North Carolina, Durham, NC). The rat monoclonal antibody to mouse LAMP-1 (clone 1D4B) developed by J. Thomas August (Johns Hopkins University, Baltimore, MD) was obtained from the Developmental Studies Hybridoma Bank maintained by the Department of Biological Sciences (University of Iowa, Iowa City, IA).…”

Section: Antibodiesmentioning

confidence: 99%

The mannose 6‐phosphate/insulin‐like growth factor II receptor restricts the tumourigenicity and invasiveness of squamous cell carcinoma cells

Probst¹,

Puxbaum²,

Svoboda³

et al. 2009

Intl Journal of Cancer

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The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) mediates biosynthetic sorting and endocytosis of various factors that impinge on the proliferation, migration and invasiveness of tumour cells. The gene encoding M6P/IGF2R is frequently lost or mutated in a wide range of malignant tumours including squamous cell carcinomas. We have previously shown that M6P/IGF2R-deficient SCC-VII murine squamous cell carcinoma cells secrete large amounts of pro-invasive lysosomal proteinases. Furthermore, the formation of mature lysosomes is impaired in SCC-VII cells. To assess the link between M6P/ IGF2R status and tumour invasion, we have now generated SCC-VII lines stably transfected with human M6P/IGF2R cDNA. Reconstitution of functional M6P/IGF2R expression in SCC-VII cells strongly improves the intracellular retention of lysosomal proteinases and restores the formation of mature lysosomes. In addition, the presence of heterologous M6P/IGF2R compromises the growth of SCC-VII cells both in vitro and in vivo. Remarkably, M6P/IGF2R expression also reduces the invasive capacity of SCC-VII cells in response to various chemoattractants. These results indicate that the M6P/IGF2R status influences the metastatic propensity of squamous cell carcinomas. ' 2008 Wiley-Liss, Inc.Key words: cathepsin; lysosome; proteolysis; squamous cell carcinoma; tumour invasion A key requirement for metastatic cancer cell invasion is the penetration of extracellular matrix (ECM) barriers. This process involves the degradation of different ECM proteins and proteoglycans. 1,2 Various proteinases have been implicated in ECM degradation associated with tumour invasion and metastasis, including urokinase-type plasminogen activator, matrix metalloproteinases and cathepsins. [3][4][5] The involvement of the latter enzymes in ECM proteolysis is perplexing, since cathepsins are normally localized in lysosomes. However, tumour cells often secrete significant amounts of these proteinases into the pericellular fluid, as first observed for cathepsin B. 6 As typical for lysosomal enzymes, the N-glycan moieties of cathepsins are modified during their biosynthesis with mannose 6-phosphate (M6P) residues which permit interaction with the main lysosomal sorting receptors, the 300-kDa mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) and the 46-kDa mannose 6-phosphate receptor (MPR46). 7 Evidence has been provided that excessive secretion of cathepsins by tumour cells may be due to transformation-induced changes to the M6P receptor pathway. [8][9][10] Lysosomal sorting via M6P/IGF2R is generally far more efficient than by MPR46, demonstrating that the former is the main lysosomal targeting receptor in mammalian cells. 11,12 However, M6P/IGF2R also binds a variety of other factors that impinge on the proliferation, migration and invasiveness of tumour cells, including insulin-like growth factor II (IGF-II), 13 transforming growth factor b, 14 urokinase-type plasminogen activator receptor 15 and plasminogen. 16 Hence, it is o...

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The Novel Drosophila Lysosomal Enzyme Receptor Protein Mediates Lysosomal Sorting in Mammalian Cells and Binds Mammalian and Drosophila GGA Adaptors

Cited by 52 publications

References 37 publications

Type II phosphatidylinositol 4-kinase regulates trafficking of secretory granule proteins inDrosophila

Type II phosphatidylinositol 4-kinase regulates trafficking of secretory granule proteins inDrosophila

Functional characterization of protein-sorting machineries at the trans-Golgi network in Drosophila melanogaster

The mannose 6‐phosphate/insulin‐like growth factor II receptor restricts the tumourigenicity and invasiveness of squamous cell carcinoma cells

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