Hrs Regulates Endosome Membrane Invagination and Tyrosine Kinase Receptor Signaling in Drosophila

Lloyd, Thomas E.; Atkinson, R.A.; Wu, Mark N.; Zhou, Yi; Pennetta, Giuseppa; Bellen, Hugo J.

doi:10.1016/s0092-8674(02)00611-6

Cited by 417 publications

(495 citation statements)

References 53 publications

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“…As described above, and consistent with previous work [66], TR-avidin showed a very high degree of colocalization with LTG in the terminal lysosomal network after a 2 h chase in wild-type garland cells (Figure 5(c,d)). In Rab2 Δ1 , Vps39 Δ1 /Df, lt 11 /Df and Gie e00336 /Df cells, however, no lysosomal network was apparent, and spherical compartments strongly labeled with LTG filled the cytoplasm (Figure 5(c); Fig.…”

Section: Resultssupporting

confidence: 92%

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Drosophila Rab2 controls endosome-lysosome fusion and LAMP delivery to late endosomes

2018

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Rab2 is a conserved Rab GTPase with a well-established role in secretory pathway function and phagocytosis. Here we demonstrate that Drosophila Rab2 is recruited to late endosomal membranes, where it controls the fusion of LAMP-containing biosynthetic carriers and lysosomes to late endosomes. In contrast, the lysosomal GTPase Gie/Arl8 is only required for late endosome-lysosome fusion, but not for the delivery of LAMP to the endocytic pathway. We also find that Rab2 is required for the fusion of autophagosomes to the endolysosomal pathway, but not for the biogenesis of lysosome-related organelles. Surprisingly, Rab2 does not rely on HOPS-mediated vesicular fusion for recruitment to late endosomal membranes. Our work suggests that Drosophila Rab2 is a central regulator of the endolysosomal and macroautophagic/autophagic pathways by controlling the major heterotypic fusion processes at the late endosome.

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Section: Resultssupporting

confidence: 92%

“…Within 40 min of endocytosis, the tracer is delivered to an acidic, LTG-positive lysosomal compartment [66]. We pulsed garland cells from wild-type control and Rab2 Δ1 animals for 3 min with Texas Red-avidin (TR-avidin), followed by a 2-h chase.…”

Section: Resultsmentioning

confidence: 99%

Drosophila Rab2 controls endosome-lysosome fusion and LAMP delivery to late endosomes

2018

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“…The role of hrs in endosomal recycling is not inconsistent with a hypothesis suggesting that hrs or Vps27p functions in endocytic protein sorting (Katzmann et al, 2001;Bilodeau et al, 2002;Lloyd et al, 2002) and in early endosome fusion (Sun et al, 2003). These studies have suggested that hrs/Vps27p is linked with proteins required for the ubiquitination and sorting of cargo (Katzmann et al, 2001;Bilodeau et al, 2002) and that hrs inhibits homotypic early endosome fusion (Sun et al, 2003).…”

Section: Discussionmentioning

confidence: 87%

“…Hrs has homologues in insects (Lloyd et al, 2002) and fungi (Raymond et al, 1992). Deletion or mutation of hrs results in an enlarged endosomal phenotype in mouse (Komada and Soriano, 1999), fly (Lloyd et al, 2002), and yeast (Raymond et al, 1992).…”

mentioning

confidence: 99%

CART: An Hrs/Actinin-4/BERP/Myosin V Protein Complex Required for Efficient Receptor Recycling

Yan

Wei

Kujala

et al. 2005

MBoC

115

121

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Altering the number of surface receptors can rapidly modulate cellular responses to extracellular signals. Some receptors, like the transferrin receptor (TfR), are constitutively internalized and recycled to the plasma membrane. Other receptors, like the epidermal growth factor receptor (EGFR), are internalized after ligand binding and then ultimately degraded in the lysosome. Routing internalized receptors to different destinations suggests that distinct molecular mechanisms may direct their movement. Here, we report that the endosome-associated protein hrs is a subunit of a protein complex containing actinin-4, BERP, and myosin V that is necessary for efficient TfR recycling but not for EGFR degradation. The hrs/actinin-4/BERP/myosin V (CART [cytoskeleton-associated recycling or transport]) complex assembles in a linear manner and interrupting binding of any member to its neighbor produces an inhibition of transferrin recycling rate. Disrupting the CART complex results in shunting receptors to a slower recycling pathway that involves the recycling endosome. The novel CART complex may provide a molecular mechanism for the actin-dependence of rapid recycling of constitutively recycled plasma membrane receptors. INTRODUCTIONEndocytosis is required for the uptake of essential nutrients from the extracellular environment as well as for retrieval of proteins and lipids that are added to the plasma membrane during fusion of regulated and constitutive secretory vesicles (De Camilli and Takei, 1996;Koenig and Ikeda, 1996;Robinson et al., 1996;Mukherjee et al., 1997;Schmid, 1997;Betz and Angleson, 1998;Koenig et al., 1998;Stoorvogel, 1998;D'Hondt et al., 2000;Gruenberg, 2001). The endocytic pathway can be separated into numerous stages based on the movement of cargo and the identification of morphologically defined compartments (De Camilli and Takei, 1996;Koenig and Ikeda, 1996;Robinson et al., 1996;Mukherjee et al., 1997;Schmid, 1997;Betz and Angleson, 1998;Koenig et al., 1998;Stoorvogel, 1998;D'Hondt et al., 2000;Gruenberg, 2001). Early events in the endocytic process include membrane invagination and vesicle budding from the plasma membrane, formation of transport vesicles, and fusion with early endosomes. Later events include cargo sorting, and additional transport/fusion steps, including those responsible for transport to the lysosome for degradation, and those responsible for recycling back to various compartments (De Camilli and Takei, 1996;Koenig and Ikeda, 1996;Robinson et al., 1996;Mukherjee et al., 1997;Schmid, 1997;Betz and Angleson, 1998;Koenig et al., 1998;Stoorvogel, 1998;D'Hondt et al., 2000;Gruenberg, 2001). Although much progress has been made in elucidating the molecular processes involved in early endocytic events, such as those involved in the genesis of clathrin-coated endocytic transport vesicles, an equally clear understanding of later events remains elusive.The early endosome is a crucial point in the endocytic pathway to sort cargo for transport to late endosomes for eventual degradation in the...

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“…Depletion of Hrs or STAM using RNA interference (RNAi) or gene disruption inhibits RTK down-regulation in mammalian cells (Bache et al, 2003b;Hammond et al, 2003;Kanazawa et al, 2003;Lu et al, 2003) and in Drosophila (Lloyd et al, 2002). The budding yeast Saccharomyces cerevisiae also has orthologues of Hrs and STAM, which are Vps27 (vacuolar protein sorting 27) and Hse1 (Hbp/STAM/EAST 1), respectively.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Epidermal Growth Factor Receptor Down-Regulation by UBPY-mediated Deubiquitination at Endosomes

Mizuno

Iura

Mukai

et al. 2005

MBoC

254

264

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Ligand-activated receptor tyrosine kinases undergo endocytosis and are transported via endosomes to lysosomes for degradation. This "receptor down-regulation" process is crucial to terminate the cell proliferation signals produced by activated receptors. During the process, ubiquitination of the receptors serves as a sorting signal for their trafficking from endosomes to lysosomes. Here, we describe the role of a deubiquitinating enzyme UBPY/USP8 in the down-regulation of epidermal growth factor (EGF) receptor (EGFR). Overexpression of UBPY reduced the ubiquitination level of EGFR and delayed its degradation in EGF-stimulated cells. Immunopurified UBPY deubiquitinated EGFR in vitro. In EGF-stimulated cells, UBPY underwent ubiquitination and bound to EGFR. Overexpression of Hrs or a dominant-negative mutant of SKD1, proteins that play roles in the endosomal sorting of ubiquitinated receptors, caused the accumulation of endogenous UBPY on exaggerated endosomes. A catalytically inactive UBPY mutant clearly localized on endosomes, where it overlapped with EGFR when cells were stimulated with EGF. Finally, depletion of endogenous UBPY by RNA interference resulted in elevated ubiquitination and accelerated degradation of EGF-activated EGFR. We conclude that UBPY negatively regulates the rate of EGFR down-regulation by deubiquitinating EGFR on endosomes.

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Hrs Regulates Endosome Membrane Invagination and Tyrosine Kinase Receptor Signaling in Drosophila

Cited by 417 publications

References 53 publications

Drosophila Rab2 controls endosome-lysosome fusion and LAMP delivery to late endosomes

Drosophila Rab2 controls endosome-lysosome fusion and LAMP delivery to late endosomes

CART: An Hrs/Actinin-4/BERP/Myosin V Protein Complex Required for Efficient Receptor Recycling

Regulation of Epidermal Growth Factor Receptor Down-Regulation by UBPY-mediated Deubiquitination at Endosomes

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