The small GTP-binding protein rab4 is associated with early endosomes

Sluijs, Peter van der; Hull, Michael; Zahraoui, Ahmed; Tavitian, Armand; Goud, Bruno; Mellman, Ira

doi:10.1016/0962-8924(91)90014-z

Cited by 30 publications

(32 citation statements)

References 28 publications

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“…For example, rab5a is present on endosomes, is involved in endosome-endosome fusion (Gournier et al, 1998), in linking early endosomes to microtubules, and in minus-end-directed movement (Nielsen et al, 1999), although rab5a has not yet been demonstrated to interact with any motor protein. Rab 4 and rab 11 are endosome-associated proteins thought to be involved in recycling (Van Der Sluijs et al, 1991;McCaffrey et al, 2001;Peden et al, 2004) but their precise roles and which of the many possible effectors are relevant for this function remains unclear (Nagelkerken et al, 2000;Cormont et al, 2001;van der Sluijs et al, 2001;Fouraux et al, 2004;Peden et al, 2004). The present data suggest that hrs may link endosomes to actin through actinin-4, BERP, and myosin Vb.…”

Section: Discussionmentioning

confidence: 60%

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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Section: Discussionmentioning

confidence: 60%

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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“…Accumulated evidence suggests that Rab GTPases recruit tethering and docking factors to establish firm contact between the membranes to fuse, after which SNAREs become involved and complete the fusion process (Pfeffer, 1999). Several Rab proteins have been localized to the early sorting and recycling endosomal compartments (Rab4a, Rab5a, Rab5b, Rab5c, Rab11, Rab18, Rab22, and Rab25) (van der Sluijs et al, 1991;Lü tcke et al, 1994;Bucci et al, 1995;Ullrich et al, 1996;Green et al, 1997;Casanova et al, 1999), whereas only two, Rab7 and Rab9, have been localized to late endosomes (Chavrier et al, 1990;Lombardi et al, 1993). Because Rab9 is also present in the trans-Golgi network (TGN) and controls transport from late endosomes to the TGN (Lombardi et al, 1993), the more likely candidate for being part of the molecular machinery responsible for the continuous fusion events between late endocytic structures and lysosomes is Rab7.…”

Section: Introductionmentioning

confidence: 99%

Rab7: A Key to Lysosome Biogenesis

Bucci

Thomsen

Nicoziani

et al. 2000

MBoC

989

870

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The molecular machinery behind lysosome biogenesis and the maintenance of the perinuclear aggregate of late endocytic structures is not well understood. A likely candidate for being part of this machinery is the small GTPase Rab7, but it is unclear whether this protein is associated with lysosomes or plays any role in the regulation of the perinuclear lysosome compartment. Previously, Rab7 has mainly been implicated in transport from early to late endosomes. We have now used a new approach to analyze the role of Rab7: transient expression of Enhanced Green Fluorescent Protein (EGFP)-tagged Rab7 wt and mutant proteins in HeLa cells. EGFP-Rab7 wt was associated with late endocytic structures, mainly lysosomes, which aggregated and fused in the perinuclear region. The size of the individual lysosomes as well as the degree of perinuclear aggregation increased with the expression levels of EGFP-Rab7 wt and, more dramatically, the active EGFP-Rab7Q67L mutant. In contrast, upon expression of the dominant-negative mutants EGFP-Rab7T22N and EGFP-Rab7N125I, which localized mainly to the cytosol, the perinuclear lysosome aggregate disappeared and lysosomes, identified by colocalization of cathepsin D and lysosome-associated membrane protein-1, became dispersed throughout the cytoplasm, they were inaccessible to endocytosed molecules such as low-density lipoprotein, and their acidity was strongly reduced, as determined by decreased accumulation of the acidotropic probe LysoTracker Red. In contrast, early endosomes associated with Rab5 and the transferrin receptor, late endosomes enriched in the cation-independent mannose 6-phosphate receptor, and the trans-Golgi network, identified by its enrichment in TGN-38, were unchanged. These data demonstrate for the first time that Rab7, controlling aggregation and fusion of late endocytic structures/lysosomes, is essential for maintenance of the perinuclear lysosome compartment. INTRODUCTIONThe "kiss-and-run" model for lysosome biogenesis proposes that maintenance of the lysosomal compartment depends on continuous fusions of late endocytic structures accompanied by fission events (Storrie and Desjardins, 1996). This model implies that, in addition to heterotypic fusions between late endosomes and lysosomes in the perinuclear region, there could also be continuous exchange within the lysosomal vesicle population (homotypic fusion). Indeed, evidence for fusions and bidirectional traffic of soluble material between lysosomes and late endosomes has been reported (Jahraus et al., 1994;Mullock et al., 1994;van Deurs et al., 1995;Futter et al., 1996;Storrie and Desjardins, 1996;Bright et al., 1997;Mullock et al., 1998).Several different molecules are part of the machinery responsible for vesicle docking and fusion, Rab GTPases and SNAREs being among the best studied (Rothman and Warren, 1994;Denesvre and Malhotra, 1996;Pfeffer, 1996Pfeffer, , 1999Olkkonen and Stenmark, 1997;Mayer, 1999;Waters and Pfeffer, 1999). Rab proteins are important regulators of membrane traffic on the biosynthetic ...

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“…We previously localized rab4 and rab5, two members of the rab family of small GTPases, together with the transferrin receptor in the early endosomal network (4,33). It is not surprising that the early endosomal compartment contains several rab GTPases (19), each of which possibly controls a distinct transport event leading to or originating from the early endosome.…”

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confidence: 99%