Rabaptin4, a novel effector of the small GTPase rab4a, is recruited to perinuclear recycling vesicles

Nagelkerken, Bas; Anken, Eelco van; Raak, M. van; Gerez, Lisya; Mohrmann, Karin; Uden, Nathalie O. van; Holthuizen, Jessica; Pelkmans, Lucas; Sluijs, Peter van der

doi:10.1042/bj3460593

Cited by 50 publications

(40 citation statements)

References 30 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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“…However, rab4 effectors may cross-talk with ARF1-dependent pathways. Rabaptin variants have been identified that interact with rab4 (and rab5) (22,44). Interestingly, rabaptins also bind to ␥-adaptin and the ARF1 effector GGA2 (45,46) and thereby might regulate ARF1-dependent budding events from endosomes.…”

Section: Discussionmentioning

confidence: 99%

“…myc-tagged human TfR cDNA was excised with SacI and XbaI from mycTfR-pCB6 (21) and ligated in pCB7 (generously provided by Jim Casanova; Harvard University). rab4, rab4S22N, and rab4Q67L were released with EcoRI from corresponding pGBT9 constructs (22) and cloned in the same site of pcDNA3 (Invitrogen). NH-tagged rab4 constructs were as described previously (23).…”

Section: Methodsmentioning

confidence: 99%

rab4 Regulates Transport to the Apical Plasma Membrane in Madin-Darby Canine Kidney Cells

Mohrmann

Leijendekker

Gerez

et al. 2002

Journal of Biological Chemistry

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The small GTPase rab4 is associated with early endosomes and regulates membrane recycling in fibroblasts. rab4 is present in epithelial cells; however, neither its localization nor function has been established in this cell type. We transfected Madin-Darby canine kidney cells with rab4, the GTPase-deficient mutant rab4Q67L, and the dominant negative mutant rab4S22N that poorly binds guanine nucleotides. Confocal immunofluorescence microscopy showed that rab4 was concentrated on internal structures at the lateral side of the cell around the nucleus. Quantitative immunoelectron microscopy revealed that the majority of rab4 was localized in the upper third of the cytoplasm. In cell surface binding experiments with 125 I-transferrin, we found a redistribution of transferrin receptor from the basolateral to the apical plasma membrane in cells expressing rab4 and rab4Q67L. After accumulation of transferrin at 16°C in basolateral early endosomes, rab4 and rab4Q67L increased the amount of apically targeted transferrin receptor. A qualitatively similar effect was obtained in control cells treated with brefeldin A. The effects of brefeldin A and rab4 on apical targeting of transferrin receptor were not additive, suggesting that brefeldin A and rab4 may act in the same transport pathway from common endosomes.

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“…Some of these proteins, namely Rabaptin-5α and Rabaptin-5δ, were implicated in EE traffic. 8,12,13 It is not known if these Rabaptin-5-like proteins, also called Rabaptin-5 isoforms, were cleaved similarly to Rabaptin-5 in apoptotic cells. In this study we addressed this question and also attempted to reveal molecular consequences of Rabaptin-5-like protein cleavage in apoptotic cells resulting in incompetence of their apoptotic fragments to support EE fusion.…”

Section: Introductionmentioning

confidence: 99%

“…Recently several Rabaptin-5-like proteins with deletions of short amino acid stretches in polypeptide chains, encoded by alternatively spliced transcripts were described [10][11][12] (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Apoptotic Cleavage of Rabaptin-5-like Proteins and a Model for Rabaptin-5 Inactivation in Apoptosis

Korobko

Palgova²,

Kiselev³

et al. 2006

Cell Cycle

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Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/abstract.php?id=3092 KEY WORDSendocytosis, Rabaptin-5, Rabaptin-5 isoforms, apoptosis, Rab5 binding site ABBREVIATIONS 3AT3 ABSTRACTIntracellular membrane transport from the plasma membrane is one of the processes affected in apoptotic cells. Apoptotic inhibition of endosomal transport occurs due to cleavage of Rabaptin-5, an effector of small GTPase Rab5, which results in inhibition of early endosome fusion. Recently several novel Rabaptin-5-like proteins were identified. We investigated whether Rabaptin-5-like proteins, Rabaptin-5γ and Rabaptin-5δ, are also cleaved in apoptosis and found that both proteins are cleaved in apoptotic cell extracts by caspase-3-related proteases. This suggests that functional inactivation of these proteins is necessary for apoptotic cell death. We also mapped a novel, N-terminal, putative Rab5 binding site in Rabaptin-5-like proteins, which becomes physically separated from the previously known C-terminal Rab5 binding site after apoptotic cleavage of these proteins. Presence of the second Rab5 binding site provides a new insight into Rabaptin-5 function in early endosome fusion and a mechanistic model for functional inactivation of Rabaptin-5 in apoptosis.

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Rabaptin4, a novel effector of the small GTPase rab4a, is recruited to perinuclear recycling vesicles

Cited by 50 publications

References 30 publications

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

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

rab4 Regulates Transport to the Apical Plasma Membrane in Madin-Darby Canine Kidney Cells

Apoptotic Cleavage of Rabaptin-5-like Proteins and a Model for Rabaptin-5 Inactivation in Apoptosis

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