Human VPS34 and p150 are Rab7 Interacting Partners

Stein, Mary‐Pat; Feng, Yan; Cooper, Karen L.; Welford, Angela; Wandinger‐Ness, Angela

doi:10.1034/j.1600-0854.2003.00133.x

Cited by 149 publications

(143 citation statements)

References 47 publications

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“…This finding is consistent with previous studies on the effects of PI 3-kinase inhibitors on the degradation of other signaling receptors, such as the PDGF receptor [16] and the EGF receptor [25,26] There are at least three PI 3-kinases in mammalian cells, and the most commonly used PI 3-kinase inhibitors act on all three [27]. Evidence from other studies implicates the type III PI 3-kinase hVps34 in controlling traffic to lysosomes [28,29]. Whether hVps34 is the PI 3-kinase responsible for controlling β 2 AR sorting to lysosomes will require additional studies.…”

Section: Discussionsupporting

confidence: 91%

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Inhibitors of phosphoinositide 3-kinase cause defects in the postendocytic sorting of β2-adrenergic receptors

Awwad

Iyer

Rosenfeld

et al. 2007

Experimental Cell Research

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Phosphatidylinositol 3-kinase inhibitors have been shown to affect the endocytosis or subsequent intracellular sorting in various receptor systems. Agonist-activated β 2 -adrenergic receptors undergo desensitization by mechanisms that include the phosphorylation, endocytosis and degradation of receptors. Following endocytosis, most internalized receptors are sorted to the cell surface, but some proportion is sorted to lysosomes for degradation. It is not known what governs the ratio of receptors that recycle versus receptors that undergo degradation. To determine if phosphatidylinositol 3-kinases regulate β 2 -adrenergic receptor trafficking, HEK293 cells stably expressing these receptors were treated with the phosphatidylinositol 3-kinase inhibitors LY294002 or wortmannin. We then studied agonist-induced receptor endocytosis and postendocytic sorting, including recycling and degradation of the internalized receptors. Both inhibitors amplified the internalization of receptors after exposure to the β-agonist isoproterenol, which was attributable to the sorting of a significant fraction of receptors to an intracellular compartment from which receptor recycling did not occur. The initial rate of β 2 -adrenergic receptor endocytosis and the default rate of receptor recycling were not significantly altered. During prolonged exposure to agonist, LY294002 slowed the degradation rate of β 2 -adrenergic receptors and caused the accumulation of receptors within rab7-positive vesicles. These results suggest that phosphatidylinositol 3-kinase inhibitors (1) cause a misrouting of β 2 -adrenergic receptors into vesicles that are neither able to efficiently recycle to the surface nor sort to lysosomes, and (2) delays the movement of receptors from late endosomes to lysosomes.

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Section: Discussionsupporting

confidence: 91%

“…5) is consistent with this interpretation. The molecular mechanisms underlying rab7 action are not clear at present, however a recent study shows that rab7 binds to hVps34 (a PI 3kinase) and localizes it to late endosomes [29]. PI 3-kinase inhibitors did not affect the initial rate of β 2 AR endocytosis in our system (Fig.…”

Section: Discussionmentioning

confidence: 58%

Inhibitors of phosphoinositide 3-kinase cause defects in the postendocytic sorting of β2-adrenergic receptors

Awwad

Iyer

Rosenfeld

et al. 2007

Experimental Cell Research

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“…mechanisms or use unique molecule(s) to interact with microtubules. Two other putative Rab7 effectors, hVps34/p150 and XAPC7, might have been overlooked in our affinity screening because hVps34/p150 generally shows the highest affinity to nucleotide-free Rab7 (Stein et al, 2003), and the molecular mass of XAPC7 is 27 kDa, which was below the limit of our detection due to contamination of GST-fusion proteins.…”

Section: Significance Of the Interaction Between Ehrab7a And The Retrmentioning

confidence: 96%

“…Homology-based genome-wide search of the putative effectors of the amoebic Rab7A using known Rab7 effectors from other organisms, including RILP, Rabring7, hVps34p/p150 (phosphatidylinositol 3-kinase), and proteasome ␣-subunit (XAPC7) indicated that this organism possesses homologues for Vps34/p150 and XAPC7, but lacks RILP and Rabring7, suggestive of the presence of novel Rab7 effectors in this organism (Cantalupo et al, 2001;Mizuno et al, 2003;Stein et al, 2003;Dong et al, 2004). Thus, we attempted to isolate the effector molecules of EhRab7A by affinity purification to gain an insight in the regulation of the amoebic Rab7A.…”

Section: Identification Of a Retromerlike Complex As A Novel Ehrab7a mentioning

confidence: 99%

A Retromerlike Complex Is a Novel Rab7 Effector That Is Involved in the Transport of the Virulence Factor Cysteine Protease in the Enteric Protozoan ParasiteEntamoeba histolytica

Nakada‐Tsukui

Saito‐Nakano

Ali

et al. 2005

MBoC

139

173

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Vesicular trafficking plays an important role in a virulence mechanism of the enteric protozoan parasite Entamoeba histolytica as secreted and lysosomal cysteine protease (CP) contributes to both cytolysis of tissues and degradation of internalized host cells. Despite the primary importance of intracellular sorting in pathogenesis, the molecular mechanism of CP trafficking remains largely unknown. In this report we demonstrate that transport of CP is regulated through a specific interaction of Rab7A small GTPase (EhRab7A) with the retromerlike complex. The amoebic retromerlike complex composed of Vps26, Vps29, and Vps35 was identified as EhRab7A-binding proteins. The amoebic retromerlike complex specifically bound to GTP-EhRab7A, but not GDP-EhRab7A through the direct binding via the carboxy terminus of EhVps26. In erythrophagocytosis the retromerlike complex was recruited to prephagosomal vacuoles, the unique preparatory vacuole of digestive enzymes, and later to phagosomes. This dynamism was indistinguishable from that of EhRab7A, and consistent with the premise that the retromerlike complex is involved in the retrograde transport of putative hydrolase receptor(s) from preparatory vacuoles and phagosomes to the Golgi apparatus. EhRab7A overexpression caused enlargement of lysosomes and decrease of the cellular CP activity. The reduced CP activity was restored by the coexpression of EhVps26, implying that the EhRab7A-mediated transport of CP to phagosomes is regulated by the retromerlike complex. INTRODUCTIONRab GTPases play an essential role to regulate intracellular membrane trafficking. The compartmentalization and functions of Rab proteins are modulated at multiple layers of mechanisms including isoprenylation of the carboxy terminus, nucleotide exchange, and binding of specific effector molecules (Stenmark and Olkkonen, 2001;Takai et al., 2001;Tuvim et al., 2001). Among these modulators, effectors play key roles in the control of 7-90 Rab proteins depending on organisms from fission yeast and amoeba to mammals and plants. A variety of effectors have been identified and shown to interact with specific Rab protein. For instance, regulatory secretions of neurotransmitters from neurons or insulin from pancreatic ␤-cells are regulated by the specific interaction of Rab3 with its effectors (Jahn and Sudhof, 1999). At least four proteins, Rabphilin3, Rim1, Rim2, and Noc2, are known to bind Rab3 and recruit cAMP-GEFII, 14 -3-3, and zyxin, respectively, to regulate cAMP responsiveness, phosphoserine-dependent signaling, and the interaction with cytoskeleton (Kotake et al., 1997;Ozaki et al., 2000;Sun et al., 2003). The specificity of the Rab-effector interaction is attributable to primary sequence motifs in only a few cases including exophilins or Slip/Slac2, Rab3, and Rab27 effectors (Izumi et al., 2003). However, the majority of Rab effectors lack recognizable conserved binding motifs. For instance, Rab5 effectors, rabaptin-5, Rabex-5, EEA1, Rabenosyn-5, hVps34/p150, p110␤/p35␣, rabip4Ј, and rabankyrin-5, which a...

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“…The chicken anti-Rab7 antibody (Stein et al, 2003;Dong et al, 2004) was a kind gift from Dr. Angela Wandinger-Ness, and rabbit anti-Rab7 was purchased from Santa Cruz Biotechnology (Santa Cruz, CA). Mouse monoclonal antibody (mAb) against the Xpress epitope was from Invitrogen, monoclonal lysosome-associated membrane protein-1 (Lamp-1) (H4A3) antibody was from Santa Cruz Biotechnology, and anti-p150 glued was from BD Biosciences (San Jose, CA).…”

Section: Antibodiesmentioning

confidence: 99%

The Oxysterol-binding Protein Homologue ORP1L Interacts with Rab7 and Alters Functional Properties of Late Endocytic Compartments

Johansson

Lehto

Tanhuanpää

et al. 2005

MBoC

204

199

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ORP1L is a member of the human oxysterol-binding protein (OSBP) family. ORP1L localizes to late endosomes (LEs)/lysosomes, colocalizing with the GTPases Rab7 and Rab9 and lysosome-associated membrane protein-1. We demonstrate that ORP1L interacts physically with Rab7, preferentially with its GTP-bound form, and provide evidence that ORP1L stabilizes GTP-bound Rab7 on LEs/lysosomes. The Rab7-binding determinant is mapped to the ankyrin repeat (ANK) region of ORP1L. The pleckstrin homology domain (PHD) of ORP1L binds phosphoinositides with low affinity and specificity. ORP1L ANK-and ANK؉PHD fragments induce perinuclear clustering of LE/lysosomes. This is dependent on an intact microtubule network and a functional dynein/dynactin motor complex. The dominant inhibitory Rab7 mutant T22N reverses the LE clustering, suggesting that the effect is dependent on active Rab7. Transport of fluorescent dextran to LEs is inhibited by overexpression of ORP1L. Overexpression of ORP1L, and in particular the N-terminal fragments of ORP1L, inhibits vacuolation of LE caused by Helicobacter pylori toxin VacA, a process also involving Rab7. The present study demonstrates that ORP1L binds to Rab7, modifies its functional cycle, and can interfere with LE/lysosome organization and endocytic membrane trafficking. This is the first report of a direct connection between the OSBP-related protein family and the Rab GTPases.

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Human VPS34 and p150 are Rab7 Interacting Partners

Cited by 149 publications

References 47 publications

Inhibitors of phosphoinositide 3-kinase cause defects in the postendocytic sorting of β2-adrenergic receptors

Inhibitors of phosphoinositide 3-kinase cause defects in the postendocytic sorting of β2-adrenergic receptors

A Retromerlike Complex Is a Novel Rab7 Effector That Is Involved in the Transport of the Virulence Factor Cysteine Protease in the Enteric Protozoan ParasiteEntamoeba histolytica

The Oxysterol-binding Protein Homologue ORP1L Interacts with Rab7 and Alters Functional Properties of Late Endocytic Compartments

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