Rab5-activating protein 6, a novel endosomal protein with a role in endocytosis

Hunker, C.M.; Galvis, Adriana; Kruk, I.; Giambini, H.; Veisaga, Maria‐Luisa; Barbieri, M. Alejandro

doi:10.1016/j.bbrc.2005.12.099

Cited by 35 publications

(45 citation statements)

References 26 publications

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“…3 Moreover, a recent study of the C. elegans homolog of GAPex-5, rme6, also suggested a PM localization (48). The exchange activity of GAPex-5, also named RAP6, for Rab5 and its effects on insulin internalization have been studied recently (55). Thus, GAPex-5 might mediate the activation of a pool of Rab5 proximal to the plasma membrane that is necessary to recruit p85␣ to tyrosyl-phosphorylated IRS1.…”

Section: Discussionmentioning

confidence: 99%

Insulin-stimulated Interaction between Insulin Receptor Substrate 1 and p85α and Activation of Protein Kinase B/Akt Require Rab5

Lodhi

Saltiel

et al. 2006

Journal of Biological Chemistry

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Binding of insulin to the insulin receptor initiates a cascade of protein phosphorylation and effector recruitment events leading to the activation of multiple distinct signaling pathways. Previous studies suggested that the diversity and specificity of insulin signal transduction are accomplished by both subcellular localization of receptor and the selective activation of downstream signaling molecules. The small GTPase Rab5 is a key regulator of endocytosis. Three Rab5 isoforms (Rab5a, -5b, and -5c) have been identified. Here we exploited the RNA interference technique to specifically knock down individual Rab5 isoforms to determine the cellular function of Rab5 in distinct insulin signaling pathways. Small interference RNA against a single Rab5 isoform had no effect on protein kinase B (PKB)/Akt or MAPK activation by insulin in NIH3T3 cells overexpressing human insulin receptor. However, simultaneous knockdown of all three Rab5 isoforms dramatically attenuated PKB/Akt activation by insulin without affecting MAPK activation. This inhibition of PKB/Akt activation was because of the impaired interaction between insulin receptor substrate 1 and the p85␣ subunit of phosphatidylinositol 3-kinase. These results indicate a requirement of Rab5 in presenting p85 to insulin receptor substrate 1. Additional evidence supporting a role for Rab5 was suggested by studies with GAPex-5, a vps9 domain containing exchange factor. Down-regulation of GAPex-5 impaired insulin-stimulated PKB/Akt activation. Collectively, this study indicates the involvement of Rab5 in insulin signaling.Both environmental and genetic factors contribute to the development of type 2 diabetes mellitus. Although detailed mechanisms underlying the development of this disorder remain unknown, impairment of insulin action has been clearly established as an early defect in the pathogenesis of type 2 diabetes (1, 2). Binding of insulin to the insulin receptor (IR) 2 causes receptor autophosphorylation and activation of its intrinsic kinase activity. Activated IR phosphorylates a variety of intracellular substrates, most notably the insulin receptor substrate (IRS) proteins (3, 4). Tyrosine phosphorylation of these proteins provides binding sites for downstream effectors with Src homolog 2 domains or phosphotyrosine binding domains that activate multiple signaling pathways required for insulin-stimulated glucose uptake and maintenance of energy homeostasis (5, 6). Type 1A phosphatidylinositol 3-kinase (PI3K) represents a primary target of insulin action (7). Phosphorylation of IRS1 and/or IRS2 on tyrosine residues by activated IR creates recognition sites for the p85 regulatory subunit of PI3K, thereby allowing the activation of the p110 catalytic subunit (8). PI3K-generated phosphoinositides PI(3,4,5)P 3 and PI(3,4)P 2 recruit protein kinase B (PKB)/Akt and 3-phosphoinositide-dependent kinase to the membrane, resulting in PKB/Akt phosphorylation and activation (9 -11). Recent studies also demonstrated a second requisite pathway that involves recruitment of ty...

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Section: Discussionmentioning

confidence: 99%

Insulin-stimulated Interaction between Insulin Receptor Substrate 1 and p85α and Activation of Protein Kinase B/Akt Require Rab5

Lodhi

Saltiel

et al. 2006

Journal of Biological Chemistry

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“…Gapvd1, is an activator of the early endosome regulator protein Rab. It regulates vesicular trafficking processes such as endocytosis of activated transmembrane proteins and exocytosis of GLUT4 vesicles (Hunker et al, 2006;Lodhi et al, 2007). Recent studies have shown that it can regulate EGFR endocytosis and degradation independently of Rab5 function (Su et al, 2007).…”

Section: Vav2 Knockdown Affects Egfr Degradationmentioning

confidence: 99%

“…Gapvd1 (Gapex-5), one of the endosomal proteins that interacted with Vav2, has been shown to regulate stability of growth factor receptors. Its expression enhanced the internalization and degradation of insulin receptor while specific siRNA inhibited EGFR degradation independently of its effect on Rab5 (Hunker et al, 2006;Su et al, 2007). Tom1L1 associates with endosomes and has been shown to regulate the activity of Src kinase as well (Puertollano, 2005;Franco et al, 2006).…”

Section: Vav2 Regulates Egfr Stability S Thalappilly Et Almentioning

confidence: 99%

“…However, it is not known whether Vav proteins have a role in EGFR endocytosis or trafficking. Recently, in a proteomic study on multi-SH3 domain containing proteins, we identified two endosome-associated proteins that interacts with Vav2: the Rab regulatory protein Gapvd1 and the endosome-associated protein Tom1L1 (Puertollano, 2005;Bache et al, 2006;Hunker et al, 2006;Thalappilly et al, 2008). The aim of this work is to better understand the role of Vav2 in EGFR endocytosis and degradation in association with the endosomal proteins (Gapvd1 and Tom1L1).…”

Section: Introductionmentioning

confidence: 99%

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VAV2 regulates epidermal growth factor receptor endocytosis and degradation

et al. 2010

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Vav proteins are guanine nucleotide exchange factors for Rho GTPases that regulate cell adhesion, motility, spreading and proliferation in response to growth factor signalling. In this work, we show that Vav2 expression delayed epidermal growth factor receptor (EGFR) internalization and degradation, and enhanced EGFR, ERK and Akt phosphorylations. This effect of Vav2 on EGFR degradation is dependent on its guanine nucleotide exchange function. Knockdown of Vav2 in HeLa cells enhanced EGFR degradation and reduced cell proliferation. epidermal growth factor stimulation led to colocalization of Vav2 with EGFR and Rab5 in endosomes. We further show that the effect of Vav2 on EGFR stability is modulated by its interaction with two endosome-associated proteins and require RhoA function. Thus, in this work, we report for the first time that Vav2 can regulate growth factors receptor signalling by slowing receptor internalization and degradation through its interaction with endosome-associated proteins.

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“…These proteins are characterized by sharing a highly conserved Vps9 (vacuolar protein sorting 9) domain that catalyzes the exchange from GDP to GTP, activating Rab5. Examples are the yeast homolog Vps9p (Hama et al, 1999), Rabex-5 (Carney et al, 2006), Rin1 (Han and Colicelli, 1995;Tall et al, 2001), Alsin2 (Otomo et al, 2008), RME-6 (Sato et al, 2005), and Rap 6 (Hunker et al, 2006a;Sato et al, 2005) (Figure 1.11).…”

Section: Signal Transduction and Endocytosismentioning

confidence: 99%

Novel Insights into the Mechanisms of Regulation of Tyrosine Kinase Receptors by Ras Interference 1

Galvis¹

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iii DEDICATION I want to dedicate this dissertation, and everything it represents, to my family. To my husband, my parents, and my siblings. I can't thank you enough for the love and support; you made this journey a lot easier. Thanks for helping me make this dream come true.Quiero dedicarle esta tesis, y todo lo que representa, a mi familia. A mi esposo, mis papas y mis hermanos. No tengo como agradecerles por todo el amor y el apoyo; ustedes hicieron de este, un camino mucho mas facil de recorrer.Muchas gracias por ayudarme a hacer este sueño realidad. Taken together, the data indicate a potential molecular mechanism by which proteins or small molecules regulate selective and specific RTK intracellular membrane trafficking and signaling during cell growth and differentiation in normal and pathological conditions.

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Rab5-activating protein 6, a novel endosomal protein with a role in endocytosis

Cited by 35 publications

References 26 publications

Insulin-stimulated Interaction between Insulin Receptor Substrate 1 and p85α and Activation of Protein Kinase B/Akt Require Rab5

Insulin-stimulated Interaction between Insulin Receptor Substrate 1 and p85α and Activation of Protein Kinase B/Akt Require Rab5

VAV2 regulates epidermal growth factor receptor endocytosis and degradation

Novel Insights into the Mechanisms of Regulation of Tyrosine Kinase Receptors by Ras Interference 1

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