Role of Rab5 in insulin receptor-mediated endocytosis and signaling

Hunker, C.M.; Kruk, I.; Hall, Jessica A.; Giambini, H.; Veisaga, Maria‐Luisa; Barbieri, M. Alejandro

doi:10.1016/j.abb.2006.01.020

Cited by 28 publications

(29 citation statements)

References 43 publications

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“…The expression of constitutively active Rab5 (Q79L) causes ligand-independent EGFR internalization, while the expression of dominant negative Rab5 (S34N) blocks EGF-stimulated and receptor-mediated endocytosis, which affects EGF activation in the Raf-Erk kinase pathway [34][35][36]. Rab5 was also found to be involved in insulin receptor-mediated endocytosis [37]. In our study, we found that AdipoR1 colocalizes with Rab5.…”

Section: Discussionmentioning

confidence: 70%

Endocytosis of adiponectin receptor 1 through a clathrin- and Rab5-dependent pathway

2008

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In eukaryotic cells, receptor endocytosis is a key event regulating signaling transduction. Adiponectin receptors belong to a new receptor family that is distinct from G-protein-coupled receptors and has critical roles in the pathogenesis of diabetes and metabolic syndrome. Here, we analyzed the endocytosis of adiponectin and adiponectin receptor 1 (AdipoR1) and found that they are both internalized into transferrin-positive compartments that follow similar traffic routes. Blocking clathrin-mediated endocytosis by expressing Eps15 mutants or depleting K + trapped AdipoR1 at the plasma membrane, and K + depletion abolished adiponectin internalization, indicating that the endocytosis of AdipoR1 and adiponectin is clathrin-dependent. Depletion of K + and overexpression of Eps15 mutants enhance adiponectinstimulated AMP-activated protein kinase phosphorylation, suggesting that the endocytosis of AdipoR1 might downregulate adiponectin signaling. In addition, AdipoR1 colocalizes with the small GTPase Rab5, and a dominant negative Rab5 abrogates AdipoR1 endocytosis. These data indicate that AdipoR1 is internalized through a clathrin-and Rab5-dependent pathway and that endocytosis may play a role in the regulation of adiponectin signaling.

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Section: Discussionmentioning

confidence: 70%

Endocytosis of adiponectin receptor 1 through a clathrin- and Rab5-dependent pathway

2008

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“…via modulation of the function of Rab5, which is a major regulator of the early endocytic pathway (5, 39 -42) known to affect internalization of VEGFR2 (43). Here, we made use of two well studied mutants of Rab5, Rab5S34N and Rab5Q79L, which exert a differential effect on endocytosis (44,45). Rab5S34N is a constitutively inactive, GDP-locked, mutant of Rab5 that inhibits endocytosis, whereas Rab5Q79L is a stably active GTP mutant that augments homotypic fusion and expansion of early endosomes, thereby causing retention of the endocytic cargo at the early endosome (44,45).…”

Section: Overexpression Of Rab5s34n Which Results In Higher Levelsmentioning

confidence: 99%

“…Here, we made use of two well studied mutants of Rab5, Rab5S34N and Rab5Q79L, which exert a differential effect on endocytosis (44,45). Rab5S34N is a constitutively inactive, GDP-locked, mutant of Rab5 that inhibits endocytosis, whereas Rab5Q79L is a stably active GTP mutant that augments homotypic fusion and expansion of early endosomes, thereby causing retention of the endocytic cargo at the early endosome (44,45). Overexpression of the dominant-negative mutant of Rab5 (Rab5S34N), by adenoviral infection, resulted in elevation of the levels of VEGR2 at the plasma membrane and a parallel increase of the p130-kDa polypeptide, at the expense of full-length VEGFR2 (Fig.…”

Section: Overexpression Of Rab5s34n Which Results In Higher Levelsmentioning

confidence: 99%

Constitutive Endocytosis of VEGFR2 Protects the Receptor against Shedding

Basagiannis

Christoforidis

2016

Journal of Biological Chemistry

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VEGFR2 plays a fundamental role in blood vessel formation and in life threatening diseases, such as cancer angiogenesis and cardiovascular disorders. Although inactive growth factor receptors are mainly localized at the plasma membrane, VEGFR2 undergoes constitutive endocytosis (in the absence of ligand) and recycling. Intriguingly, the significance of these futile transport cycles of VEGFR2 remains unclear. Here we found that, unexpectedly, the function of constitutive endocytosis of VEGFR2 is to protect the receptor against plasma membrane cleavage (shedding), thereby preserving the functional state of the receptor until the time of activation by VEGF. Inhibition of constitutive endocytosis of VEGFR2, by interference with the function of clathrin, dynamin, or Rab5, increases dramatically the cleavage/shedding of VEGFR2. Shedding of VEGFR2 produces an N-terminal soluble fragment (100 kDa, s100), which is released in the extracellular space, and a residual C-terminal part (130 kDa, p130) that remains integrated at the plasma membrane. The released soluble fragment (s100) co-immunoprecipitates with VEGF, in line with the topology of the VEGF-binding domain at the N terminus of VEGFR2. Increased shedding of VEGFR2 (via inhibition of constitutive endocytosis) results in reduced response to VEGF, consistently with the loss of the VEGF-binding domain from the membrane remnant of VEGFR2. These data suggest that constitutive internalization of VEGFR2 protects the receptor against shedding and provides evidence for an unprecedented mechanism via which endocytosis can regulate the fate and activity of growth factor receptors.Growth factor receptors are synthesized and processed in the ER/Golgi biosynthetic network. Subsequently, they are delivered to the plasma membrane to become available for binding to their extracellular cognate ligands. In principle, in the absence of ligand, quiescent receptors are preferentially localized at the plasma membrane, whereas only a small percentage of the surface molecules are constitutively internalized (1-3). On the other hand, ligand binding and subsequent receptor activation increases dramatically the efficiency of receptor internalization (3, 4). Internalized receptors explore the different endocytic itineraries and the diverse endocytic compartments to finetune the intensity, nature, and duration of the signaling events (2, 4, 5). Subsequently, growth factor receptors are either recycled back to plasma membrane, for another round of activation, or they are sorted to lysosomes or the proteasome for degradation, leading to irreversible termination of the receptor function (6). In fact, in general, the degradative role of endocytosis is considered to be one of the major housekeeping functions of the cell that eventually down-regulates the levels of the internalized, extracellular or plasma membrane, molecules (7-9).VEGFR2 is a receptor-tyrosine kinase that plays a critical role in blood vessel formation and pathological angiogenesis (10,11). Similarly to other receptor-tyrosine kinas...

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“…The cellular permeability to chemotherapeutic agents can be enhanced via a process known as insulin-mediated endocytosis. 39,40 This specific process enables cells to take up small and large molecular ligands, such as hormones, growth factors, enzymes, and plasma proteins.…”

Section: Insulin Receptors and Drug Uptakementioning

confidence: 99%

Insulin-induced enhancement of MCF-7 breast cancer cell response to 5-fluorouracil and cyclophosphamide

et al. 2017

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The study was designed to evaluate the potential use of insulin for cancer-specific treatment. Insulin-induced sensitivity of MCF-7 breast cancer cells to chemotherapeutic agents 5-fluorouracil and cyclophosphamide was evaluated. To investigate and establish the possible mechanisms of this phenomenon, we assessed cell proliferation, induction of apoptosis, activation of apoptotic and autophagic pathways, expression of glucose transporters 1 and 3, formation of reactive oxygen species, and wound-healing assay. Additionally, we reviewed the literature regarding theuse of insulin in cancer-specific treatment. We found that insulin increases the cytotoxic effect of 5-fluorouracil and cyclophosphamide in vitro up to two-fold. The effect was linked to enhancement of apoptosis, activation of apoptotic and autophagic pathways, and overexpression of glucose transporters 1 and 3 as well as inhibition of cell proliferation and motility. We propose a model for insulin-induced sensitization process. Insulin acts as a sensitizer of cancer cells to cytotoxic therapy through various mechanisms opening a possibility for metronomic insulin-based treatments.

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Role of Rab5 in insulin receptor-mediated endocytosis and signaling

Cited by 28 publications

References 43 publications

Endocytosis of adiponectin receptor 1 through a clathrin- and Rab5-dependent pathway

Endocytosis of adiponectin receptor 1 through a clathrin- and Rab5-dependent pathway

Constitutive Endocytosis of VEGFR2 Protects the Receptor against Shedding

Insulin-induced enhancement of MCF-7 breast cancer cell response to 5-fluorouracil and cyclophosphamide

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