Rin1 regulates insulin receptor signal transduction pathways

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

doi:10.1016/j.yexcr.2005.12.021

Cited by 21 publications

(18 citation statements)

References 38 publications

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“…Rac1 binding to ALS2 may be important for the initiation of the ALS2 redistribution but not for functional modulation, such as potentiation of the Rab5GEF activity. Interestingly, the Rab5GEF RIN1 is recruited to tyrosine-phosphorylated residues in cytoplasmic tails of many receptor-tyrosine kinases upon activation of the receptors (42,43). Thus, alteration of the subcellular localization of Rab5GEFs, such as ALS2 and RIN1, may be a common means of the spatiotemporal activation of Rab5 signaling in response to upstream signals.…”

Section: Discussionmentioning

confidence: 99%

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The Rab5 Activator ALS2/alsin Acts as a Novel Rac1 Effector through Rac1-activated Endocytosis

Kunita

Otomo

Mizumura

et al. 2007

Journal of Biological Chemistry

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Mutations in the ALS2 gene cause a number of recessive motor neuron diseases, indicating that the ALS2 protein (ALS2/ alsin) is vital for motor neurons. ALS2 acts as a guanine nucleotide exchange factor (GEF) for Rab5 (Rab5GEF) and is involved in endosome dynamics. However, the spatiotemporal regulation of the ALS2-mediated Rab5 activation is unclear. Here we identified an upstream activator for ALS2 and showed a functional significance of the ALS2 activation in endosome dynamics. ALS2 preferentially interacts with activated Rac1. In the cells activated Rac1 recruits cytoplasmic ALS2 to membrane ruffles and subsequently to nascent macropinosomes via Rac1-activated macropinocytosis. At later endocytic stages macropinosomal ALS2 augments fusion of the ALS2-localized macropinosomes with the transferrin-positive endosomes, depending on the ALS2-associated Rab5GEF activity. These results indicate that Rac1 promotes the ALS2 membranous localization, thereby rendering ALS2 active via Rac1-activated endocytosis. Thus, ALS2 is a novel Rac1 effector and is involved in Rac1-activated macropinocytosis. All together, loss of ALS2 may perturb macropinocytosis and/or the following membrane trafficking, which gives rise to neuronal dysfunction in the ALS2-linked motor neuron diseases.

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Section: Discussionmentioning

confidence: 99%

“…Thus, multiple Rab5GEFs might be cooperatively/redundantly responsible for endocytic processes in organisms. Importantly, it has been suggested that two Rab5GEFs, RAP6/GAPex-5 and RIN1, both enhance macropinocytosis (43,51,52). These Rab5GEFs can be candidates for redundant Rab5GEFs in the ALS2-mediated cellular processes.…”

Section: Discussionmentioning

confidence: 99%

The Rab5 Activator ALS2/alsin Acts as a Novel Rac1 Effector through Rac1-activated Endocytosis

Kunita

Otomo

Mizumura

et al. 2007

Journal of Biological Chemistry

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“…Rin1 also exhibits Rab5-specific GEF activity, which regulates Rab5-dependent endosome fusion, EGF receptor-mediated endocytosis, insulin receptor-mediated endocytosis and IL3 receptor-dependent kinase pathways (Tall et al, 2001;Hunker et al, 2006a;Hunker et al, 2006b). In addition, Rin1 affects axon guidance of neuronal cells through physical interaction with the ephrin receptor EphA4, which acts as a repulsive guidance signal during neuronal circuit formation (Deininger et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

The novel Rac effector RIN-1 regulates neuronal cell migration and axon pathfinding inC. elegans

et al. 2013

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SUMMARYCell migration and axon guidance require proper regulation of the actin cytoskeleton in response to extracellular guidance cues. Rho/Rac small GTPases are essential regulators of actin remodeling. Caenorhabditis elegans CED-10 is a Rac1 homolog that is required for various cellular morphological changes and migration events and is under the control of several guidance signaling pathways. There is still considerable uncertainty regarding events following the activation of guidance receptors by extracellular signals and the regulation of actin dynamics based on spatiotemporally restricted Rac activity. Here we show that the VPS9 domain protein RIN-1 acts as a novel effector for CED-10 in C. elegans. The orthologous mammalian Rin1 protein has previously been identified as an effector for Ras GTPase and is now known to function as a guanine nucleotide exchange factor for Rab5 GTPase. We found that RIN-1 specifically binds to the GTP-bound form of CED-10 and that mutations in rin-1 cause significant defects in migration and axon guidance of restricted neuronal cell types including AVM and HSN neurons, in contrast to the various defects observed in ced-10 mutants. Our analyses place RIN-1 in the Slit-Robo genetic pathway that regulates repulsive signaling for dorsoventral axon guidance. In rin-1 mutants, actin accumulated on both the ventral and dorsal sides of the developing HSN neuron, in contrast to its ventral accumulation in wild type. These results strongly suggest that RIN-1 acts as an effector for CED-10/Rac1 and regulates actin remodeling in response to restricted guidance cues.

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“…Thus, these data establish that tyrosine kinase activity of the insulin receptor is, in part, responsible for the formation of enlarged Rab5-positive endosomes, which is linked to the activation of Rab5. The potential mechanism of this inhibitory effect may be associated with Rin1, since it is associated with the insulin receptor upon ligand stimulation [Hunker et al, 2006a], and because it is also required for the fusion assay, whose fusogeneic activity is partially reversed by AG1024 inhibitor. These observations raise the possibility that the tyrosine kinase enzymatic activity of the insulin receptor may be required during the fusion assay.…”

Section: Discussionmentioning

confidence: 99%

“…However, in cells expressing Rab5: Q79L, the addition of HNMPA-(AM) 3 inhibitor did not exhibit any effect at all ( Figure 12B). Insulin receptor's activation leads to autophosphorylation, which is followed by the downstream phosphorylation of IRS [Fan et al, 1982;Russell et al, 1987] and association of molecules such as Grb2 [Liu and Roth, 1995] and Rin1 [Hunker et al, 2006a] through the clathrin mediated pathway. To further examine whether the insulin receptor kinase activity is linked to the membrane targeting to Rin1, the effect of HNMPA-(AM) 3 inhibitor was evaluated to determine whether this nucleotide exchange factor for Rab5 was targeted to membranes upon insulin stimulation.…”

Section: Hnmpa-(am) 3 Inhibitor Blocks Rab5 Activation and Targeting mentioning

confidence: 99%

Selective and Specific Activation of Rab5 during Endocytosis of Receptor Tyrosine Kinases

Jozic¹

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The Rab family of proteins are low molecular weight GTPases that have the ability to switch between GTP-(active) and GDP-(inactive) bound form, and in that sense act as molecular switches. Through distinct localization on various vesicles and organelles and by cycling through GTP/GDP bound forms, Rabs are able to recruit and activate numerous effector proteins, both spatially and temporally, and hence behave as key regulators of trafficking in both endocytic and biosynhtetic pathways. The Rab5 protein has been shown to regulate transport from plasma membrane to the early endosome as well as activate signaling pathways from the early endosome. This dissertation focused on understanding Rab5 activation via endocytosis of receptor tyrosine kinases (RTKs).First, tyrosine kinase activity of RTKs was linked to endosome fusion by demonstrating that tyrosine kinase inhibitors block endosome fusion and activation of Rab5, and a constitutively active form of Rab5 is able to rescue endosome fusion. However, depending on how much ligand is available at the cell surface, the receptor-ligand complexes can be internalized via a number of distinct pathways. Similarly, Rab5 was activated in a ligand-dependent concentration dependent manner via clathrin-and vii caveolin-mediated pathways, as well as a pathway independent of both. However, overexpression Rabex-5, a nucleotide exchange factor for Rab5, is able to rescue activation even when all of the pathways of EGF-receptor internalization were blocked.Next, the three naturally occurring splice variants of Rabex-5 selectively activated Rab5.Lastly, Rabex-5 inhibits differentiation of 3T3-L1 and PC12 cells through 1) degradation of signaling endosome via Rab5-dependent fusion with the early endosome, 2) and inhibition of signaling cascade via ubiquitination of Ras through the ZnF domain at the N-terminus of Rabex-5.In conclusion, these data shed light on complexity of the endosomal trafficking system where tyrosine kinase activity of the receptor is able to affect endosome fusion; how different endocytic pathways affect activation of one of the key regulators of early endocytic events; and how selective activation of Rab5 via Rabex-5 can control adipogenesis and neurogenesis.

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Rin1 regulates insulin receptor signal transduction pathways

Cited by 21 publications

References 38 publications

The Rab5 Activator ALS2/alsin Acts as a Novel Rac1 Effector through Rac1-activated Endocytosis

The Rab5 Activator ALS2/alsin Acts as a Novel Rac1 Effector through Rac1-activated Endocytosis

The novel Rac effector RIN-1 regulates neuronal cell migration and axon pathfinding inC. elegans

Selective and Specific Activation of Rab5 during Endocytosis of Receptor Tyrosine Kinases

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