Dynamin Associates with Src-Homology Collagen (SHC) and Becomes Tyrosine Phosphorylated in Response to Insulin

Baron, Véronique; Alengrin, F; Obberghen, Emmanuel Van

doi:10.1210/endo.139.6.6131

Cited by 24 publications

(11 citation statements)

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“…While tyrosine phosphorylation has been observed in response to various ligands (13)(14)(15)(25)(26)(27)(28), this event is thought to play a role in the regulation of ligand-induced uptake of various receptors. However, the mechanisms involved in regulating Dyn2 function during secretion and, more specifically, whether Src kinase-mediated phosphorylation plays a role in this process have remained largely unexplored.…”

Section: Discussionmentioning

confidence: 99%

Src kinase regulates the integrity and function of the Golgi apparatus via activation of dynamin 2

Weller

Capitani²,

Cao

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The size and integrity of the Golgi apparatus is maintained via a tightly controlled regulation of membrane traffic using a variety of different signaling and cytoskeletal proteins. We have recently observed that activation of c-Src has profound effects on Golgi structure, leading to dramatically vesiculated cisternae in a variety of cell types. As the large GTPase dynamin (Dyn2) has been implicated in Golgi vesiculation during secretion, we tested whether inhibiting Dyn2 activity by expression of a Dyn2K44A mutant or siRNA knockdown could attenuate active Src-induced Golgi fragmentation. Indeed, these perturbations attenuated fragmentation, and expression of a Dyn2Y(231/597)F mutant protein that cannot be phosphorylated by Src kinase had a similar effect . Finally, we find that Dyn2 is markedly phosphorylated during the transit of VSV-G protein through the TGN whereas expression of the Dyn2Y(231/597)F mutant significantly reduces exit of the nascent protein from this compartment. These findings demonstrate that activation of Dyn2 by Src kinase regulates Golgi integrity and vesiculation during the secretory process.

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Section: Discussionmentioning

confidence: 99%

Src kinase regulates the integrity and function of the Golgi apparatus via activation of dynamin 2

Weller

Capitani²,

Cao

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…In a previous study, Gasparini et al (24) describe insulin effects on A␤ levels that may involve both insulin receptor signaling and the competitive inhibition of insulin degrading enzyme, a known A␤-degrading protease. In this regard, a probable mechanism of action of insulin signaling that could lead to the observed alteration of APP trafficking and processing is the known ability of insulin to enhance the phosphorylation of dynamin (25). Dynamin phosphorylation inhibits dynamin function (25), thus retarding the endocytosis of a broad range of surface molecules, including APP.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Receptor-mediated Endocytosis Demonstrates Generation of Amyloid β-Protein at the Cell Surface

Chyung

Selkoe

2003

Journal of Biological Chemistry

109

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Sequential cleavages of the amyloid ␤-protein precursor (APP) by the ␤-and ␥-secretases generate the amyloid ␤-protein (A␤), which plays a central role in Alzheimer's disease. Previous work provided evidence for involvement of both the secretory and endocytic pathways in A␤ generation. Here, we used HeLa cells stably expressing a tetracycline-regulated dominant-negative dynamin I (dyn K44A), which selectively inhibits receptor-mediated endocytosis, and analyzed the effects on the processing of endogenous APP. Upon induction of dyn K44A, levels of mature APP rose at the cell surface, consistent with retention of APP on the plasma membrane. The ␣-secretase cleavage products of APP were increased by dyn K44A, in that ␣-APPs in medium and the C83 C-terminal stub in the membrane both rose. The ␤-secretase cleavage of APP, C99, also increased modestly. The use of specific ␥-secretase inhibitors to study the accumulation of ␣-and ␤-cleavage products independent of their processing by ␥-secretase confirmed that retention of APP on the plasma membrane results in increased processing by both ␣-and ␤-secretases. Unexpectedly, endogenous A␤ secretion was significantly increased by dyn K44A, as detected by three distinct methods: metabolic labeling, immunoprecipitation/ Western blotting, and enzyme-linked immunosorbent assay. Levels of p3 (generated by sequential ␣-and ␥-cleavage) also rose. We conclude that endogenous A␤ can be produced directly at the plasma membrane and that alterations in the degree of APP endocytosis may help regulate its production. Our findings are consistent with a role for the ␥-secretase complex in the processing of numerous single-transmembrane receptors at the cell surface.Genetic, neuropathological, biochemical, and animal modeling studies all suggest that the progressive accumulation of the amyloid ␤-protein (A␤) 1 in limbic and association cortices initiates Alzheimer's disease. Such evidence has recently led to the development of therapeutic agents aimed at decreasing the production or enhancing the clearance of A␤. Despite this progress, a central unresolved question remains: precisely where in the cell is A␤ generated from the membrane-anchored amyloid ␤-protein precursor (APP)? This question has taken on greater interest with emerging evidence that APP appears to function as a cell surface receptor that can undergo regulated intramembrane proteolysis (RIP) (1, 2). Sequential cleavage of APP by the aspartyl proteases BACE/ ␤-secretase and presenilin/␥-secretase releases A␤ into the lumen/extracellular space and liberates the APP intracellular domain into the cytoplasm in a process strikingly similar to the cleavage of the Notch receptors that enables their signaling in myriad cell fate decisions (2-4). An increasing number of cell surface proteins, including nectin-1␣ (5), CD44 (6), LRP (7), E-cadherin (8), andErbB4 (9), has been discovered to undergo RIP, with some of these releasing intracellular domains that may function as transcriptional regulators. Thus, the processing of APP by RIP, ...

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“…These results suggest that the formation of this higher-order complex either inhibits dynamin activity and/or results in the sequestration of dynamin away from the GLUT4-containing, clathrin-coated pits. Alternatively, a recent study reported that insulin induces the tyrosine phosphorylation of dynamin (Baron et al, 1998). In either case, the functional role of these events remains to be determined, as there is currently no evidence that insulin modulates dynamin localization, GTPase activity, or pinchase function in viva VIII.…”

Section: Glut4 Endocytosismentioning

confidence: 99%

Intracellular Organization of Insulin Signaling and GLUT4 Translocation

Watson

Pessin

2001

Recent Progress in Hormone Research

209

151

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Dynamin Associates with Src-Homology Collagen (SHC) and Becomes Tyrosine Phosphorylated in Response to Insulin

Cited by 24 publications

References 0 publications

Src kinase regulates the integrity and function of the Golgi apparatus via activation of dynamin 2

Src kinase regulates the integrity and function of the Golgi apparatus via activation of dynamin 2

Inhibition of Receptor-mediated Endocytosis Demonstrates Generation of Amyloid β-Protein at the Cell Surface

Intracellular Organization of Insulin Signaling and GLUT4 Translocation

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