Specific factors are required for kinase-dependent endocytosis of insulin receptors.

Welsh, J B; Worthylake, Rebecca A.; Wiley, H. Steven; Gill, Gordon N.

doi:10.1091/mbc.5.5.539

Cited by 10 publications

(7 citation statements)

References 40 publications

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“…B82L fibroblasts expressing the human wild-type EGFR (B82L-wt), kinase-defective EGFR (B82L-Kin − ) and the COOH terminally truncated EGFR at Tyr-958 (B82L-958) have been described previously ( Welsh et al, 1994 ). B82L-EGFR cells stably expressing FLAG-6His-Ub were obtained by transfecting pSG213-FLAG-6His-Ub using LipofectAMINE™ (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

Proteomic snapshot of the EGF‐induced ubiquitin network

Argenzio

Bange

Oldrini

et al. 2011

Molecular Systems Biology

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Section: Methodsmentioning

confidence: 99%

Proteomic snapshot of the EGF‐induced ubiquitin network

Argenzio

Bange

Oldrini

et al. 2011

Molecular Systems Biology

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“…The stripping efficiency was approximately 93%. The data were converted to internalization plots as described previously (9) and normalized to total surface binding of 13A9 (36).…”

Section: Methodsmentioning

confidence: 99%

The Enhanced Tumorigenic Activity of a Mutant Epidermal Growth Factor Receptor Common in Human Cancers Is Mediated by Threshold Levels of Constitutive Tyrosine Phosphorylation and Unattenuated Signaling

Huang

Nagane

Klingbeil

et al. 1997

Journal of Biological Chemistry

532

508

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Deregulation of signaling by the epidermal growth factor receptor (EGFR) is common in human malignancy progression. One mutant EGFR (variously named ⌬EGFR, de2-7 EGFR, or EGFRvIII), which occurs frequently in human cancers, lacks a portion of the extracellular ligand-binding domain due to genomic deletions that eliminate exons 2 to 7 and confers a dramatic enhancement of brain tumor cell tumorigenicity in vivo. In order to dissect the molecular mechanisms of this activity, we analyzed location, autophosphorylation, and attenuation of the mutant receptors. The mutant receptors were expressed on the cell surface and constitutively autophosphorylated at a significantly decreased level compared with wild-type EGFR activated by ligand treatment. Unlike wild-type EGFR, the constitutively active ⌬EGFR were not down-regulated, suggesting that the altered conformation of the mutant did not result in exposure of receptor sequence motifs required for endocytosis and lysosomal sorting. Mutational analysis showed that the enhanced tumorigenicity was dependent on intrinsic tyrosine kinase activity and was mediated through the carboxyl terminus. In contrast with wild-type receptor, mutation of any major tyrosine autophosphorylation site abolished these activities suggesting that the biological functions of ⌬EGFR are due to low constitutive activation with mitogenic effects amplified by failure to attenuate signaling by receptor down-regulation. Ligand binding to wild-type epidermal growth factor receptor (wt EGFR)1 results in receptor dimerization, kinase activation, and autophosphorylation that provides both docking sites for proteins involved in signal transduction and exposure of endocytic and lysosomal targeting sequence codes required for receptor internalization and down-regulation (1). The biochemical and biological roles of each autophosphorylation site in wt EGFR have been explored by mutational analysis, and mutation of any single autophosphorylation site does not significantly abrogate binding of the activated receptor to specific SH2-containing proteins associated with distinct signaling pathways (2). Likewise, such single mutations are generally incapable of reducing the biological functions of the receptor in in vitro models (3, 4). Correspondingly, the mitogenic and transforming activities of wild-type receptor were diminished only when combinations of favorable autophosphorylation sites (i.e. Tyr-1068, Tyr-1148, and Tyr-1173) were mutated (3), suggesting that the autophosphorylation sites of wt EGFR may have less specificity for signaling proteins and can compensate for each other. Sites of tyrosine phosphorylation may be provided via heterodimerization with other members of the erb B family of receptors (5-7). Point mutations that inactivated the tyrosine kinase activity of wt EGFR eliminated occupancyinduced receptor internalization (8,9,40,41), whereas mutant receptors lacking multiple autophosphorylation sites also lacked the ability to undergo ligand-induced endocytosis, suggesting that kinase-regulated re...

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“…Further evidence for this idea comes from the finding that recombinant insulin receptors are efficiently internalized when expressed in rat-1 cells but not when expressed in B82L mouse cells (which are able to efficiently internalize recombinant EGF-R). Moreover, fusion of insulin receptor-expressing B82L cells with nontransfected rat-1 cells restores efficient insulin-R internalization (194), suggesting that rat-1 cell cytosol can supply a factor that is absent in mouse B82L cell cytosol.…”

Section: Auxiliary Sorting Factors Are Required For Ligand-induced Enmentioning

confidence: 98%

CLATHRIN-COATED VESICLE FORMATION AND PROTEIN SORTING: An Integrated Process

Schmid

1997

Annu. Rev. Biochem.

739

563

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Clathrin-coated vesicles were the first discovered and remain the most extensively characterized transport vesicles. They mediate endocytosis of transmembrane receptors and transport of newly synthesized lysosomal hydrolases from the trans-Golgi network to the lysosome. Cell-free assays for coat assembly, membrane binding, and coated vesicle budding have provided detailed functional and structural information about how the major coat constituents, clathrin and the adaptor protein complexes, interact with each other, with membranes, and with the sorting signals found on cargo molecules. Coat constituents not only serve to shape the budding vesicle, but also play a direct role in the packaging of cargo, suggesting that protein sorting and vesicle budding are functionally integrated. The functional interplay between the coated vesicle machinery and its cargo could ensure sorting fidelity and packaging efficiency and might enable modulation of vesicular trafficking in response to demand.

show abstract

Specific factors are required for kinase-dependent endocytosis of insulin receptors.

Cited by 10 publications

References 40 publications

Proteomic snapshot of the EGF‐induced ubiquitin network

Proteomic snapshot of the EGF‐induced ubiquitin network

The Enhanced Tumorigenic Activity of a Mutant Epidermal Growth Factor Receptor Common in Human Cancers Is Mediated by Threshold Levels of Constitutive Tyrosine Phosphorylation and Unattenuated Signaling

CLATHRIN-COATED VESICLE FORMATION AND PROTEIN SORTING: An Integrated Process

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