Kinase activity controls the sorting of the epidermal growth factor receptor within the multivesicular body

  title={Kinase activity controls the sorting of the epidermal growth factor receptor within the multivesicular body},
  author={Stephen Felder and Karen Miller and G. Moehren and Axel Ullrich and Joseph Schlessinger and Colin R. Hopkins},

c-Cbl/Sli-1 regulates endocytic sorting and ubiquitination of the epidermal growth factor receptor.

An endosomal sorting machinery capable of controlling the fate, and, hence, signaling potency, of growth factor receptors is revealed.

Recruitment of epidermal growth factor receptors into coated pits requires their activated tyrosine kinase

It is shown that EGF bound to wild-type receptors is efficiently sequestered in coated pits, suggesting that a tyrosine kinase substrate(s) other than the EGF-R itself, is required for its efficient ligand-induced recruitment into coated pits.

Endocytosis and Lysosomal Targeting of Epidermal Growth Factor Receptors Are Mediated by Distinct Sequences Independent of the Tyrosine Kinase Domain (*)

The results indicate that induced internalization is necessary, but not sufficient, for enhanced EGFR degradation, and that down-regulation requires exposure of previously cryptic internalization and lysosomal targeting sequences.

Threonine Phosphorylation Diverts Internalized Epidermal Growth Factor Receptors from a Degradative Pathway to the Recycling Endosome*

By sorting EGFR to the recycling endosome, heterologous desensitization restrains ligand-induced down-regulation of EGFR, and evidence that PKC can inhibit this process is provided.

Sorting of Ligand-activated Epidermal Growth Factor Receptor to Lysosomes Requires Its Actin-binding Domain*

It is demonstrated that sorting of endocytosed EGFR into the degradation pathway requires both its kinase activity and actin-binding domain.

Annexin I is phosphorylated in the multivesicular body during the processing of the epidermal growth factor receptor

Observations suggest that inward vesiculation in MVBs is induced by the EGF-R and is mediated by phosphorylated annexin I, which is associated with both plasma membrane and MVBs in a calcium-independent manner but can beosphorylated in vitro only in MVB.

Novel mechanism for regulation of epidermal growth factor receptor endocytosis revealed by protein kinase A inhibition.

The results reveal that PKA basal activity controls EGFR function at two levels: residence time of inactive EGFR at the cell surface by a process of "endocytic evasion," modulating the accessibility of receptors to stimuli; and sorting events leading to the down-regulation pathway of ligand-activated EGFR, determining the length of its intracellular signaling.

Lysosomal Targeting of Epidermal Growth Factor Receptors via a Kinase-dependent Pathway Is Mediated by the Receptor Carboxyl-terminal Residues 1022-1123*

The data suggest that two regions of the EGF receptor molecule, residues 1022-1063 and to a lesser extent residues 1063-1123, contribute in the regulation of routing of EGF receptors to the degradation pathway.

Phosphatidylinositol 4-kinase is required for endosomal trafficking and degradation of the EGF receptor

It is demonstrated that phosphatidylinositol 4-kinase IIα is necessary for the correct endocytic traffic and downregulation of activated epidermal growth factor receptor.

Polyubiquitination of the Epidermal Growth Factor Receptor Occurs at the Plasma Membrane upon Ligand-induced Activation*

The data show that EGF-induced polyubiquitination of the EGFR occurs at the plasma membrane, and that the E GF-induced monoubiquitinations of Eps15 was somewhat reduced upon overexpression of mutant dynamin.



Separate endocytic pathways of kinase-defective and -active EGF receptor mutants expressed in same cells

Intracellular trafficking of EGF receptors must be determined by a sorting mechanism that specifically recognizes EGF receptor molecules according to their intrinsic kinase activity.

Perinuclear location and recycling of epidermal growth factor receptor kinase: immunofluorescent visualization using antibodies directed to kinase and extracellular domains

The results demonstrate the following: the receptor kinase domain migrates to the perinuclear region upon challenge with EGF; both extracellular and cytoplasmic domains of the receptor are involved in migration as a unit; withdrawal of EGF results in rapid recycling of the perInuclear receptors to the plasma membrane; this return to the cell surface is inhibited by methylamine, chloroquine, and monensin.

Localization of the epidermal growth factor (EGF) receptor within the endosome of EGF-stimulated epidermoid carcinoma (A431) cells

Observations suggest that the prelysosomal endosome compartment extends to the pericentriolar complex and that the transfer of EGF receptor complexes to the acid phosphatase-positive lysosome involves a discontinuous, temperature-dependent step.

Receptor-mediated endocytosis of epidermal growth factor by hepatocytes in the perfused rat liver: ligand and receptor dynamics

Results suggest that EGF receptors are internalized and that their rate of recycling to the surface from intracellular sites is governed by the rate of entry of ligand and/or receptor into lysosomes.

Requirement for intrinsic protein tyrosine kinase in the immediate and late actions of the EGF receptor

It is concluded that the tyrosine kinase activity of the EGF receptor is essential for the diverse biochemical effects of EGF, including rapid alterations in intracellular calcium, activation of gene transcription, receptor down-regulation and the ultimate stimulatory effects on cell proliferation.