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PMID:21340027

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Citation

Wang, PY and Pai, LM (2011) D-Cbl binding to Drk leads to dose-dependent down-regulation of EGFR signaling and increases receptor-ligand endocytosis. PLoS ONE 6:e17097

Abstract

Proper control of Epidermal Growth Factor Receptor (EGFR) signaling is critical for normal development and regulated cell behaviors. Abnormal EGFR signaling is associated with tumorigenic process of various cancers. Complicated feedback networks control EGFR signaling through ligand production, and internalization-mediated destruction of ligand-receptor complexes. Previously, we found that two isoforms of D-Cbl, D-CblS and D-CblL, regulate EGFR signaling through distinct mechanisms. While D-CblL plays a crucial role in dose-dependent down-regulation of EGFR signaling, D-CblS acts in normal restriction of EGFR signaling and does not display dosage effect. Here, we determined the underlying molecular mechanism, and found that Drk facilitates the dose-dependent regulation of EGFR signaling through binding to the proline-rich motif of D-CblL, PR. Furthermore, the RING finger domain of D-CblL is essential for promoting endocytosis of the ligand-receptor complex. Interestingly, a fusion protein of the two essential domains of D-CblL, RING- PR, is sufficient to down-regulate EGFR signal in a dose-dependent manner by promoting internalization of the ligand, Gurken. Besides, RING-SH2(Drk), a fusion protein of the RING finger domain of D-Cbl and the SH2 domain of Drk, also effectively down-regulates EGFR signaling in Drosophila follicle cells, and suppresses the effects of constitutively activated EGFR. The RING-SH2(Drk) suppresses EGFR signaling by promoting the endosomal trafficking of ligand-receptor complexes, suggesting that Drk plays a negative role in EGFR signaling by enhancing receptor endocytosis through cooperating with the RING domain of D-Cbl. Interfering the recruitment of signal transducer, Drk, to the receptor by the RING-SH2(Drk) might further reduces EGFR signaling. The fusion proteins we developed may provide alternative strategies for therapy of cancers caused by hyper-activation of EGFR signaling.

Links

PubMed PMC3038869 Online version:10.1371/journal.pone.0017097

Keywords

Animals; Animals, Genetically Modified; Biological Transport/genetics; Biological Transport/physiology; Cells, Cultured; Down-Regulation/genetics; Drosophila; Drosophila Proteins/genetics; Drosophila Proteins/metabolism; Drosophila Proteins/physiology; Endocytosis/genetics; Endocytosis/physiology; Endosomes/genetics; Endosomes/metabolism; Epidermal Growth Factor/metabolism; Gene Dosage/physiology; Ligands; Protein Binding/genetics; Protein Binding/physiology; Protein Interaction Domains and Motifs/genetics; Protein Interaction Domains and Motifs/physiology; Proto-Oncogene Proteins c-cbl/genetics; Proto-Oncogene Proteins c-cbl/metabolism; Proto-Oncogene Proteins c-cbl/physiology; Receptor, Epidermal Growth Factor/metabolism; Receptors, Invertebrate Peptide/metabolism; Signal Transduction/genetics; Signal Transduction/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DROME:EGFR

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

FB:FBgn0004638

F

Seeded From UniProt

complete

DROME:GRAP

enables

GO:0005154: epidermal growth factor receptor binding

ECO:0000353: physical interaction evidence used in manual assertion

FB:FBgn0003731

F

Seeded From UniProt

complete

DROME:GRAP

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

FB:FBgn0020224

F

Seeded From UniProt

complete

DROME:GRAP

involved_in

GO:0048260: positive regulation of receptor-mediated endocytosis

ECO:0000316: genetic interaction evidence used in manual assertion

FB:FBgn0020224

P

Seeded From UniProt

complete

DROME:Q9VSK2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

FB:FBgn0004638

F

Seeded From UniProt

complete

DROME:Q9VSK2

involved_in

GO:0009953: dorsal/ventral pattern formation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q9VSK2

involved_in

GO:0048260: positive regulation of receptor-mediated endocytosis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q9VSK2

enables

GO:0061630: ubiquitin protein ligase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

DROME:Q9VSK2

involved_in

GO:0042059: negative regulation of epidermal growth factor receptor signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

FB:FBgn0004638

P

Seeded From UniProt

complete

DROME:EGFR

GO:0005006: epidermal growth factor receptor activity

ECO:0000315:

F

Figure 1. (A and A') The EGFR activity is correlated with the morphology of dorsal appendages. Two dorsal appendages indicate normal activity of EGFR (wt). (B and B') Two dorsal appendages fused at the base indicate low level of EGFR activity (V1), whereas (C and C') one fused dorsal appendage indicates a even lower level of EGFR activity (V2). (D and D') No appendage indicates the lowest level of EGFR activity (V3).

complete

DROME:O46034

GO:0055131: C3HC4-type RING finger domain binding

ECO:0000314:

F

Table 3 Figure 4

complete


See also

References

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