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PMID:23549788

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Citation

Hahn, I, Fuss, B, Peters, A, Werner, T, Sieberg, A, Gosejacob, D and Hoch, M (2013) The Drosophila Arf GEF Steppke controls MAPK activation in EGFR signaling. J. Cell. Sci. 126:2470-9

Abstract

Guanine nucleotide exchange factors (GEFs) of the cytohesin protein family are regulators of GDP/GTP exchange for members of the ADP ribosylation factor (Arf) of small GTPases. They have been identified as modulators of various receptor tyrosine kinase signaling pathways including the insulin, the vascular epidermal growth factor (VEGF) and the epidermal growth factor (EGF) pathways. These pathways control many cellular functions, including cell proliferation and differentiation, and their misregulation is often associated with cancerogenesis. In vivo studies on cytohesins using genetic loss of function alleles are lacking, however, since knockout mouse models are not available yet. We have recently identified mutants for the single cytohesin Steppke (Step) in Drosophila and we could demonstrate an essential role of Step in the insulin signaling cascade. In the present study, we provide in vivo evidence for a role of Step in EGFR signaling during wing and eye development. By analyzing step mutants, transgenic RNA interference (RNAi) and overexpression lines for tissue specific as well as clonal analysis, we found that Step acts downstream of the EGFR and is required for the activation of mitogen-activated protein kinase (MAPK) and the induction of EGFR target genes. We further demonstrate that step transcription is induced by EGFR signaling whereas it is negatively regulated by insulin signaling. Furthermore, genetic studies and biochemical analysis show that Step interacts with the Connector Enhancer of KSR (CNK). We propose that Step may be part of a larger signaling scaffold coordinating receptor tyrosine kinase-dependent MAPK activation.

Links

PubMed Online version:10.1242/jcs.120964

Keywords

Adaptor Proteins, Signal Transducing/genetics; Adaptor Proteins, Signal Transducing/metabolism; Animals; Drosophila Proteins/genetics; Drosophila Proteins/metabolism; Drosophila melanogaster; Enzyme Activation/physiology; Extracellular Signal-Regulated MAP Kinases/genetics; Extracellular Signal-Regulated MAP Kinases/metabolism; Guanine Nucleotide Exchange Factors/genetics; Guanine Nucleotide Exchange Factors/metabolism; MAP Kinase Signaling System/physiology; Mice; Mutation; Receptors, Fibroblast Growth Factor/genetics; Receptors, Fibroblast Growth Factor/metabolism

Significance

Annotations

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

DROME:RAS1

involved_in

GO:0007474: imaginal disc-derived wing vein specification

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:KRAF1

involved_in

GO:0007474: imaginal disc-derived wing vein specification

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:ERKA

involved_in

GO:0007474: imaginal disc-derived wing vein specification

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:STAR

involved_in

GO:0001751: compound eye photoreceptor cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q0E8N2

involved_in

GO:0007474: imaginal disc-derived wing vein specification

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q0E8N2

located_in

GO:0005938: cell cortex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:Q0E8N2

involved_in

GO:0070374: positive regulation of ERK1 and ERK2 cascade

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q0E8N2

involved_in

GO:0045742: positive regulation of epidermal growth factor receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q7KNQ9

involved_in

GO:0007474: imaginal disc-derived wing vein specification

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q7KNQ9

involved_in

GO:0007173: epidermal growth factor receptor signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

FB:FBgn0086779

P

Seeded From UniProt

complete

DROME:Q7KNQ9

located_in

GO:0005938: cell cortex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:EGFR

involved_in

GO:0007474: imaginal disc-derived wing vein specification

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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