Document Detail

Flotillin-1/reggie-2 protein plays dual role in activation of receptor-tyrosine kinase/mitogen-activated protein kinase signaling.
MedLine Citation:
PMID:  22232557     Owner:  NLM     Status:  MEDLINE    
Our previous work has shown that the membrane microdomain-associated flotillin proteins are potentially involved in epidermal growth factor (EGF) receptor signaling. Here we show that knockdown of flotillin-1/reggie-2 results in reduced EGF-induced phosphorylation of specific tyrosines in the EGF receptor (EGFR) and in inefficient activation of the downstream mitogen-activated protein (MAP) kinase and Akt signaling. Although flotillin-1 has been implicated in endocytosis, its depletion affects neither the endocytosis nor the ubiquitination of the EGFR. However, EGF-induced clustering of EGFR at the cell surface is altered in cells lacking flotillin-1. Furthermore, we show that flotillins form molecular complexes with EGFR in an EGF/EGFR kinase-independent manner. However, knockdown of flotillin-1 appears to affect the activation of the downstream MAP kinase signaling more directly. We here show that flotillin-1 forms a complex with CRAF, MEK1, ERK, and KSR1 (kinase suppressor of RAS) and that flotillin-1 knockdown leads to a direct inactivation of ERK1/2. Thus, flotillin-1 plays a direct role during both the early phase (activation of the receptor) and late (activation of MAP kinases) phase of growth factor signaling. Our results here unveil a novel role for flotillin-1 as a scaffolding factor in the regulation of classical MAP kinase signaling. Furthermore, our results imply that other receptor-tyrosine kinases may also rely on flotillin-1 upon activation, thus suggesting a general role for flotillin-1 as a novel factor in receptor-tyrosine kinase/MAP kinase signaling.
Monia Amaddii; Melanie Meister; Antje Banning; Ana Tomasovic; Juliane Mooz; Krishnaraj Rajalingam; Ritva Tikkanen
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-01-09
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-03-05     Completed Date:  2012-04-24     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  7265-78     Citation Subset:  IM    
From the Institute of Biochemistry, University of Giessen, Friedrichstrasse 24, 35392 Giessen, Germany.
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MeSH Terms
Enzyme Activation / physiology
Epidermal Growth Factor / genetics,  metabolism
Gene Knockdown Techniques
HeLa Cells
MAP Kinase Kinase 1 / genetics,  metabolism
MAP Kinase Signaling System / physiology*
Membrane Proteins / genetics,  metabolism*
Mitogen-Activated Protein Kinase 1 / genetics,  metabolism
Mitogen-Activated Protein Kinase 3 / genetics,  metabolism
Multiprotein Complexes / genetics,  metabolism*
Protein Kinases / genetics,  metabolism
Proto-Oncogene Proteins c-akt / genetics,  metabolism
Receptor, Epidermal Growth Factor / genetics,  metabolism*
Reg. No./Substance:
0/Membrane Proteins; 0/Multiprotein Complexes; 0/flotillins; 62229-50-9/Epidermal Growth Factor; EC 2.7.-/Protein Kinases; EC 2.7.1.-/KSR-1 protein kinase; EC 2.7.1.-/MAP2K1 protein, human; EC protein, human; EC, Epidermal Growth Factor; EC Proteins c-akt; EC protein, human; EC Protein Kinase 1; EC Protein Kinase 3; EC Kinase Kinase 1

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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