Increased activity of mitogen activated protein kinase pathway in flotillin-2 knockout mouse model.

Abstract

Flotillins are highly conserved and widely spread proteins that function in receptor tyrosine kinase signaling and membrane trafficking processes. Flotillin-1 and flotillin-2 have been shown to form both homo- and hetero-oligomers, and their cellular localization changes during signaling. Increased expression of flotillins has been detected in several types of cancer and shown to correlate with poor survival. Consistently, flotillin-2 knockout mice show a reduced formation of metastases in a breast cancer animal model. Our recent data have shown that flotillin-1 depletion results in diminished activation of the epidermal growth factor receptor and impairs its downstream signaling towards the mitogen activated protein kinases and the respective transcriptional response. Here we show that genetic ablation of flotillin-2 in a mouse model or its knockdown in cultured cells increases extracellular signal regulated kinase (ERK) activation. Furthermore, the downstream transcriptional targets of ERK and p53 are upregulated at both mRNA and protein levels. These data suggest that opposite effects are obtained upon ablation of one of the two flotillins, with flotillin-2 knockout/knockdown enhancing and flotillin-1 knockdown inhibiting ERK signaling. Due to their overexpression in cancers, flotillins may be considered as cancer therapy targets. However, our findings suggest that care needs to be taken when interfering with flotillin function, as undesired effects such as deregulation of growth-associated genes may emerge in certain cell types.

• Authors: Antje Banning, Christian R A Regenbrecht, Ritva Tikkanen
• Journal: Cellular signalling (Cell Signal) Vol. 26 Issue 2 Pg. 198-207 (Feb 2014) ISSN: 1873-3913 [Electronic] England
• PMID: 24216609 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Early Growth Response Protein 1
• Egr1 protein, mouse
• Membrane Proteins
• Proto-Oncogene Proteins c-fos
• RNA, Small Interfering
• Tumor Suppressor Protein p53
• flotillins
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases
• Dual Specificity Phosphatase 1
• Dusp1 protein, mouse

Topics

• Animals
• Cell Line
• Dual Specificity Phosphatase 1 (genetics, metabolism)
• Early Growth Response Protein 1 (genetics, metabolism)
• HeLa Cells
• Humans
• Lung (metabolism)
• Membrane Proteins (deficiency, genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitogen-Activated Protein Kinase 1 (genetics, metabolism)
• Mitogen-Activated Protein Kinase 3 (genetics, metabolism)
• Mitogen-Activated Protein Kinases (metabolism)
• Models, Animal
• Proto-Oncogene Proteins c-fos (metabolism)
• RNA, Small Interfering (metabolism)
• Signal Transduction
• Tumor Suppressor Protein p53 (genetics, metabolism)