Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 29, Issue 5, Pages 1338-1353Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.01359-08
Keywords
-
Categories
Funding
- Spanish Ministry of Education [BFU2005-00777, GEN2003-20239-C06-03]
- EU Sixth Framework Program [LSHC CT-2006-037731]
- SIMAP [IST-2004-027265]
- Red Tematica de Investigacion Cooperativa en Cancer [RD06/0020/0105]
- Fondo de Investigaciones Sanitarias
- Carlos III Institute
- Spanish Ministry of Health
Ask authors/readers for more resources
Subcellular localization influences the nature of Ras/extracellular signal-regulated kinase (ERK) signals by unknown mechanisms. Herein, we demonstrate that the microenvironment from which Ras signals emanate determines which substrates will be preferentially phosphorylated by the activated ERK1/2. We show that the phosphorylation of epidermal growth factor receptor (EGFr) and cytosolic phospholipase A(2) (cPLA(2)) is most prominent when ERK1/2 are activated from lipid rafts, whereas RSK1 is mainly activated by Ras signals from the disordered membrane. We present evidence indicating that the underlying mechanism of this substrate selectivity is governed by the participation of different scaffold proteins that distinctively couple ERK1/2, activated at defined microlocalizations, to specific substrates. As such, we show that for cPLA2 activation, ERK1/2 activated at lipid rafts interact with KSR1, whereas ERK1/2 activated at the endoplasmic reticulum utilize Sef-1. To phosphorylate the EGFr, ERK1/2 activated at lipid rafts require the participation of IQGAP1. Furthermore, we demonstrate that scaffold usage markedly influences the biological outcome of Ras site-specific signals. These results disclose an unprecedented spatial regulation of ERK1/2 substrate specificity, dictated by the microlocalization from which Ras signals originate and by the selection of specific scaffold proteins.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available