PMID- 21364986
OWN - NLM
STAT- MEDLINE
DCOM- 20110901
LR  - 20211020
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 6
IP  - 2
DP  - 2011 Feb 22
TI  - Sprouty2 and Spred1-2 proteins inhibit the activation of the ERK pathway elicited 
      by cyclopentenone prostanoids.
PG  - e16787
LID - 10.1371/journal.pone.0016787 [doi]
LID - e16787
AB  - Sprouty and Spred proteins have been widely implicated in the negative regulation 
      of the fibroblast growth factor receptor-extracellular regulated kinase (ERK) 
      pathway. In considering the functional role of these proteins, we explored their 
      effects on ERK activation induced by cyclopentenone prostanoids, which bind to 
      and activate Ras proteins. We therefore found that ectopic overexpression in HeLa 
      cells of human Sprouty2, or human Spred1 or 2, inhibits ERK1/2 and Elk-1 
      activation triggered by the cyclopentenone prostanoids PGA(1) and 15d-PGJ(2). 
      Furthermore, we found that in HT cells that do not express Sprouty2 due to 
      hypermethylation of its gene-promoter, PGA(1)-provoked ERK activation was more 
      intense and sustained compared to other hematopoietic cell lines with unaltered 
      Sprouty2 expression. Cyclopentenone prostanoids did not induce Sprouty2 tyrosine 
      phosphorylation, in agreement with its incapability to activate tyrosine-kinase 
      receptors. However, Sprouty2 Y55F, which acts as a defective mutant upon 
      tyrosine-kinase receptor stimulation, did not inhibit cyclopentenone 
      prostanoids-elicited ERK pathway activation. In addition, Sprouty2 did not affect 
      the Ras-GTP levels promoted by cyclopentenone prostanoids. These results unveil 
      both common and differential features in the activation of Ras-dependent pathways 
      by cyclopentenone prostanoids and growth factors. Moreover, they provide the 
      first evidence that Sprouty and Spred proteins are negative regulators of the 
      ERK/Elk-1 pathway activation induced not only by growth-factors, but also by 
      reactive lipidic mediators.
FAU - Garcia-Dominguez, Carlota A
AU  - Garcia-Dominguez CA
AD  - Unidad de Biologia Celular, Area de Biologia Celular y del Desarrollo, Centro 
      Nacional de Microbiologia, Instituto de Salud Carlos III (ISCIII), Majadahonda, 
      Madrid, Spain.
FAU - Martinez, Natalia
AU  - Martinez N
FAU - Gragera, Teresa
AU  - Gragera T
FAU - Perez-Rodriguez, Andrea
AU  - Perez-Rodriguez A
FAU - Retana, Diana
AU  - Retana D
FAU - Leon, Gonzalo
AU  - Leon G
FAU - Sanchez, Agustin
AU  - Sanchez A
FAU - Oliva, Jose Luis
AU  - Oliva JL
FAU - Perez-Sala, Dolores
AU  - Perez-Sala D
FAU - Rojas, Jose M
AU  - Rojas JM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110222
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Cyclopentanes)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (Prostaglandins)
RN  - 0 (Repressor Proteins)
RN  - 0 (SPRED1 protein, human)
RN  - 0 (SPRED2 protein, human)
RN  - 0 (SPRY2 protein, human)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - Q0U2IGF9CK (cyclopentenone)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing
MH  - Cell Line, Tumor
MH  - Cyclopentanes/*pharmacology
MH  - Down-Regulation/drug effects/genetics
MH  - Enzyme Activation/drug effects/genetics
MH  - Extracellular Signal-Regulated MAP Kinases/*antagonists & inhibitors/metabolism
MH  - HeLa Cells
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/genetics/metabolism/*physiology
MH  - MAP Kinase Signaling System/drug effects
MH  - Membrane Proteins/genetics/metabolism/*physiology
MH  - Models, Biological
MH  - Prostaglandins/*pharmacology
MH  - Repressor Proteins/genetics/metabolism/*physiology
MH  - Signal Transduction/drug effects/genetics
MH  - Transfection
PMC - PMC3043057
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2011/03/03 06:00
MHDA- 2011/09/02 06:00
PMCR- 2011/02/22
CRDT- 2011/03/03 06:00
PHST- 2010/08/18 00:00 [received]
PHST- 2011/01/12 00:00 [accepted]
PHST- 2011/03/03 06:00 [entrez]
PHST- 2011/03/03 06:00 [pubmed]
PHST- 2011/09/02 06:00 [medline]
PHST- 2011/02/22 00:00 [pmc-release]
AID - PONE-D-10-00855 [pii]
AID - 10.1371/journal.pone.0016787 [doi]
PST - epublish
SO  - PLoS One. 2011 Feb 22;6(2):e16787. doi: 10.1371/journal.pone.0016787.