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  current news   Press   selected story    
     
  13th May 2011  
 

Sprouty-related ENA/VASP homology 1- Domain-containing protein (SPRED) 1, a SHP2 substrate in the RAS/ERK pathway.

 
 




Authors
Martina Quintanar-AUDELO, Permeen YUSOFF, Saravanan SINNIAH , Sumana CHANDRAMOULI, and Graeme R. GUY.

Published in J Biol Chem., 2011 Apr 29. [Epub ahead of print]

Abstract
SHP2 is a tyrosine phosphatase involved in the activation of the Ras/ERK signaling pathway downstream of a number of receptor tyrosine kinases (RTKs)1. One of the proposed mechanisms involving SHP2 in this context is to dephosphorylate and inactivate inhibitors of the Ras/ERK pathway. Two protein families bearing a unique, common domain, Sprouty and SPRED proteins, are possible candidates since they have been reported to inhibit the Ras/ERK pathway upon FGF activation. We tested whether any of these proteins are likely substrates of SHP2. Our findings indicate that Sprouty2 binds to the C-terminal tail of SHP2, which is an unlikely substrate binding site, whereas SPRED proteins bind to the tyrosine phosphatase domain that is known to be the binding site for its substrates. Over-expressed SHP2 was able to dephosphorylate SPREDs but not Sprouty2. Finally, we found two tyrosine residues on SPRED1 that are required, when phosphorylated, to inhibit Ras/ERK activation, and identified Tyr420 as a specific dephosphorylation target of SHP2. The evidence obtained indicates that SPRED1 is a likely substrate of SHP2, whose tyrosine dephosphorylation is required to attenuate the inhibitory action of SPRED1 in the Ras/ERK pathway.

 
 

 
 


Figure Legend : SHP2 dephosphorylates Y420 on SPRED1. A. HEK293 cells were transfected with the indicated plasmids (FLAG-SPRED and RasV12) or the pXJ40 vector control. Whole cell lysates (WCL) were analyzed by Western blotting with the indicated antibodies on the left. B. Endogenous SHP2 was immunoprecipitated, with anti-SHP2, in cells overexpressing FLAG-SPRED1 WT or respective mutants. Immunoprecipitates were resolved by SDS-PAGE. C. FLAG-SPRED1Y377F was co-transfected with increasing concentrations of HA-SHP2 (0.5 to 3 mg) and lysates were immunoprecipitated with anti-FLAG. Immunoblots were probed with the antibodies indicated on the left. D. Cells overexpressing FLAG-SPRED1Y420F and HA-SHP2 were treated as mentioned in A. Numbers next to * indicates quantification of the tyrosine phosphorylation levels on the PY20 blot. Arrow indicates the light band at 50 kDa corresponding to the immunoglobulin heavy chain.


For more information on Graeme GUY’s laboratory, please click here.