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Referee comments: Referee 1

Posted by PLOS_ONE_Group on 07 Mar 2008 at 18:18 GMT

Referee 1's review:

This paper by H. Schneider et al describes a novel function for the adaptor SKAP-55 in the regulation of Ras-Erk signaling pathway in T cells. Although SKAP-55 has been previously implicated in the modulation of T cell adhesion as a negative regulator, its effect on the T cell receptor-mediated Erk activation remains unknown. Here the authors demonstrated a positive role of SKAP-55 in anti-CD3-induced Erk activation using both SKAP-55-/- mouse primary T cells and T cells with SKAP-55 shRNA knockdown. They went further to show that SKAP-55 associates with RasGRP1, and this association and colocalization contributes to the negative regulation of Ras-Erk signaling. Overall, this paper provides a novel previously un-identified function of SKAP-55 in T cells, and represents a significant step forward in helping us understanding the biological function of the adaptor SKAP-55. There are a few issues for further consideration, which may help improve the manuscript:

1). It is not clear whether the association between SKAP-55 and RasGRP1 is activation-dependent, since the results in Fig. 4A lacks a control to show the amounts of the precipitated SKAP-55.

2). Another issue for consideration is what is the mechanistic insight regarding the SKAP-55 and RasGRP1 interaction. If the SH3 domain of SKAP-55 mediates its association with RasGRP1, then what is the protein motif or sequences in RasGRP1 is responsible for such interaction?

3). The description of RasGRP1 imaging in Fig. 6B lacks the details. It is unclear what are the changes before or after anti-CD3 stimulation, and what is the difference between wild-type and SKAP-55-/- T cells.

4). The authors mentioned a previously published paper (ref. 36). It would be helpful for the authors to describe in details what could be the difference or similarity between the two papers.

N.B. These are the comments made by the referee when reviewing an earlier version of this paper. Prior to publication the manuscript has been revised in light of these comments and to address other editorial requirements.