Research ArticleImmunology

The Ability of Sos1 to Oligomerize the Adaptor Protein LAT Is Separable from Its Guanine Nucleotide Exchange Activity in Vivo

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Science Signaling  12 Nov 2013:
Vol. 6, Issue 301, pp. ra99
DOI: 10.1126/scisignal.2004494

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Separating Signals Mediated by Sos

Activation of the small guanosine triphosphatase Ras is central to both the development of thymocytes into T cells and the effector functions of mature T cells. Antigen-dependent activation of the T cell receptor (TCR) leads to Ras activation through Ras guanine nucleotide exchange factors (GEFs), including Sos1. Kortum et al. found that T cell–specific deletion of Sos1 in mice [Sos1(T)−/−] blocked the development of thymocytes into T cells. Furthermore, Sos1(T)−/− thymocytes exhibited reduced clustering of the adaptor protein LAT, decreased activation of the kinase extracellular signal–regulated kinase (ERK) and phospholipase C–γ1 (PLC-γ1), and reduced Ca2+ mobilization in response to TCR stimulation. Generation of Sos1(T)−/− mice expressing a GEF-defective Sos1 mutant transgene restored PLC-γ1 activation and Ca2+ mobilization, but not ERK activation, in the thymocytes, whereas a transgene expressing a Sos1 mutant unable to cluster LAT had the opposite effect. However, coexpression of both mutant Sos1 proteins in trans in the same cells was required to restore thymocyte development. These data demonstrate that the ability of Sos1 to oligomerize adaptor proteins is separate from its role as a RasGEF, suggesting that these two functions might be differentially targeted therapeutically.