Abstract
The function of Sprouty2 (Spry2) in T cells is unknown. Using 2 different (inducible and T cell–targeted) knockout mouse strains, we found that Spry2 positively regulated extracellular signal-regulated kinase 1/2 (ERK1/2) signaling by modulating the activity of LCK. Spry2−/− CD4+ T cells were unable to activate LCK, proliferate, differentiate into T helper cells, or produce cytokines. Spry2 deficiency abrogated type 2 inflammation and airway hyperreactivity in a murine model of asthma. Spry2 expression was higher in blood and airway CD4+ T cells from patients with asthma, and Spry2 knockdown impaired human T cell proliferation and cytokine production. Spry2 deficiency up-regulated the lipid raft protein caveolin-1, enhanced its interaction with CSK, and increased CSK interaction with LCK, culminating in augmented inhibitory phosphorylation of LCK. Knockdown of CSK or dislodgment of caveolin-1–bound CSK restored ERK1/2 activation in Spry2−/− T cells, suggesting an essential role for Spry2 in LCK activation and T cell function.
Highlights
Since its discovery as an inhibitor of fibroblast growth factor (FGF)-stimulated tubular morphogenesis [1], Sprouty (Spry) proteins have been implicated in numerous biological processes including limb development [2], lens morphogenesis [3], inner ear development [4], and kidney development [5]
While the role of Spry proteins as negative feedback regulators of receptor tyrosine kinase (RTK) signaling in stromal cells is well established [9,37], very little is known about their role in lymphoid cells
We show that Spry2 functions as a positive regulator of CD4+ T cell function and differentiation by modulating the activity of non-RTKs
Summary
Since its discovery as an inhibitor of fibroblast growth factor (FGF)-stimulated tubular morphogenesis [1], Sprouty (Spry) proteins have been implicated in numerous biological processes including limb development [2], lens morphogenesis [3], inner ear development [4], and kidney development [5] (reviewed in [6,7]). While the expression of Spry is restricted to brain and testis, the rest of the Spry proteins are ubiquitously expressed and have been shown to inhibit the Ras/ERK1/2 signaling pathway [9,10]. This general inhibitory function of Spry is due to its ability to interact with key signaling molecules in the Ras/ERK1/2 signaling pathway such as Grb, Shp, Raf, Sos, TESK, and FRS2 [11,12,13]. A role for Spry in enhancing epidermal growth factor (EGF)-induced
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