Dual Effects of Sprouty1 on TCR Signaling Depending on the Differentiation State of the T Cell

Abstract

Sprouty (Spry) is known to be a negative feedback inhibitor of growth factor receptor signaling through inhibition of the Ras/MAPK pathway. Several groups, however, have reported a positive role for Spry involving sequestration of the inhibitory protein c-Cbl. Thus, Spry may have various functions in the regulation of receptor-mediated signaling depending on the context. In the immune system, the function of Spry is unknown. In this study, we investigated the role of Spry1 in T cell activation. Spry1, among the four mammalian homologs, was specifically induced by TCR signaling of CD4+ murine T cells. In fully differentiated Th1 clones, overexpressed Spry1 inhibited TCR signaling and decreased IL-2 production while reducing expression with specific siRNA transfection had the opposite effect, increasing IL-2 production. In contrast, in naive T cells, Spry1 overexpression enhanced TCR signaling, and increased proliferation and IL-2 production, while siRNA transfection again had the opposite effect, reducing IL-2 production following activation. The enhancing effect in naive cells was abrogated by preactivation of the T cells with Ag and APC, indicating that the history of exposure to Ag is correlated with a hierarchy of T cell responsiveness to Spry1. Furthermore, both the NF-AT and MAPK pathways were influenced by Spry1, implying a different molecular mechanism from that for growth factor receptor signaling. Thus, Spry1 uses a novel mechanism to bring about differential effects on TCR signaling through the same receptor, depending on the differentiation state of the T cell.

Expression of sprouty2 inhibits B-cell proliferation and is epigenetically silenced in mouse and human B-cell lymphomas

“…3 For example, in CD4 ϩ T cells, Spry1 is the family member that is induced by TCR stimulation and regulates a negative feedback loop that suppresses ERK activity. 22 As yet, it is not known which, if any, family member responds to B cell-specific signaling. However, given that SPRY2 is expressed in human B cells ( Figures 3A, 4A) and is repressed in mouse and human B-cell tumors (Figures 1-4, S2), SPRY2 seemed a logical choice to examine as a potential regulator of B-cell ERK pathway signaling.…”

“…3,19,21 Alternatively, sprouty can increase cell proliferation by enhancing MAPK-ERK signaling in naive T cells after T-cell receptor (TCR) engagement or after EGF receptor (EGFR) activation in multiple nonlymphoid cell types. 19,[22][23][24][25] Precisely how sprouty proteins modulate RTK signaling is not yet clear, and several mechanisms for pathway inhibition or activation have been proposed, including antagonism of MAPK-ERK pathway signaling at the level of RAS activation, RAF activation, or upstream of RAS by sequestering the adaptor, GRB2. 3,19,21 SPRY2 also can augment EGF-dependent MAPK-ERK signaling by sequestering a negative pathway regulator, CBL (Cas-BR-M murine ectopic retroviral transforming sequence homolog), which ubiquitinates the EGFR, causing its degradation.…”

Recruitment of Sprouty1 to Immune Synapse Regulates T Cell Receptor Signaling

“…Previously, we reported that Sprouty1, an intracellular signaling adaptor, was induced by TCR signaling and that overexpressed Sprouty1 inhibited TCR signaling in fully differentiated murine CD4 ϩ T cell clones (13). Sproutys have been known to be negative regulators of many receptor tyrosine kinases, such as fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF).…”

SPRY1 (Sprouty Homolog 1, Antagonist Of FGF Signaling (Drosophila))

“…Spry1 expression increases upon serum starvation, decreases after 2 hours of FGF treatment, and then increases after 6-18 hours of FGF treatment (Impagnatiello et al, 2001). Spry1 mRNA expression is increased in Th1 cells upon activation of T-cell receptor (TCR) signaling pathways (Choi et al, 2006). SPRY1 protein expression increases in U937 cells upon interferon α or β treatment (Sharma et al, 2012).…”

“…SPRY1 regulates TCR signaling pathway activation in a cell-type specific manner. In Th1 cells (Choi et al, 2006) and CD4+ cells (Collins et al, 2012), Spry1 inhibits signaling pathway activation, while in naïve T-cells Spry1 potentiates signaling pathway activation (Choi et al, 2006).…”