Figure 1.

The Yin and Yang of NKG2D endocytosis: functional consequences on NKG2D-mediated signaling and NK cell effector functions. In human NK cells, NKG2D engagement by MICA induces Vav1 phosphorylation and PI3K activation, which are responsible for the initiation of intracellular signals leading to effector functions. On the other hand, MICA engagement activates the ubiquitin ligase c-Cbl and promotes DAP10 ubiquitination that provides a signal responsible for NKG2D internalization and lysosomal degradation, that ultimately induces a hyporesponsiveness towards NKG2DL-bearing target cells (the black part of the Yin-Yang symbol). However, internalized NKG2D receptors before being degraded continue to signal from endosomes: they promote ERK1/2 phosphorylation allowing the full activation of NK cells (the white part of the Yin-Yang symbol). NKG2D/DAP10 receptor complexes are depicted with intact rectangles (cell surface membrane and endosomes), and with fragmented rectangles (lysosomes) to indicate that their degradation was occurred. Arrows represent relationships that were well established (solid lines) or not yet demonstrated (dashed lines). Modified from Quatrini et al. [69].