PMID:22585739

Citation	Serrano-Pertierra, E, Cernuda-Morollón, E and López-Larrea, C (2012) Wiskott-Aldrich syndrome protein (WASp) and N-WASp are involved in the regulation of NK-cell migration upon NKG2D activation. Eur. J. Immunol. 42:2142-51
Abstract	NKG2D is a transmembrane receptor mainly expressed on CD8(+) T cells and NK cells. Engagement of NKG2D with its ligands can trigger a cytotoxic response. It has been shown that tumor cells deliver soluble NKG2D ligands as a mechanism of immune evasion through the downregulation of surface-expressed NKG2D. These ligands may be also secreted in microvesicles and regulate NK-cell function, but the existence of alternative mechanisms has not been explored. In this study, we describe that NKG2D activation inhibits NK-cell chemotaxis toward a CXCL12 gradient. Costimulation of the inhibitory receptor NKG2A rescues NK-cell migration rates. Thus, the balance of NKG2D/NKG2A activation may determine the migratory ability of NK cells. Furthermore, our data indicated that NKG2D cross-linking induces the activation of the Rho GTPases Rac1 and Cdc42, while RhoA activity is decreased. Pharmacological inhibition of the Cdc42 effectors Wiskott-Aldrich syndrome protein (WASp)/N-WASp, and the reduction of their levels using RNA interference partially abolished NKG2D-mediated impairment of cell migration, suggesting a pivotal role of Cdc42 in the regulation of NK-cell migration by NKG2D activation. Therefore, our results provide a new mechanism that may contribute to the immune response or evasion in tumors.
Links	PubMed Online version:10.1002/eji.201142070
Keywords	Cells, Cultured; Chemokine CXCL12; Chemotaxis, Leukocyte; Down-Regulation; Humans; Immune Evasion; Killer Cells, Natural/physiology; NK Cell Lectin-Like Receptor Subfamily C/metabolism; NK Cell Lectin-Like Receptor Subfamily K/biosynthesis; NK Cell Lectin-Like Receptor Subfamily K/metabolism; RNA Interference; RNA, Small Interfering; Wiskott-Aldrich Syndrome Protein/genetics; Wiskott-Aldrich Syndrome Protein/metabolism; cdc42 GTP-Binding Protein/metabolism; rac1 GTP-Binding Protein/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:NKG2D		GO:2000502: negative regulation of natural killer cell chemotaxis	ECO:0000314:		P		Fig 1A shows that the presence of NKG2D caused a smaller percent of the activated NK-cells to migrate toward a CXCL12 gradient.	complete CACAO 5737
HUMAN:NKG2D		GO:0034260: negative regulation of GTPase activity	ECO:0000314: direct assay evidence used in manual assertion		P		Fig 4A shows that when NKG2D is activated, Rho A activity decreases.	complete CACAO 5740
HUMAN:NKG2D	involved_in	GO:2000502: negative regulation of natural killer cell chemotaxis	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:NKG2D	involved_in	GO:0034260: negative regulation of GTPase activity	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:WASL		GO:2000402: negative regulation of lymphocyte migration	ECO:0000315:		P		Fig 5A shows that the presence of N-WASp successfully lowers the percentage of NK cells whose migration was inhibited by NKG2D.	complete CACAO 5744
HUMAN:WASL	involved_in	GO:2000402: negative regulation of lymphocyte migration	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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