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NKG2D Receptors and Ligands

NKG2D is a homodimeric natural killer (NK) cell-activating receptor that is distantly related to the NKG2 family. It recognizes several tumor-associated and stress-induced ligands such as MICA, MICB, and ULBP1-6 in human and members of the Rae1 family, H60, and MULT-1/ULBP-1 in mouse. NKG2D signals through either Dap10 or Dap12. Dap10 contains a YxxM motif and signals through the SH2 domain-containing GRB2 adaptor protein or PI 3-Kinase, while Dap12 contains an immunoreceptor tyrosine-based activation motif (ITAM) that serves as a docking site for Syk subfamily tyrosine kinases such as Syk and ZAP70. Activation of these kinases initiates downstream signaling pathways that promote NK cell degranulation and cytokine production.