ULBPs activate multiple signaling pathways in primary NK cells, resulting in the production of cytokines and chemokines. Binding of ULBPs ligands to NKG2D induces calcium mobilization and activation of the JAK2, STAT5, ERK and PI3K kinase/Akt signal transduction pathway. The name ULBP derives from the original identification of three proteins, ULBP-1, -2, and -3, as ligands for the human cytomegalovirus glycoprotein UL16; they were designated UL16 binding proteins (ULBP). The genes for ULBPs reside in a cluster of ten related genes, six of which encode potentially functional glycoproteins. ULBP-2 has also been described under the names RaeT1H (retinoic acid early transcript), NKG2DL2, and ALCAN-alpha.
ULBP-5 is also known as RaeT1G and ULBP-6 is also known as RaeT1L. These proteins are distantly related to MHC class I proteins, but they possess only the alpha 1 and alpha 2 Ig-like domains, and they have no capacity to bind peptide or interact with beta 2-Microglobulin. Some family members, including ULBP-2, are anchored to the membrane via a GPI-linkage, whereas others have transmembrane domains. Engagement of NKG2D results in the activation of cytolytic activity and/or cytokine production by these effector cells. The ULBPs are expressed on some tumor cells and have been implicated in tumor surveillance. Over aa 26-217, ULBP-2 shares 92% and 95% aa sequence identity with the human ULBP-5 and ULBP-6, respectively.