The isoforms of phospholipase C-gamma are differentially used by distinct human NK activating receptors.
The two isoforms of phospholipase C (PLC)-gamma couple immune recognition receptors to important calcium- and protein kinase C-dependent cellular functions. It has been assumed that PLC-gamma1 and PLC-gamma2 have redundant functions and that the receptors can use whichever PLC-gamma isoform is preferentially expressed in a cell of a given hemopoietic lineage. In this study, we demonstrate that ITAM-containing immune recognition receptors can use either PLC-gamma1 or PLC-gamma2, whereas the novel NK cell-activating receptor NKG2D preferentially couples to PLC-gamma2. Experimental models evaluating signals from either endogenous receptors (FcR vs NKG2D-DAP10) or ectopically expressed chimeric receptors (with ITAM-containing cytoplasmic tails vs DAP10-containing cytoplasmic tails) demonstrate that PLC-gamma1 and PLC-gamma2 both regulate the functions of ITAM-containing receptors, whereas only PLC-gamma2 regulates the function of DAP10-coupled receptors. These data suggest that specific immune recognition receptors can differentially couple to the two isoforms of PLC-gamma. More broadly, these observations reveal a basis for selectively targeting the functions initiated by distinct immune recognition receptors.
Department of Immunology, and Division of Oncology Research, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Jadee L
JL
Upshaw
Renee A
RA
Schoon
Christopher J
CJ
Dick
Daniel D
DD
Billadeau
Paul J
PJ
Leibson
D000818:Animals; D020013:Calcium Signaling; D045744:Cell Line, Tumor; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D007694:Killer Cells, Natural / Q000201:enzymology* / Q000276:immunology*; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D055655:NK Cell Lectin-Like Receptor Subfamily K; D051966:Phospholipase C gamma; D010766:Phosphorylation; D011961:Receptors, Fc / Q000378:metabolism; D011971:Receptors, Immunologic / Q000737:chemistry / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D010738:Type C Phospholipases / Q000737:chemistry / Q000378:metabolism*; D014443:Tyrosine / Q000737:chemistry
C120528:HCST protein, human; D007527:Isoenzymes; C527085:KLRK1 protein, human; C527086:Klrk1 protein, mouse; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011961:Receptors, Fc; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D011993:Recombinant Fusion Proteins; D014443:Tyrosine; D010738:Type C Phospholipases; D051966:Phospholipase C gamma