Association of the p56lck protein tyrosine kinase with the FCγRIIIA/CD16 complex in human natural killer cells

Publisher Website
Google Scholar
Abstract
The multimeric FcγRIIIA (CD16) complex is expressed on the surface of natural killer (NK) cells and is composed of a 50–70‐kDa transmembrane glycoprotein Fcγ receptor (CD16), the T cell receptor (TCR)‐ζ chain, and the FcεRIγ chain. Cross‐linking FcγRIIIA initiates the rapid tyrosine phosphorylation of multiple substrates including the ζ, subunit and causes subsequent cell activation and antibody‐dependent cellular cytotoxicity (ADCC). The subunits of the FcγRIIIA complex lack intrinsic protein tyrosine kinase (PTK) activity, suggesting that receptor‐induced tyrosine phosphorylation events are mediated by a nonreceptor PTK. We report here that the human FcγRIIIA is complexed with p56lck, a src‐family PTK previously found associated with the CD4 and CD8 receptors on T cells. Upon engagement of the CD16 receptor, p56lck is rapidly (within 30 s) and transiently phosphorylated on tyrosine residues. Several FcγRIIIA‐associated proteins are identified in immune complex kinase assays including the TCR‐ζ, subunit, a p70–90 ζ‐associated protein (ZAP), p50a (acidic) and p50b (basic), and p56lck. We demonstrate that the src‐family protein tyrosine kinase inhibitor, herbimycin A, blocks increased intracellular calcium levels and ADCC caused by CD16 cross‐linking on NK3.3 cells. Likewise cross‐linking CD16 with the protein tyrosine phosphatase CD45, abrogates CD16‐induced calcium mobilization. These data suggest that p56lck is physically associated with FcγRIIIA(CD16) and functions to mediate signaling events related to the control of NK cellular cytotoxicity.