Nck and Cdc42 co-operate to recruit N-WASP to promote FcγR-mediated phagocytosis

The adaptor protein Nck has been shown to link receptor ligation to actin-based signalling in a diverse range of cellular events, such as changes in cell morphology and motility. It has also been implicated in phagocytosis. However, its molecular role in controlling actin remodelling associated with phagocytic uptake remains to be clarified. Here, we show that Nck, which is recruited to phagocytic cups, is required for Fc gamma receptor (Fc gamma R)-but not complement receptor 3 (CR3)-induced phagocytosis. Nck recruitment in response to Fc gamma R ligation is mediated by the phosphorylation of tyrosine 282 and 298 in the ITAM motif in the cytoplasmic tail of the receptor. In the absence of Fc gamma R phosphorylation, there is also no recruitment of N-WASP or Cdc42 to phagocytic cups. Nck promotes Fc gamma R-mediated phagocytosis by recruiting N-WASP to phagocytic cups. Efficient phagocytosis, however, only occurs, if the CRIB domain of N-WASP can also interact with Cdc42. Our observations demonstrate that Nck and Cdc42 collaborate to stimulate N-WASP-dependent Fc gamma R-mediated phagocytosis.