Diversity in phagocytic signalling.

Phagocytosis is a phylogenetically ancient process triggered by particulate ligands, such as bacteria, fungi and environmental particles. The spectrum of phagocytically competent cell types and receptors is diverse, but many of the basic processes of cytoskeletal rearrangement and membrane trafficking that accompany phagocytosis are conserved. Insights from studies of lower eukaryotes, such as Dictyostelium, Caenorhabditis elegans and Drosophila have contributed greatly to our understanding of the phagocytic pathway. Here, I focus on only a few examples of phagocytosis and bacterial invasion in mammalian cells, in which specific receptors have been identified and signal transduction pathways have been mapped. Owing to space constraints, the roles of lipid microdomains in phagocytosis and clearance of apoptotic bodies are not covered. The examples provided below emphasize the ability of the host cell to utilize different surface receptors to engage the phagocytic machinery. Phagocytosis mediated by receptors for the Fc portion of IgG (FcγRs) Receptors for the Fc portion of immunoglobulins are expressed in myeloid cells obtained from organisms ranging from lower vertebrates to humans. There are two fundamental types of FcγR in phagocytic leukocytes: those that either contain or are associated with immunoreceptor tyrosine-based activation motifs (ITAMs); and those that contain immunoreceptor tyrosinebased inhibition motifs (ITIMs). The former, but not the latter, trigger phagocytosis. Signalling is initiated by ligand binding and clustering of cell surface FcγRs. Members of the Src family of tyrosine kinases associate with FcγRs and are probably responsible for the early phase of phosphorylation of tyrosine residues within FcγR-associated ITAMs. This serves to recruit Syk, an SH2-domain-containing tyrosine kinase, which becomes activated to phosphorylate multiple substrates, including neighboring ITAMs. Syk is recruited from a cytosolic as well as a plasma-membrane-associated pool. It is also possible that a small number of preformed Syk-ITAM complexes exist in resting cells. Following receptor clustering, the local concentration of Syk increases relative to the local concentrations of protein tyrosine phosphatases (PTPases), thus favoring the localized accumulation of phosphorylated substrates.