Phagocytosis favoring the localized accumulation of phosphorylated

Phagocytosis mediated by receptors for the Fc portion of IgG (Fc?Rs)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 Fc?R in phagocytic leukocytes: those that either contain or are associated with immunoreceptor tyrosine-based activation motifs (ITAMs); and those that contain immunoreceptor tyrosine-based inhibition motifs (ITIMs). The former, but not the latter, trigger phagocytosis. Signalling is initiated by ligand binding and clustering of cell surface Fc?Rs. Members of the Src family of tyrosine kinases associate with Fc?Rs and are probably responsible for the early phase of phosphorylation of tyrosine residues within Fc?R-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.Events downstream of Syk activation are less well understood; however, it is clear that programs of both actin assembly and membrane trafficking are needed to trigger cytoskeletal alterations, pseudopod extension and phagosomal closure. It is apparent that Arp2/3, members of the Rho family and ARF6 are essential for Fc?R-directed actin assembly, whereas phosphoinositide 3-kinase (PI 3-kinase), members of the Rab family and multiple SNARE proteins are required for pseudopod extension. In addition, unconventional myosins are likely to play keys roles in pseudopod extension and phagosomal closure.

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