syk protein tyrosine kinase regulates Fc receptor gamma-chain-mediated transport to lysosomes.
B- and T-cell receptors, as well as most Fc receptors (FcR), are part of a large family of membrane proteins named immunoreceptors and are expressed on all cells of the immune system. Immunoreceptors' biological functions rely on two of their fundamental attributes: signal transduction and internalization. The signals required for these two functions are present in the chains associated with immunoreceptors, within conserved amino acid motifs called immunoreceptor tyrosine-based activation motifs (ITAMs). We have examined the role of the protein tyrosine kinase (PTK) syk, a critical effector of immunoreceptor-mediated cell signalling through ITAMs, in FcR-associated gamma-chain internalization and lysosomal targeting. A point mutation in the immunoreceptor-associated gamma-chain ITAM affecting syk activation, as well as overexpression of a syk dominant negative mutant, inhibited signal transduction without affecting receptor coated-pit localization or internalization. In contrast, blocking of gamma-chain-mediated syk activation impaired FcR transport from endosomes to lysosomes and selectively inhibited the presentation of certain T-cell epitopes. Therefore, activation of the PTK syk is dispensable for receptor internalization, but necessary for cell signalling and for gamma-chain-mediated FcR delivery to lysosomes.
INSERM CJF 95-01, Institut Curie, Section Recherche, 12 rue Lhomond, 75005, Paris, France. bonnerot@curie.fr
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Bonnerot
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Briken
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Brachet
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Lankar
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Cassard
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Jabri
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Amigorena
D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D011992:Endosomes / Q000378:metabolism; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008247:Lysosomes / Q000378:metabolism*; D008969:Molecular Sequence Data; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D017452:Receptors, IgG / Q000378:metabolism*; D000072377:Syk Kinase
D004792:Enzyme Precursors; D000949:Histocompatibility Antigens Class II; D047908:Intracellular Signaling Peptides and Proteins; D017452:Receptors, IgG; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606898:Syk protein, rat