Role of ITAM-containing adapter proteins and their receptors in the immune system and bone.
The immunoreceptor tyrosine-based activation motif (ITAM) is a highly conserved region in the cytoplasmic domain of signaling chains and receptors and is a critical mediator of intracellular signals. ITAM-mediated signals depend on the Syk or zeta-associated protein of 70 kDa tyrosine kinases, and ITAM signaling is required for the differentiation and function of B and T cells in adaptive immunity. ITAM-dependent receptors also regulate the function of innate immune cells, including natural killer cells, and myeloid-derived cells such as macrophages, neutrophils, dendritic cells, and mast cells. Myeloid lineage cells also include osteoclasts (OCLs), the cells required for bone resorption, and recent studies show a critical role for the ITAM-containing adapter proteins DAP12 and the FcRgamma chain (Fcepsilon receptor I gamma chain) in OCL differentiation. Mice deficient in both the DAP12 and FcRgamma ITAM-bearing adapters are significantly osteopetrotic with a severe defect in OCL differentiation, demonstrating the requirement for ITAM signals in bone and further implicating this pathway in the development of highly specialized cell functions in hematopoietic cells. Regulation of osteoclastogenesis by ITAM-dependent receptors suggests that OCLs, similar to related myeloid cells, are tightly controlled by arrays of receptors that allow them to sense and respond to their local microenvironment like other innate immune cells.
Humphrey
Mary Beth
MB
Department of Medicine, University of California, San Francisco, CA 94121, USA.
Lanier
Lewis L
LL
Nakamura
Mary C
MC
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D003713:Dendritic Cells / Q000502:physiology; D004792:Enzyme Precursors / Q000502:physiology; D006801:Humans; D007107:Immune System / Q000502:physiology*; D007113:Immunity, Innate; D047908:Intracellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural / Q000502:physiology; D008565:Membrane Proteins / Q000502:physiology*; D008969:Molecular Sequence Data; D010010:Osteoclasts / Q000502:physiology; D010012:Osteogenesis; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D017452:Receptors, IgG / Q000502:physiology*; D011971:Receptors, Immunologic / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D000072377:Syk Kinase
D048868:Adaptor Proteins, Signal Transducing; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; D017452:Receptors, IgG; D011971:Receptors, Immunologic; C110546:TYROBP protein, human; C054979:antigen T cell receptor, zeta chain; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse