Figure 6-20
Immunoreceptor tyrosine based inhibitory motifs ITIM Sequences
• Mediators of signal modification that block activation by raising the stimulation threshold, found in many receptors that modulate activation signals in lymphocytes
• Common motif: I/V X Y X X L
I=isoleucine, V=valine, Y=tyrosine, L=leucine, X=any amino acid
• Functions by recruiting an inhibitory phosphatase, one of the SHP-1s, and SHIP. These enzymes carry SH2 domains that allow them to associate with phosphorylated ITIMs.
• SHP-1 removes the phosphate groups added by tyrosine kinases. SHIP is thought to inhibit the activation of PLC-γ by inhibiting the recruitment of Tec kinases (Btk, Itk) and thus inhibits production of DAG and IP3.
• Some examples:
• FcγRIIB-1 – contains an ITIM and inhibits activation of B-cells by bringing SHIP into the BCR complex
• CTLA-4 – competes with CD28 for B7 on APC and if stimulated, recruits SHP-2 and inhibits signaling through the TCR