Chapter 12 - Immunoreceptor Tyrosine-based Inhibition Motif-dependent Negative Regulation of Mast Cell Activation and Proliferation

Abstract

This chapter discusses the negative regulation of mast cell activation and proliferation mediated by the immunoreceptor tyrosine-based Inhibition motifs (ITIMs), signal regulatory protein-⍺ (SIRP-⍺), which was known to negatively regulate receptor tyrosine kinase (RTK)-dependent cell proliferation, can also negatively regulate immunoreceptor tyrosine-based activation motifs (ITAM)-dependent cell activation and that inhibition is correlated with the recruitment of SHP-2 (Src homology phosphatase-2) and SHP-1 by phosphorylated SIRP-⍺. Conversely, it was found that FcγRIIB, which was known to negatively regulate ITAM-dependent cell activation, can also negatively regulate RTK-dependent cell proliferation and that inhibition is correlated with the recruitment of SHIP by phosphorylated FcγRIIB. It follows that negative regulation of ITAM dependent cell activation and negative regulation of RTK-dependent cell proliferation may be two general properties of ITIM-bearing molecules and that the same receptors may co-ordinately control the development and the functions of hematopoietic cells. The biological consequences of negative regulation of cell activation by SIRP-⍺ will depend on whether SIRP-⍺ expressed by mast cells are or are not constitutively associated with FcɛRI as they are with RTKs. They also depend on the nature and on the distribution of SIRP-⍺ ligands. FcγRIIB and SIRP-⍺ can be envisioned as the potential targets for new immunotherapeutic approaches of clinical disorders associated with exaggerated mast cell responses and/or proliferation.