SHP-1 twelve years on: structure, ligands, substrates and biological roles

Abstract

SHP-1 is an SH2 domain-containing protein tyrosine phosphatase (PTP) implicated in the negative regulation of a diverse range of activatory signaling pathways in leukocytes. Structural studies have revealed that SHP-1 PTP activity is subject to direct inhibition by its amino terminal SH2 domain whereby autoinhibition is predicted to be relieved by a series of allosteric changes involving the sequential engagement of the carboxy and amino terminal SH2 domains of SHP-1 by phosphotyrosine-containing ligands. The major physiological ligands for SHP- 1 are a super-family of inhibitory receptors found in leukocytes that possess Immune receptor Tyrosine-based Inhibition Motifs (ITIMs) in their cytoplasmic domains which when tyrosine phosphorylated are capable of binding with high affinity to the SH2 domains of SHP-1. Hence, fully activated SHP-1 is localized to the plasma membrane. SHP-1 appears to mediate inhibition of the early steps of activatory signaling pathways but the mechanisms of SHP-1 action still remain to be elucidated.