Protein tyrosine phosphatase SHP-1: resurgence as new drug target for human autoimmune disorders

Abstract

Recognition of self-antigen and its destruction by the immune system is the hallmark of autoimmune diseases. During the developmental stages, immune cells are introduced to the self-antigen, for which tolerance develops. The inflammatory insults that break the immune tolerance provoke immune system against self-antigen, progressively leading to autoimmune diseases. SH2 domain containing protein tyrosine phosphatase (PTP), SHP-1, was identified as hematopoietic cell-specific PTP that regulates immune function from developing immune tolerance to mediating cell signaling post-immunoreceptor activation. The extensive research on SHP-1-deficient mice elucidated the diversified role of SHP-1 in immune regulation, and inflammatory process and related disorders such as cancer, autoimmunity, and neurodegenerative diseases. The present review focalizes upon the implication of SHP-1 in the pathogenesis of autoimmune disorders, such as allergic asthma, neutrophilic dermatosis, atopic dermatitis, rheumatoid arthritis, and multiple sclerosis, so as to lay the background in pursuance of developing therapeutic strategies targeting SHP-1. Also, new SHP-1 molecular targets have been suggested like SIRP-α, PIPKIγ, and RIP-1 that may prove to be the focal point for the development of therapeutic strategies.

Notch Signaling Modulates Macrophage Polarization and Phagocytosis Through Direct Suppression of Signal Regulatory Protein α Expression

“…Signal regulatory protein α is enriched in myeloid cells, while its ligand CD47 is universally expressed. Interaction between CD47 and SIRPα induces SHP1/SHP2 activation through tyrosine phosphorylation in the SH2 domains ( 27 , 28 ), leading to inhibited macrophage phagocytosis and pro-inflammatory response. BMDMs from normal mice were transfected with SIRPα siRNA (si-SIRPα) or control oligonucleotide (NC), which were proven to inhibit SIRPα expression efficiently (Figures S2A,B in Supplementary Material), and stimulated with PBS or LPS + IFNγ for 24 h. Western blotting showed that knock-down of SIRPα by siRNA (si-SIRPα) significantly reduced SHP1 phosphorylation in M PBS and M LPS macrophages (Figures 2 A,B).…”

Shp1 function in myeloid cells

“…This is particularly apparent in motheaten (me) mice that have a spontaneous mutation in Ptpn6, resulting in loss of Shp1, and develop a broad array of inflammatory and autoimmune symptoms. Given the important regulatory function of Shp1 in immune cells, there is growing interest in targeting this phosphatase in autoimmune disease and cancer [1,2]. Indeed, compounds that could enhance Shp1 function may be useful for suppression of immune function [3].…”

Enterohemorrhagic Escherichia coli Tir inhibits TAK1 activation and mediates immune evasion

“…These results suggest that tyrosine phosphorylation of the ITIMs of Tir may have inhibited intestinal immunity during EDL933 infection. modulate the immune response [ 43,44]. To determine the role of SHP-1 in Tir-mediated inhibition of cytokine production, we transfected RAW264.7 cells with negative control small interfering RNA (siRNA) (NC) or SHP-1-specific siRNA by electroporation ( Figure 7a).…”