Mining the Complex Family of Protein Tyrosine Phosphatases for Checkpoint Regulators in Immunity

Abstract

The family of protein tyrosine phosphatases (PTPs) includes 107 genes in humans that are diverse in their structures and expression profiles. The majority are present in immune cells and play various roles in either inhibiting or promoting the duration and amplitude of signaling cascades. Several PTPs, including TC-PTP (PTPN2) and SHP-1 (PTPN6), have been recognized as being crucial for maintaining proper immune response and self-tolerance, and have gained recognition as true immune system checkpoint modulators. This chapter details the most recent literature on PTPs and immunity by examining their known functions in regulating signaling from either established checkpoint inhibitors or by their intrinsic properties, as modulators of the immune response. Notably, we review PTP regulatory properties in macrophages, antigen-presenting dendritic cells, and T cells. Overall, we present the PTP gene family as a remarkable source of novel checkpoint inhibitors wherein lies a great number of new targets for immunotherapies.

Up-regulation of S100P predicts the poor long-term survival and construction of prognostic signature for survival and immunotherapy in patients with pancreatic cancer

“…PTPN6, a non-receptor protein tyrosine phosphatase also known as SHP-1, is an important protein that regulates basic cellular processes and acts as a checkpoint regulator to maintain appropriate immune responses and self-tolerance 39,40 . In addition, PTPN6 has been reported to control cell proliferation and determine the therapeutic potential of somatostatin in pancreatic cancer 41 .…”

“…Here, we demonstrated that low TLR1 and ADA2 expression play vital roles in pancreatic cancer immunity and can both mediate immune cell infiltration to affect tumor immune status. PTPN6, a non-receptor protein tyrosine phosphatase also known as SHP-1, is an important protein that regulates basic cellular processes and acts as a checkpoint regulator to maintain appropriate immune responses and self-tolerance [ 39 , 40 ]. In addition, PTPN6 has been reported to control cell proliferation and determine the therapeutic potential of somatostatin in pancreatic cancer [ 41 ].…”

GTPase-activating protein Rasal1 associates with ZAP-70 of the TCR and negatively regulates T-cell tumor immunity

“…The GAP activity of Rasal1 differs from the mode of action of other established negative regulators, such as the SHP-1/2 phosphatases and the E3 ubiquitin ligases. SHP-1/2 dephosphorylate substrates 62 , and E3 ligases such as Cbl-b, Itch and Grail regulate the ubiquitin pathway 25 . Perhaps the most similar mediator is the CAPRI (Ca 2+ promoted Ras inactivator), which is also a Ca 2+ -dependent GAP that switches off the Ras-MAPK pathway following stimuli that elevate intracellular Ca 2+ 40 .…”

Deciphering the Role of Protein Phosphatases in Apicomplexa: The Future of Innovative Therapeutics?

“…It is likely that tyrosine phosphatases have emerged alongside their kinase counterparts and have allowed the eukaryotic to set up new cell–cell signaling pathways [ 24 ]. It is therefore not surprising that deregulations of the expression or catalytic activity of these phosphatases can lead to disruption of immunity [ 32 , 33 ], organ dysfunction such as heart failure [ 34 ], or diseases such as cancer [ 35 , 36 , 37 ]. It is thus astonishing to observe that Apicomplexa have found ways to minimize the use of tyrosine phosphorylation.…”