Targeting SHP-1, 2 and SHIP Pathways: A Novel Strategy for Cancer Treatment?

Abstract

Well-balanced levels of tyrosine phosphorylation, maintained by the reversible and coordinated actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), are critical for a wide range of cellular processes including growth, differentiation, metabolism, migration, and survival. Aberrant tyrosine phosphorylation, as a result of a perturbed balance between the activities of PTKs and PTPs, is linked to the pathogenesis of numerous human diseases, including cancer, suggesting that PTPs may be innovative molecular targets for cancer treatment. Two PTPs that have an important inhibitory role in haematopoietic cells are SHP-1 and SHP-2. SHP-1, 2 promote cell growth and act by both upregulating positive signaling pathways and by downregulating negative signaling pathways. SHIP is another inhibitory phosphatase that is specific for the inositol phospholipid phosphatidylinositol-3,4,5-trisphosphate (PIP3). SHIP acts as a negative regulator of immune response by hydrolysing PIP3, and SHIP deficiency results in myeloproliferation and B-cell lymphoma in mice. The validation of SHP-1, 2 and SHIP as oncology targets has generated interest in the development of inhibitors as potential therapeutic agents for cancers; however, SHP-1, 2 and SHIP have proven to be an extremely difficult target for drug discovery, primarily due to the highly conserved and positively charged nature of their PTP active site, and many PTP inhibitors lack either appro­priate selectivity or membrane permeability. To overcome these caveats, novel techniques have been employed to synthesise new inhibitors that specifically attenuate the PTP-dependent signaling inside the cell and amongst them; some are already in clinical development which are discussed in this review.

Inhibition of TRPV1 by SHP-1 in nociceptive primary sensory neurons is critical in PD-L1 analgesia

“…SHP-1 is a widely expressed cytosolic protein tyrosine phosphatase ( 63 – 65 ). Its importance is underscored by a myriad of its substrates and its dephosphorylation correlating with cancer ( 66 ) and pain ( 67 , 68 ). Tyrosine phosphorylation was also reported to be important for TRPV1 activation ( 20 , 69 , 70 ).…”

Plasticity in Pro- and Anti-tumor Activity of Neutrophils: Shifting the Balance

“…Protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) are two important regulators of immune cell responses. As they bind directly to the ITIM motif of the cytoplasmic tails of inhibitory receptors, drugs targeting their function could potentially amplify the neutrophil effector function against tumor cells ( 236 ). Despite the above-mentioned promising data on neutrophil effector function, evidence from in vivo experiments will shed more light on the complexity of neutrophil anti-tumor response.…”

Oncogenic Tyrosine Phosphatases: Novel Therapeutic Targets for Melanoma Treatment

“…SHP-1, also known as protein tyrosine phosphatase non-receptor type 6 (PTPN6), encoded by the PTPN6 gene, belongs to the family of non-receptor PTPs. This enzyme localizes to the cytosol and it is primarily expressed in hematopoietic cells, whereas it is present only at low levels in epithelial cells [ 176 , 177 ]. Similarly to SHP-2, SHP-1 is characterized by two tandem N-terminal SH2 domains that regulate the enzyme activity.…”