Consideration of SHP-1 as a Molecular Target for Tumor Therapy

Abstract

Abnormal activation of receptor tyrosine kinases (RTKs) contributes to tumorigenesis, while protein tyrosine phosphatases (PTPs) contribute to tumor control. One of the most representative PTPs is Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1), which is associated with either an increased or decreased survival rate depending on the cancer type. Hypermethylation in the promoter region of PTPN6, the gene for the SHP-1 protein, is a representative epigenetic regulation mechanism that suppresses the expression of SHP-1 in tumor cells. SHP-1 comprises two SH2 domains (N-SH2 and C-SH2) and a catalytic PTP domain. Intramolecular interactions between the N-SH2 and PTP domains inhibit SHP-1 activity. Opening of the PTP domain by a conformational change in SHP-1 increases enzymatic activity and contributes to a tumor control phenotype by inhibiting the activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT3) pathway. Although various compounds that increase SHP-1 activation or expression have been proposed as tumor therapeutics, except sorafenib and its derivatives, few candidates have demonstrated clinical significance. In some cancers, SHP-1 expression and activation contribute to a tumorigenic phenotype by inducing a tumor-friendly microenvironment. Therefore, developing anticancer drugs targeting SHP-1 must consider the effect of SHP-1 on both cell biological mechanisms of SHP-1 in tumor cells and the tumor microenvironment according to the target cancer type. Furthermore, the use of combination therapies should be considered.

Keywords: Src homology region 2 (SH2) domain-containing phosphatase 1; anticancer drug; protein tyrosine phosphatases; receptor tyrosine kinases.

Figure 1

PTPN6 gene structure and regulation of SHP-1 expression. (A) Schematic diagram of the SHP-1 gene (PTPN6). The PTPN6 has 17 exons; promoters 1 and promoter 2 are located in exon 1 and exon 2, respectively. Promoter 1 and 2 are mainly active in epithelial and hematopoietic cells, respectively. (B) The epigenetic regulatory mechanism regulating SHP-1 expression. JAK induces phosphorylation of STAT3 (pSTAT3), and the pSTAT3 forms a dimer and induces the transcription of DNMT3B.The methylation of the SHP-1 promoter region via DNMT and H3L9 acetylation (Ac) via histone acetyltransferases can down- and upregulate SHP-1 expression, respectively. USF—upstream stimulatory factor; DNMT—DNA methyltransferases; HDAC—histone deacetylase; 5-AZA—5-Aza-2′-deoxycytidine.

Figure 2

Protein structures and regulation of SHP-1. The enzymatic activity of SHP-1 is inhibited by intramolecular interaction between the N-SH2 and PTP domains. (A) The binding of the SH2 domain by tyrosine-phosphorylated substrates and (B) phosphorylation of tyrosine residues in the C-terminal tail causes a conformational change that opens the phosphatase active site and contributes to phosphatase activation. ITIM—immunoreceptor tyrosine-based inhibitory motif; ITSM—immunoreceptor tyrosine-based switch motif.

Figure 3

SHP-1-mediated inhibition of the JAK/STAT signaling pathway. Several growth factors and cytokines activate their associated receptors, which, in turn, activate JAK. Activated JAK then activates STAT through phosphorylation and moves the activated STAT (p-STAT) to the nucleus, upregulating the expression of STAT-related genes. SHP-1 directly dephosphorylates STAT3 or its upstream JAKs, thereby inhibiting cell proliferation, survival, migration, and invasion. EPO—erythropoietin; EPOR—erythropoietin receptor; TYK2—tyrosine kinase 2.

Figure 4

Chemical structures of SHP-1 agonists, regorafenib, and sorafenib and their derivatives.

Figure 5

SHP-1-mediated regulation in the tumor microenvironment. SHP-1 blocks T cell activation by negatively regulating TCR signaling through binding to the ITSM site and ITIM domain of the coinhibitory molecules, PD-1 and BTLA, respectively. APC—antigen-presenting cell; LAG—lymphocyte-activating gene 3; LCK—lymphocyte-cell-specific protein-tyrosine kinase; ZAP70—zeta-chain-associated protein kinase 70; PD1—programmed cell death protein 1; HVEM—herpes virus entry mediator; BTLA—B and T-lymphocyte attenuator.