New and Unexpected Biological Functions for the Src-Homology 2 Domain-Containing Phosphatase SHP-2 in the Gastrointestinal Tract

Abstract

SHP-2 is a tyrosine phosphatase expressed in most embryonic and adult tissues. SHP-2 regulates many cellular functions including growth, differentiation, migration, and survival. Genetic and biochemical evidence show that SHP-2 is required for rat sarcoma viral oncogene/extracellular signal-regulated kinases mitogen-activated protein kinase pathway activation by most tyrosine kinase receptors, as well as by G-protein–coupled and cytokine receptors. In addition, SHP-2 can regulate the Janus kinase/signal transducers and activators of transcription, nuclear factor-κB, phosphatidyl-inositol 3-kinase/Akt, RhoA, Hippo, and Wnt/β-catenin signaling pathways. Emerging evidence has shown that SHP-2 dysfunction represents a key factor in the pathogenesis of gastrointestinal diseases, in particular in chronic inflammation and cancer. Variations within the gene locus encoding SHP-2 have been associated with increased susceptibility to develop ulcerative colitis and gastric atrophy. Furthermore, mice with conditional deletion of SHP-2 in intestinal epithelial cells rapidly develop severe colitis. Similarly, hepatocyte-specific deletion of SHP-2 induces hepatic inflammation, resulting in regenerative hyperplasia and development of tumors in aged mice. However, the SHP-2 gene initially was suggested to be a proto-oncogene because activating mutations of this gene were found in pediatric leukemias and certain forms of liver and colon cancers. Moreover, SHP-2 expression is up-regulated in gastric and hepatocellular cancers. Notably, SHP-2 functions downstream of cytotoxin-associated antigen A (CagA), the major virulence factor of Helicobacter pylori, and is associated with increased risks of gastric cancer. Further compounding this complexity, most recent findings suggest that SHP-2 also coordinates carbohydrate, lipid, and bile acid synthesis in the liver and pancreas. This review aims to summarize current knowledge and recent data regarding the biological functions of SHP-2 in the gastrointestinal tract.

Lentivirus-Mediated Silencing of Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase 2 Inhibits Release of Inflammatory Cytokines and Apoptosis in Renal Tubular Epithelial Cells Via Inhibition of the TLR4/NF-kB Pathway in Renal Ischemia-Reperfusion Injury

“…Rats with renal I/R injury have higher IL-6, TNF-α, IL-1β and SHP27 expression in serum with reperfusion time prolonging. Notes: TNF-α, tumor necrosis factor-α; IL-6, interleukin-6; SHP-2, Src homology 2 domain-containing protein tyrosine phosphatase 2; LPS, lipopolysaccharide; NC, negative control; *, p < 0.05 vs. the sham group; #, p < 0.05 vs. the model-blank group As a tyrosine phosphatase, SHP-2 is highly correlated with multiple cell signaling processes, such as growth, survival, proliferation, differentiation and apoptosis, and is particularly important in chronic inflammation [23]. The current study demonstrated that the silencing of SHP-2 inhibited the release of inflammatory cytokines.…”

Canine histiocytic sarcoma cell lines with SHP2 p.Glu76Gln or p.Glu76Ala mutations are sensitive to allosteric SHP2 inhibitor SHP099

“…At the same time, SHP099 did not suppress the downstream signalling pathways examined in CHS‐3, a HS line that produces SHP2 p.Glu76Gln. SHP2 also is known to be involved in a variety of signalling pathways such as the NF‐κB, JNK, Wnt/β‐catenin, Hippo and RhoA pathways, suggesting that SHP2 activates growth in CHS‐3 by utilizing signalling pathway(s) other than ERK, AKT and STAT3. Alternatively, because SHP2 variants may have different affinities for SHP099 depending on the relative time spent in the open and closed states by proteins with different types of mutations, concentrations that allow for SHP099 to inhibit phosphorylation of ERK and/or AKT could exceed the SHP099 concentration (1 μM) used in CHS‐3.…”

The Hippo Kinase LATS2 Controls Helicobacter pylori-Induced Epithelial-Mesenchymal Transition and Intestinal Metaplasia in Gastric Mucosa

“…8,9,[44][45][46] It is noteworthy that CagA targets and triggers the Src-homology phosphatase-2 (SHP-2), which directly interacts with YAP1 and potentiates its cotranscriptional function. 47,48 This tripartite connection of CagA/SHP2/YAP1 may be critical in the early phases of human gastric carcinogenesis. 49 Nuclear localization of YAP1 is thus the sum of multiple, possibly parallel, regulatory layers.…”