SHP-1 phosphatase acts as a coactivator of PCK1 transcription to control gluconeogenesis.

We previously reported that the protein-tyrosine phosphatase SHP-1 (PTPN6) negatively regulates insulin signaling, but its impact on hepatic glucose metabolism and systemic glucose control remains poorly understood. Here, we use co-immunoprecipitation assays, chromatin immunoprecipitation sequencing, in silico methods, and gluconeogenesis assay, and found a new mechanism whereby SHP-1 acts as a coactivator for transcription of the phosphoenolpyruvate carboxykinase 1 (PCK1) gene to increase liver gluconeogenesis. SHP-1 is recruited to the regulatory regions of the PCK1 gene and interacts with RNA polymerase II. The recruitment of SHP-1 to chromatin is dependent on its association with the transcription factor signal transducer and activator of transcription 5 (STAT5). Loss of SHP-1 as well as STAT5 decrease RNA polymerase II recruitment to the PCK1 promoter and consequently PCK1 mRNA levels leading to blunted gluconeogenesis. This work highlights a novel nuclear role of SHP-1 as a key transcriptional regulator of hepatic gluconeogenesis adding a new mechanism to the repertoire of SHP-1 functions in metabolic control.

Regulation of PPARγ2 Stability and Activity by SHP-1.

The protein tyrosine phosphatase Src homology region 2 domain-containing phosphatase-1 (SHP-1) plays an important role in modulating glucose and lipid homeostasis. We previously suggested a potential role of SHP-1 in the regulation of peroxisome proliferator-activated receptor γ2 (PPARγ2) expression and activity but the mechanisms were unexplored. PPARγ2 is the master regulator of adipogenesis, but how its activity is regulated by tyrosine phosphorylation is largely unknown. Here, we found that SHP-1 binds to PPARγ2 primarily via its N-terminal SH2-domain. We confirmed the phosphorylation of PPARγ2 on tyrosine-residue 78 (Y78), which was reduced by SHP-1 in vitro resulting in decreased PPARγ2 stability. Loss of SHP-1 led to elevated, agonist-induced expression of the classical PPARγ2 targets FABP4 and CD36, concomitant with increased lipid content in cells expressing PPARγ2, an effect blunted by abrogation of PPARγ2 phosphorylation. Collectively, we discovered that SHP-1 affects the stability of PPARγ2 through dephosphorylation thereby influencing adipogenesis.

Protein tyrosine phosphatases in multiple myeloma.

Many cell signaling pathways are activated or deactivated by protein tyrosine phosphorylation and dephosphorylation, catalyzed by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), respectively. Even though PTPs are as important as PTKs in this process, their role has been neglected for a long time. Multiple myeloma (MM) is a cancer of plasma cells, which is characterized by production of monoclonal immunoglobulin, anemia and destruction of bone. MM is still incurable with high relapse frequency after treatment. In this review, we highlight the PTPs that were previously described in MM or have a role that can be relevant in a myeloma context. Our purpose is to show that despite the importance of PTPs in MM pathogenesis, many unanswered questions in this field need to be addressed. This might help to detect novel treatment strategies for MM patients.

The control of oligodendrocyte bioenergetics by interferon-gamma (IFN-γ) and Src homology region 2 domain-containing phosphatase-1 (SHP-1).

Glycolysis and mitochondrial respiration are essential for oligodendrocyte metabolism in both the developing and adult CNS. Based on recent reports on the effects of the proinflammatory cytokine IFN-γ on metabolism and on oligodendrocytes, we addressed whether IFN-γ may affect oligodendrocyte bioenergetics in ways relevant to CNS disease. Oligodendrocytes of mice treated with IFN-γ showed significant reductions in aerobic glycolysis and mitochondrial respiration. As expected, IFN-γ treatment led to the induction of STAT1 in oligodendrocytes indicating active signaling into these cells. To determine the direct effects of IFN-γ on oligodendrocyte metabolism, cultured oligodendrocytes were treated with IFN-γ in vitro, which resulted in suppression of glycolysis similar to oligodendrocytes of animals treated with IFN-γ in vivo. Mice lacking SHP-1, a key regulator of IFN-γ and STAT1 signaling in CNS glia, had high constitutive levels of STAT1 and decreased aerobic glycolysis and mitochondrial respiration rates relative to wild type mouse oligodendrocytes. Together, these data show that IFN-γ and SHP-1 control oligodendrocyte bioenergetics in ways that may relate to the role of this cytokine in CNS disease.

Inhibition of Src homology 2 domain-containing phosphatase 1 increases insulin sensitivity in high-fat diet-induced insulin-resistant mice.

Insulin resistance plays a crucial role in the development of type 2 diabetes. Insulin receptor signalling is antagonized and tightly controlled by protein tyrosine phosphatases (PTPs). However, the precise role of the PTP src homology 2 domain-containing phosphatase 1 (SHP-1) in insulin resistance has not been explored. Male C57BL/6J mice were fed a high-fat diet (HFD, 60% kcal from fat), to induce insulin resistance, or a low-fat diet (LFD, 10% kcal from fat) for 10 weeks. Afterwards, HFD-fed mice were pharmacologically treated with the SHP-1 (Ptpn6) inhibitor sodium stibogluconate and the broad spectrum pan-PTP inhibitor bis(maltolato)oxovanadium(IV) (BMOV). Both inhibitors ameliorated the metabolic phenotype, as evidenced by reduced body weight, improved insulin sensitivity and glucose tolerance, which was not due to altered PTP gene expression. In parallel, phosphorylation of the insulin receptor and of the insulin signalling key intermediate Akt was enhanced, and both PTP inhibitors and siRNA-mediated SHP-1 downregulation resulted in an increased glucose uptake in vitro. Finally, recombinant SHP-1 was capable of dephosphorylating the ligand-induced tyrosine-phosphorylated insulin receptor. These results indicate a central role of SHP-1 in insulin signalling during obesity, and SHP-1 inhibition as a potential therapeutic approach in metabolic diseases.