WNK2 delays the proliferation and invasion of hepatocellular carcinoma by inhibiting the ERK1/2/ROS/SHP2 signaling pathway / 中国实验动物学报

Objective To investigate the effect of WNK2 on the ERK1/2/ROS/SHP2 signaling pathway in hepatocellular carcinoma(HCC)and to explore its role in cell proliferation and migration in HCC.Methods HepG2 cells were transfected with WNK2-mimic,sh-RNA WNK2,and corresponding negative control.The effect of WNK2 on the proliferation of HCC was examined by subcutaneous tumorigenesis assay in BALB/c nude mice.The expressions of WNK2,p40,gp90,p-SHP2,p-AKT,and p-ERK1/2 in tumor tissues were detected by Western Blot.After treatment with SHP2 inhibitor PHPS1,the expressions of WNK2,P40,gp90,p-SHP2,p-AKT,and p-ERK1/2 in HepG2 cells were detected by Western Blot.The migration ability and invasion ability of HepG2 cells were detected by cell scratch assay and Transwell.The proliferation ability of HepG2 cells was detected by monoclonal proliferation assay.Results Compared with the sh-NC group,the tumor volume of nude mice in the sh-RNA WNK2 group was significantly increased(P＜0.01);Compared with the NC-mimic group,the tumor volume of nude mice in the WNK2-mimic group was significantly reduced(P＜0.01).Western Blot result showed that compared with the sh-NC group,the expression of WNK2 in the sh-RNA WNK2 group was significantly decreased(P＜0.01),while the expressions of p40,gp90,p-SHP2,p-AKT and p-ERK1/2 were significantly increased(P＜0.01).Compared with the NC-mimic group,the expression of WNK2 was significantly increased in the WNK2-mimic group(P＜0.01),and the expressions of p40,gp90,p-SHP2,p-AKT,and p-ERK1/2 were significantly decreased(P＜0.01).In vitro experiment,compared with the sh-NC group,the expression of WNK2 was significantly decreased in the sh-RNA WNK2 group(P＜0.01),while the expressions of p40,gp90,p-SHP2,p-AKT and p-ERK1/2 were significantly increased in the sh-RNA WNK2 group(P＜0.01).Compared with the sh-NC+PHPS1 group,the expression of WNK2 was significantly decreased in the sh-RNA WNK2+PHPS1 group(P＜0.01),while the expressions of p40,gp90,p-SHP2,p-AKT,and p-ERK1/2 were reversed and had no significant differences compared with the sh-NC+PHPS1 group(P＞0.05).The cell scratch assay and Transwell result showed that the migration and invasion ability of HepG2 cells in the sh-RNA WNK2 group was significantly increased compared with the sh-NC group(P＜0.01).The migration and invasion ability of HepG2 cells in the sh-NC+PHPS1 group and sh-RNA WNK2+PHPS1 group were significantly decreased with no significant difference(P＞0.05).The result of the monoclonal proliferation experiment showed that the proliferation capacity of HepG2 cells in the sh-RNA WNK2 group was significantly increased compared with the sh-NC group(P＜0.01),while the proliferation ability of HepG2 cells in the sh-NC+PHPS1 group and sh-RNA WNK2+PHPS1 group was significantly decreased with no significant difference(P＞0.05).Conclusions WNK2 can inhibit the ERK1/2/ROS/SHP2 signaling pathway,thereby inhibiting ERK1/2/Akt signaling and delaying the proliferation and migration of HCC.

Advances of SHP2 modulators in the cancer immunotherapy / 药学学报

Src homology phosphotyrosyl phosphatase 2 (SHP2) is a protein tyrosine phosphatase encoded by PTPN11, which catalyzes the dephosphorylation of protein tyrosine. As a convergence node, SHP2 mediates multiple signaling pathways such as rat sarcoma (RAS)-rapidly accelerated fibrosarcoma (RAF)-mitogen-activated extracellular signal-regulated kinase (MEK)-extracellular regulated protein kinases (ERK), phosphatidylinositol 3-kinase (PI3K)-serine/threonine kinase (AKT), janus kinase (JAK)-signal transducer and activator of transcription (STAT) and programmed death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1). It can not only regulate the growth and proliferation of tumor cells, but also mediate the immune escape of tumor cells by influencing the tumor microenvironment. Given its dual biological functions in tumor immune regulation, SHP2 is a promising target for cancer immunotherapy. To date, several SHP2 allosteric inhibitors have been advanced into clinical trials for tumor immunotherapy with single or combination therapeutic strategies. Additionally, SHP2 activators also showed therapeutic potential in the field of tumor immune modulation. In this paper, we reviewed the dual function of SHP2 in both tumor and immune cells. Besides, the challenges and prospects of SHP2 modulators in cancer immunotherapy were also briefly discussed, aiming to explore new horizon of SHP2 modulators for tumor immunotherapy.

Effect and mechanism of SHP2 protein phase isolation induced by activated mutation on proliferation of mouse mesenchymal stem cells / 安徽医科大学学报

Objective @# To investigate the effect of SHP2 protein phase separation induced by activation mutation on cell proliferation and its mechanism through construct a mouse model of SHP2E76K mutation . @*Methods @#Hybrid PTPN11 E76K⁃NEO/ + C57BL/6J mouse were hybridizedwith Mx1 ⁃cre tool mice to obtain the required Mx1 ⁃cre;Ptpn11 + / + and Mx1 ⁃cre;Ptpn11 E76K/ + . The later genotype mice were injected with pI⁃pC to induce the expression of Cre enzyme and mutate Ptpn11E76K in bone marrow mesenchymal stem cells(MSC) . The Mx1 ⁃cre ; Ptpn11 + / + and Mx1 ⁃cre;Ptpn11 E76K/ + genotype mice ′s cells were isolated and cultured in vitro and identified as MSCs by immunofluorescence staining . With Ptpn11 + / + MSC as the control group and Ptpn11 E76K/ + MSC as the experimental group , the two kinds of cells were divided into 6 groups by adding drugs : Ptpn11 + / + group ; Ptpn11 + / + + SHP099 group ; Ptpn11 + / + + ET070 group ; Ptpn11 E76K/ + group ; Ptpn11 E76K/ + + SHP099 group ; Ptpn11 E76K/ + + ET070 group . The differences of SHP2 protein phase separation in the six groups were observed by immunofluorescencestaining, and the differences of SHP2 protein expression were detectedby Western blot . CCK⁃8 was used to observe the changes of cell proliferation after phase separation was affected . Western blot was used to detect the expression levels of ERK/ cell proliferation after phase separation was affected . Western blot was used to detect the expression levels of ERK/ p ⁃ERK , AMPK/p⁃AMPK , mTOR/p⁃mTOR and other molecules between the six groups . @*Results @# Genotypes Mx1 ⁃cre ; Ptpn11 E76K/ + and Mx1 ⁃cre ; Ptpn11 + / + mice were obtained by genotyping , and the primary MSCs were isolated . Compared with Ptpn11 + / + group , SHP2 proteins in the Ptpn11 E76K/ + group produced more phase separation condensates , and compared with Ptpn11 E76K/ + group , the SHP2 proteins in the Ptpn11 E76K/ + + SHP099 and Ptpn11 E76K/ ++ ET070 groups produced less phase separation condensates . No difference in SHP2 protein expression levels between groups was detected by Western blot . Compared with Ptpn11 + / + group , the proliferation ability of MSC in Ptpn11 + / + + SHP099 and Ptpn11 + / + + ET070 groups decreased , the expression of p ⁃ERK and p ⁃mTOR decreased, and the expression of p ⁃AMPK protein increased . Compared with Ptpn11 E76K/ + group , the proliferation ability of MSC in Ptpn11 E76K/ + + SHP099 and Ptpn11 E76K/ + + ET070 groups decreased , the expression of p ⁃ERK and p ⁃ mTOR decreased , and the expression of p⁃AMPK protein increased . @*Conclusion @# SHP2 phase isolation is involved in the alteration of proliferative capacity of SHP2E76K ⁃activated MSCs by stimulating the expression of AMPK⁃mTOR signaling pathway .

Targeting macrophagic SHP2 for ameliorating osteoarthritis via TLR signaling

Osteoarthritis (OA), in which M1 macrophage polarization in the synovium exacerbates disease progression, is a major cause of cartilage degeneration and functional disabilities. Therapeutic strategies of OA designed to interfere with the polarization of macrophages have rarely been reported. Here, we report that SHP099, as an allosteric inhibitor of src-homology 2-containing protein tyrosine phosphatase 2 (SHP2), attenuated osteoarthritis progression by inhibiting M1 macrophage polarization. We demonstrated that M1 macrophage polarization was accompanied by the overexpression of SHP2 in the synovial tissues of OA patients and OA model mice. Compared to wild-type (WT) mice, myeloid lineage conditional Shp2 knockout (cKO) mice showed decreased M1 macrophage polarization and attenuated severity of synovitis, an elevated expression of cartilage phenotype protein collagen II (COL2), and a decreased expression of cartilage degradation markers collagen X (COL10) and matrix metalloproteinase 3 (MMP3) in OA cartilage. Further mechanistic analysis showed thatSHP099 inhibited lipopolysaccharide (LPS)-induced Toll-like receptor (TLR) signaling mediated by nuclear factor kappa B (NF-κB) and PI3K-AKT signaling. Moreover, intra-articular injection of SHP099 also significantly attenuated OA progression, including joint synovitis and cartilage damage. These results indicated that allosteric inhibition of SHP2 might be a promising therapeutic strategy for the treatment of OA.

Effect of hemoglobin on Shp2 expression in brain tissues and adherens junction in blood brain barrier in rats after intracerebral hemorrhage / 中华神经医学杂志

Objective:To investigate the effect of hemoglobin on Shp2 expression in brain tissues and adherens junction in blood brain barrier in rats after cerebral hemorrhage.Methods:Eighty male SD rats were randomly allocated into sham-operated group and groups of cerebral hemorrhage for 6 h, 24 h, 3 d, and 7 d ( n=16). Rat models in the groups of cerebral hemorrhage were established by intracerebral injection of 20 μL of hemoglobin. Six h, 24 h, 3 d, and 7 d after injection, neurological functions were assessed by Longa scale; brain water content and brain organ coefficient in the harvested cerebral tissues were calculated by wet-dry weighting method; Shp2 mRNA expression was analyzed by real-time fluorescence quantification reverse transcription PCR (qRT-PCR); Shp2 positive neurons was detected by immunohistochemistry; the protein expressions of Shp2, α-catenin, β-catenin and vascular endothelial (VE)-cadherin, and phosphorylated (p-) α-catenin, p-β-catenin and p-VE-cadherin were explored by Western blotting. Results:As compared with those in the sham-operated group, Longa scale scores in groups of intracerebral hemorrhage for 6 h, 24 h, 3 d and 7 d were significantly increased ( P<0.05). As compared with the sham-operated group, groups of intracerebral hemorrhage for 24 h, 3 d and 7 d had significantly increased brain water content and brain organ coefficient, statistically reduced Shp2 mRNA expression, statistically samller amount of Shp2 positive neurons, and statistically reduced Shp2 protein expression, and significantly increased protein expressions of p-α-catenin, p-β-catenin and p-VE-cadherin ( P<0.05). Conclusion:Intracerebral injection of hemoglobin can downregulate Shp2 expression and promote phosphorylation of adherens junction proteins, therefore induce the disruption of adherens junction, which might be a critical mechanism of blood-brain barrier disruption and brain edema.

Study on the secondary metabolites of grasshopper-derived fungi Arthrinium sp. NF2410 / 中国天然药物

Two new 2-carboxymethyl-3-hexyl-maleic anhydride derivatives, arthrianhydride A (1) and B (2), along with three known compounds 3-5, were isolated from the fermentation broth of a grasshopper-associated fungus Arthrinium sp. NF2410. The structures of new compounds 1 and 2 were determined based on the analysis of the HR-ESI-MS and NMR spectroscopic data. Furthermore, compounds 1 and 2 were evaluated on inhibitory activity against the enzyme SHP2 and both of them showed moderate inhibitory activity against SHP2.

SHP2 inhibition triggers anti-tumor immunity and synergizes with PD-1 blockade

Tyrosine phosphatase SHP2 is a promising drug target in cancer immunotherapy due to its bidirectional role in both tumor growth promotion and T-cell inactivation. Its allosteric inhibitor SHP099 is known to inhibit cancer cell growth both and . However, whether SHP099-mediated SHP2 inhibition retards tumor growth anti-tumor immunity remains elusive. To address this, a CT-26 colon cancer xenograft model was established in mice since this cell line is insensitive to SHP099. Consequently, SHP099 minimally affected CT-26 tumor growth in immuno-deficient nude mice, but significantly decreased the tumor burden in CT-26 tumor-bearing mice with intact immune system. SHP099 augmented anti-tumor immunity, as shown by the elevated proportion of CD8IFN- T cells and the upregulation of cytotoxic T-cell related genes including , which decreased the tumor load. In addition, tumor growth in mice with SHP2-deficient T-cells was markedly slowed down because of enhanced anti-tumor responses. Finally, the combination of SHP099 and anti-PD-1 antibody showed a higher therapeutic efficacy than either monotherapy in controlling tumor growth in two colon cancer xenograft models, indicating that these agents complement each other. Our study suggests that SHP2 inhibitor SHP099 is a promising candidate drug for cancer immunotherapy.

Tumor-targeted therapy based on allosteric inhibitor of tyrosine phosphatase SHP2 / 中国肿瘤生物治疗杂志

@#蛋白质酪氨酸磷酸化对细胞的生命活动至关重要，其调控异常与多种疾病的发生密切相关。在酪氨酸磷酸酶家族 中，SHP2是目前唯一被证实的原癌蛋白，参与调控多个癌症相关过程。其活化突变会导致白血病、黑色素瘤、乳腺癌及肺癌的发 生。2016年以来，随着高特异性、可口服的SHP2新型变构抑制剂成功开发，靶向抑制SHP2在抑制肿瘤生长以及改善肿瘤耐药性 方面逐渐显现出了强大的临床应用潜力，提示SHP2抑制剂有望成为首个靶向酪氨酸磷酸酶的抗肿瘤靶向药物。

Study on influence of the CpG DNA on activation of IFN-γ signaling transduction regulatory proteins / Монголын Анагаах Ухаан

Introduction@#When human body encounters external pathogens primary/innate immunity cells are activated by recognizing them and secondary/adaptive immunity is activated consecutively. In our previous study, we revealed that there is a synergistic action between TLR9 and IFN-γ signaling in the endothelial cells. @*Purpose@#To determine the role of negative and positive regulator proteins on the IFN-γ/TLR9 signaling pathway. @*Methods@#In this study, murine endothelial cell (END-D) culture was used. END-D cells pre-treated with TLR9 ligand CpG DNA and then stimulated with IFN-γ. The negative (SHP-2, SOCS1, PIAS1) and positive (p38) regulator protein expression was detected by Western blotting. @*Results and Conclusion@#Treatment by TLR9 ligand CpG DNA and IFN-γ increased positive regulator p38 phosphorylation in 0.5 hour. CpG DNA inhibited IFN-γ negative regulator PIAS1 protein expression in 6 hour and SOCS1 and SHP-2 expression could not affect in 4 hour.

Role of protein tyrosine phosphatase SHP-2 in group I metabotropic glutamate receptors-induced allodynia / 中国药理学通报

Aim To investigate whether the pain modi-fication by group I metabotropic glutamate receptors (mGluRs)required the involvement of Src homology-2 domain-containing phosphatase-2 (SHP-2 ).Methods Co-immunoprecipitation was performed to examine the possible interaction between SHP-2 and group I mGluRs in spinal cord dorsal horn of mice.By measur-ing the paw withdrawal thresholds,the effects of SHP-2 inhibitor NSC-87877 or its catalytically inactive SHP-2 (C459S ) mutant on allodynia induced by group I mGluRs agonist DHPG (50 nmol)were observed.Re-sults Anti-mGluR5 antibody was able to co-immuno-precipitate SHP-2 from spinal dorsal horn of mice, while no SHP-2 was precipitated by anti-mGluR1 anti-body.Inactivation of SHP-2 by NSC-87877 (6 nmol) or SHP-2 (C459S ) effectively attenuated allodynia caused by DHPG.Conclusion SHP-2 can physically interact with mGluR5.The activation of SHP-2 may be necessary for group I mGluRs to process the nocicep-tive information.

Shp2 regulates cigarette smoke extract-induced epithelial-mesenchymal transition / 中国药理学通报

Aim To explore the effects of Shp2 on cig-arette smoke extract (CSE)-induced epithelial-mesen-chymal transition (EMT). Methods The effects of CSE on TGF-β1 levels in epithelial cells were meas-ured by Q-PCR and ELISA. Immunofluorescent stai-ning was used to assess the expressions of CSE-induced EMT-related markers. The activation of CSE-induced Shp2,Smad2 was investigated by Western blot. Re-sults CSE induced Shp2 phosphorylation in a concen-tration-dependent manner in A549 cells. PHPS1 inhib-ited the increase in mRNA and protein expression of TGF-β1 induced by CSE. PHPS1 regulated the expres-sions of CSE-induced EMT markers (down-regulation of E-cadherin,up-regulation expression of Vimentin and α-SMA). The inhibition of either Shp2 inhibitor or Shp2 siRNA decreased Smad2 phosphorylation induced by CSE. Conclusions CSE initiates EMT through the Shp2 / Smad2 signaling pathway,which is activated by CSE through TGF-β1 generation. It is suggested that Shp2 might be a possible new target for COPD and lung cancer therapy.

Effect of 5-FU on the expression of SHP2 gene in colorectal cancer cells RKO / 药学实践杂志

Objective To investigate the effect of 5-FU on the expression of SHP2 gene in colorectal cancer cells RKO . Methods The human colorectal cancer cell line RKO of logarithmic growth phase was cultured 48 h with 5-FU .The expression of SHP2 was observed by immunofluorescence and Western blotting ;siSHP2 which specifically inhibits the expression of SHP2 was transfected into RKO cells and cultured 48 h with 5-FU .The cell absorbance (A) values were measured with CCK8 and apoptosis was determined by flow cytometry .The sensitivity of RKO to 5-FU and the effect of 5-FU on apoptosis of RKO cells were observed .Results The expression of nuclear protein of SHP2 was improved remarkably after colorectal cancer cell RKO was cultured 48 h with 5-FU .The sensitivity of RKO cells to 5-FU and the cell apoptosis rate induced by 5-FU were decreased after siSHP2 transfection .Conclusion 5-FU exerts anti-cancer activity possibly due to its promoting the apoptosis of RKO cells by influencing the expression of SHP2 .

Anticancer function of Shp2 in lung adenocarcinoma A549 cells and rela-ted molecular mechanisms / 中国病理生理杂志

AIM: To explore the anticancer function of Shp2 in lung adenocarcinoma A549 cells and the related molecular mechanisms.METHODS: The viability and proliferation of A549 cells treated with Shp2 specific inhibi-tor Phps-1 or cisplatin (DDP) were measured by CCK-8 assay and EdU assay.Annexin V-FITC/PI double staining was ap-plied to detect apoptotic rate of A549 cells with different interventions.The protein levels of caspase-3-17p, Bcl-2, Bax, p-STAT3 /STAT3 and p-ERK/ERK were determined by Western blot.RESULTS: Compared with control group, Phps-1 at the concentration of 20 μmol/L significantly increased the viability of A549 cells after 24 h of treatment ( P <0.05). Meanwhile, the proliferation rate of A549 cells in Phps-1 20 μmol/L group was significant increased compared with control group (P <0.05).The apoptotic rate of A549 cells in DDP treatment group decreased from 13.01% ±2.62% to 3.67%±0.93% after adding Phps-1 (P <0.05).Phps-1 down-regulated the protein levels of caspase-3-17p, Bax and p-ERK, but up-regulated p-STAT3.CONCLUSION: Shp2 is a tumor suppressor in A549 cells, which may be associated with the activation of STAT3 signal pathway.

LRRK2 Inhibits FAK Activity by Promoting FERM-mediated Autoinhibition of FAK and Recruiting the Tyrosine Phosphatase, SHP-2

Mutation of leucine-rich repeat kinase 2 (LRRK2) causes an autosomal dominant and late-onset familial Parkinson's disease (PD). Recently, we reported that LRRK2 directly binds to and phosphorylates the threonine 474 (T474)-containing Thr-X-Arg(Lys) (TXR) motif of focal adhesion kinase (FAK), thereby inhibiting the phosphorylation of FAK at tyrosine (Y) 397 residue (pY397-FAK), which is a marker of its activation. Mechanistically, however, it remained unclear how T474-FAK phosphorylation suppressed FAK activation. Here, we report that T474-FAK phosphorylation could inhibit FAK activation via at least two different mechanisms. First, T474 phosphorylation appears to induce a conformational change of FAK, enabling its N-terminal FERM domain to autoinhibit Y397 phosphorylation. This is supported by the observation that the levels of pY397-FAK were increased by deletion of the FERM domain and/or mutation of the FERM domain to prevent its interaction with the kinase domain of FAK. Second, pT474-FAK appears to recruit SHP-2, which is a phosphatase responsible for dephosphorylating pY397-FAK. We found that mutation of T474 into glutamate (T474E-FAK) to mimic phosphorylation induced more strong interaction with SHP-2 than WT-FAK, and that pharmacological inhibition of SHP-2 with NSC-87877 rescued the level of pY397 in HEK293T cells. These results collectively show that LRRK2 suppresses FAK activation through diverse mechanisms that include the promotion of autoinhibition and/or the recruitment of phosphatases, such as SHP-2.

Significance study of SHP2 Expression in brain tissue of bacterial meningitis rat / 中国基层医药

Objective To study the significance of protein tyrosine phosphatase (SHP2)expression in bac-terial meningitis.Methods 90 rats were divided into meningitis group (72)and healthy controls (18)two groups based on the random number table,The SHP2 expression in rat brain tissue at different time points of meningitis group and healthy control group were tested by reverse transcription (RT)a PCR,Western blotting,immunohistochemical methods,then the relationship between SHP2 protein expression and tumor necrosis factor-α(TNF-α),white blood cell (WBC)counts were observed and analyzed.Results The cortical SHP2 mRNA expression of meningitis rat in-cluding (0.035 ±0.020),(0.200 ±0.049),(0.129 ±0.032)and (0.057 ±0.039),were significantly higher than those of the healthy control group (0.031 ±0.028)(F=12.74,P0.05)and 0.77 (t=4.303,P<0.05).Conclusion SHP2 participates in pathophysiology of bacterial meningitis,the main role may be in suppressing inflammation and repairing inflammatory response,it can be used as a reference indicator of condition changes.

Efecto del factor de crecimiento de fibroblastos 21 / Fibroblast growht factor 21 effects over phosphatase SHP-2 expression in Malme-3 cells

Almost 50 percent of Noonan syndrome patients, characterized by short stature, present activating mutations of the citoplasmatic phosphatase SHP-2, which induce hyperactivation of the Ras/MAPK pathway. On the other hand, the fibroblast growth factor 21 (FGF-21), recently suggested as a FGF with “endocrine” function, would affect longitudinal growth inhibiting growth hormone signaling at chondrocytes level. Union and activation of FGF-21 to its receptor is regulated by the co-factor beta Klotho (KLB). Aims: To determine if FGF-21 and/or FGF-21+KLB are able to modify the genetic expression of SHP-2 ina human skin fibroblast cell line (Malme-3). Methods: cells were incubated with or without FGF-21, FGF-21 + KLB. At 12 and 24 hours after induction total RNA was extracted andSHP-2 mRNA levels were determine by quantitative PCR. Expression of GADPH gene was employed for normalization. Results: Incubation with FGF-21 produce a 36 percent (p = < 0,05)increment in SHP-2 expression, which was not modified with KLB co-incubation. Discussion: it is shown by the first time that FGF-21 is able to produce an increase in SHP-2 gene expression in human fibroblast, which was independent of KLB presence...

Síndrome de Noonan / Noonan syndrome

El Síndrome de Noonan fue descrito por Noonan y Ehmke en 1963. La incidencia se ha estimado en 1 de 1000 y 1 de 2500 nacimientos vivos.1 El gen se encuentra localizado en el cromosoma 12q22 y se hereda en forma autosómica dominante y tiene una expresividad muy variable. La principal característica incluye estatura baja, defectos cardiacos, dismorfismo facial entre otros. Estatura La severidad de los síntomas varían mucho en estos pacientes. Lo que no siempre es fácil hacer el diagnóstico en los primeros años, y muchas veces son subdiagnosticados, condición que nos motivo a revisar el caso.

Noonan Syndrome is a relative common autosomic dominant congenital disorder, with an incidence between 1:1,000 and 1:2,500 children worldwide. The gen is in 12q22 chromosome. The principal features include short stature, typical facial dysmorphology and congenital heart disease, among others. The range and severity of features can vary greatly in patients with NS, therefore, establishing a diagnose is difficult. The syndrome is not always identified at an early age, and many times misdiagnosed.

Advance research on protein tyrosine phosphatase SHP-2 and the regulating role of it in osteoclastogenesis / 医学研究生学报

SHP-2 is one of the protein tyrosine phosphatases which plays a role in the progress of dephosphorylation in organ -isms, participating in many kinds of signal transduction pathways .The mutation of SHP-2 is associated with many kinds of malignant diseases .In recent years , scholars have found that SHP-2 is the key factor in osteoclastogenesis , playing a positive role in the progress of reversible phosphorylation of osteoclasts .The objective of this article is to review the molecular biological characteristics of SHP-2, th diseases associated with the mutation of SHP-2 and the effects of SHP-2 in regulation of osteoclastogenesis .

Role of SHP2 in invasion and metastasis of breast cancer / 中国肿瘤临床

Src homology 2 domain-containing phosphatase (SHP2), which is encoded by proto-oncogene PTPN11, is one of the transmembrane protein-tyrosine phosphatases. SHP2 has an important function in signal transduction pathways and activities of cells through the regulation of tyrosine phosphorylation level of intracellular proteins. The status of SHP2 activation is closely connected with the regulation of hormone levels, state of invasion and metastasis of tumor, development and progression of tumor stem cells of breast cancer, as well as signal pathways including Ras/ERK and PI3K/Akt/mTOR. Gene knockout or gene silencing expression helps inhibit tumor growth, irreversibly hindering the ability of the tumor to regain stem cells and disturb the signal pathways of the invasion and metastasis of breast cancer. Recent studies have shown that SHP2 may help in bringing anticancer drugs to a higher level. This arti-cle concentrates on the research progress in relationship of SHP2 with invasion and metastasis of breast cancer.