[Mortality of drowning and road traffic injury among children aged 5-14 in China from 2008 to 2019].

Objective: To analyze the trajectory of drowning and road traffic injury mortality among children aged 5-14 years in China from 2008 to 2019. Methods: Mortality data of unintentional injuries were from the Mortality Surveillance Data Set of National Disease Surveillance System from 2009 to 2018 and grouped by regions, urban and rural areas, genders, and age groups. The trajectory model was used to analyze the trend of drowning and road traffic injury mortality with years. Results: The mortality of drowning and road traffic injury showed a similar trend. In the trajectory model of drowning mortality, east, middle and west rural boys and western urban boys of all ages belonged to the high mortality group. The moderate mortality group included eastern urban boys and western girls aged 5-9 years and also contained eastern and middle urban boys and western urban girls aged 10-14 years. The other combinations belonged to the low mortality group. In the trajectory model of road traffic injury mortality, western urban boys, all rural boys and western rural girls aged 5-9 years, middle and western rural boys and western urban boys aged 10-14 years belonged to the high mortality group. Eastern urban girls aged 5-9 years and 10-14 years belonged to the low mortality group. The other combinations belonged to the moderate mortality group. Conclusion: There are different groups in the trajectory model of drowning and road traffic injury mortality among children in China. Identifying the trajectory of injury mortality is helpful to carry out more targeted prevention in China.

[Statistical methods for repeated measurement data in scientific research].

Repeated measurement data is a common type of data in medicine, whichcan not be simply compared at each time point, and a professional statistical analysis method should be used to analysis this kind of data. Three common statistical methods were introduced for repeated measurement data, including repeated measurement analysis of variance, generalized estimation equations and multilevel models.The implementation of specific software and related results for the three methods based on some cases were also explainedin the article. Additionally, we compared the actual application of the three methods, in order to help clinical researchers to analyze repeated measurement data correctly and to improve their efficiency of data analysis.

[The application of Hoffmann method in the establishment of children's reference intervals of erythrocyte count].

OBJECTIVE: To verify the reliability and feasibility of Hoffmann method in establishing pediatric reference intervals (RI) of erythrocyte count. METHODS: Three hundreds and ninty-two thousands of hospital-based data for erythrocyte count of children aged in 1 to 17, measured by the Sysmex Xs-800i, was collected from Beijing Children's Hospital during January to December 2014. Outliers were removed using the Dixon method, then Hoffmann method was conducted to establish the gender and age stratified pediatric RIs of erythrocyte count. The erythrocyte count of 2 217 healthy children, recruited from Beijing Children's Hospital and Liaocheng Children's Hospital in Shandong province, was conducted as normal reference to verify the reliability of Hoffmann method in establishing RIs and to compare with existing RIs. RESULTS: In 4 subgroups as following, male aging 1 to 12 years, male aging 13 to 17 years, female aging 1 to 12 years, female aging 13 to 17 years, the RIs of erythrocyte count established using Hoffmann method were (4.1-5.4)×10(12)/L, (4.4-5.7)×10(12)/L, (4.0-5.3)×10(12)/L, (4.0-5.3)×10(12)/L, respectively. The verification results in 2 217 healthy children showed that the proportions of out of range in four subgroups were 6.17%, 8.81%, 6.22%, 7.78%, respectively. CONCLUSION: Hoffmann method produce reliable RIs according with the actual situation in healthy children, which is also convenient and is worth popularizing in clinical practice.

[Clinical and prognostic characteristics of REM sleep related obstructive sleep apnea in children].

Objective: To analyze the clinical and prognostic characteristics of rapid eye movement sleep related obstructive sleep apnea (REM-OSA) in children. Methods: A retrospective analysis was performed on the clinical data of 62 children aged from 2 to 14 years who were admitted to Beijing Children's Hospital, Capital Medical University from December 2017 to April 2021, diagnosed with moderate to severe OSA by polysomnography monitoring (PSG), underwent adenoid tonsillectomy, and completed follow-up 6 months after surgery. There were 45 males (72.6%) and 17 females (27.4%). The age range was 2.0-12.3 years. All children completed the clinical data collection, PSG, OSA-18 quality of life questionnaire and Children's Sleep questionnaire-sleep related breathing disorder subscale at baseline. PSG and OSA-18 quality of life questionnaire were reexamined at 6 months after surgery. Children were divided into REM-OSA group (33 cases) and non-REM-OSA group (29 cases) according to whether the obstructive apnea-hypopnea index (OAHI) during rapid eye movement sleep and OAHI during non-rapid eye movement sleep ratio was≥2. Baseline PSG parameters and scale scores, 6-month postoperative cure rate and OSA-18 quality of life questionnaire scores of the 2 groups were compared, and statistical analysis was performed using SPSS 23.0 software. Results: There were no significant differences in age, sex, body mass index, neck circumference/height ratio, overweight or obesity, history of disease, tonsil and adenoid size between the two groups (all P>0.05). Compared with non-REM-OSA group, REM-OSA group had higher oxygen desaturation index and proportion of SpO2<90% of total sleep time (Z=-2.723, P=0.006;Z=-3.414; P=0.001 respectively), and lower SpO2 nadir (Z=-3.957, P<0.001). The proportion of obstructive apnea in total respiratory events (related to anatomical factors) in REM-OSA group was higher than that in non-REM-OSA group (t=2.840, P=0.006). However, the proportion of central apnea in total respiratory events and arousal index (related to functional factors) in REM-OSA group was lower than that in non-REM-OSA group (t=-2.597, P=0.012;Z=-2.956, P=0.003), and there were no significant differences in other PSG parameters between the two groups (all P>0.05). There was an interaction effect between the two groups in the change trend of OSA cure rate at 6 months after surgery under different baseline OAHI (χ2=4.282, P=0.039). Conclusions: The weight of anatomic factors and functional factors in the etiology of children with REM-OSA and non-REM OSA was different, and the postoperative OSA cure rate of children with different baseline OAHI changed in reverse trend.

[Poisonous substances and geographical distribution of poisoning in hospitalized children based on data from 25 hospitals in China from 2016 to 2020].

Objective: To investigate the poisonous substances and geographical distribution of poisoning in children in China. Methods: A cross-sectional study. The clinical data of 8 385 hospitalized children from January 2016 to December 2020 were extracted from the FUTang Updating Medical Records database. These children aged 0 to 18 years and were admitted due to poisoning. They were grouped according to age (newborns and infants, toddlers, preschoolers, school-age children, adolescents), place of residence (Northeast China, North China, Central China, East China, South China, Southwest China, Northwest China), and mode of discharge (discharge under medical advice, transfer to another hospital under medical advice, discharge without medical advice, death, other). The poisonous substance and causes of poisoning in different groups were analyzed. Results: Among these 8 385 children, 4 734 (56.5%) were male and 3 651 (43.5%) female, with a male-to-female ratio of 1.3∶1. The age was 3 (2, 7) years. The prevalence of poisoning was 51.8% (4 343/8 385) in toddlers, 16.5% (1 380/8 385) in adolescents, 14.8% (1 242/8 385) in preschoolers, 14.4% (1 206/8 385) in school-age children, and 2.5% (214/8 385) in newborns and infants. Drug poisoning accounted for 43.5% (3 649/8 385) and pesticide accounted for 26.8% (2 249/8 385). Drug poisoning was more common in adolescents (684/1 380, 49.6%) and toddlers (2 041/4 343, 47.0%); non-drug poisoning was more common in school-age children (891/1 206, 73.9%), of which carbon monoxide was mainly in newborns and infants (41/214, 19.2%) and food poisoning in children of school age (241/1 206, 20.0%). Regarding regional characteristics, drug poisoning was more frequent in South China (188/246, 64.2%) and non-drug poisoning was more frequent in Southwest China (815/1 123, 72.5%). For drugs, anti-epileptic drugs, sedative-hypnotic drugs and anti-Parkinson's disease drugs had a higher proportion of poisoning in North China (138/1 034, 13.0%) than that in other regions. For non-drug poisoning, pesticides (375/1 123, 33.3%), food poisoning (209/1 123, 18.6%) and contact with poisonous animals (86/1 123, 7.7%) were more common in Southwest China than in other regions; carbon monoxide poisoning was more common in North China (81/1 034, 7.6%) and Northwest China (65/1 064, 6.3%). In Central China, poisoning happened more in toddlers (792/1 295, 61.2%) and less in adolescents (115/1 295, 8.8%) than in other regions. Regarding different age groups, poisoning in adolescent happened more in Northeast China (121/457, 26.5%), North China (240/1 034, 23.2%), and Northwest China (245/1 064, 23.0%). The rate of discharge under medical advice, discharge without medical advice, and mortality rate within the 5 years were 77.0% (6 458/8 385), 20.8% (1 743/8 385), 0.5% (40/8 385), respectively. Conclusions: Poisoning is more common in male and toddlers. Poisonous substances show a regional characteristic and vary in different age groups, with drugs and insecticides as the most common substances.

Modulation of the nuclear factor kappa B pathway by Shp-2 tyrosine phosphatase in mediating the induction of interleukin (IL)-6 by IL-1 or tumor necrosis factor.

Shp-2, a src homology (SH)2-containing phosphotyrosine phosphatase, appears to be involved in cytoplasmic signaling downstream of a variety of cell surface receptors, although the mechanism is unclear. Here, we have determined a role of Shp-2 in the cytokine circuit for inflammatory and immune responses. Production of interleukin (IL)-6 in response to IL-1 alpha or tumor necrosis factor (TNF)-alpha was nearly abolished in homozygous mutant (Shp-2(-/)-) fibroblast cells. The targeted Shp-2 mutation has no significant effect on the activation of the three types of mitogen-activated protein (MAP) kinases, extracellular signal-regulated kinase (Erk), c-Jun NH(2)-terminal kinase (Jnk), and p38, by IL-1/TNF, indicating that Shp-2 does not work through MAP kinase pathways in mediating IL-1/TNF-induced IL-6 synthesis. In contrast, IL-1/TNF-stimulated nuclear factor (NF)-kappa B DNA binding activity and inhibitor of kappa B (I kappa B) phosphorylation was dramatically decreased in Shp-2(-/)- cells, while the expression and activity of NF-kappa B-inducing kinase (NIK), Akt, and I kappa B kinase (IKK) were not changed. Reintroduction of a wild-type Shp-2 protein into Shp-2(-/)- cells rescued NF-kappa B activation and IL-6 production in response to IL-1/TNF stimulation. Furthermore, Shp-2 tyrosine phosphatase was detected in complexes with IKK as well as with IL-1 receptor. Thus, this SH2-containing enzyme is an important cytoplasmic factor required for efficient NF-kappa B activation. These results elucidate a novel mechanism of Shp-2 in cytokine signaling by specifically modulating the NF-kappa B pathway in a MAP kinase-independent fashion.

Expression and catalytic activity of the tyrosine phosphatase PTP1C is severely impaired in motheaten and viable motheaten mice.

Mutations in the gene encoding the phosphotyrosine phosphatase PTP1C, a cytoplasmic protein containing a COOH-terminal catalytic and two NH2-terminal Src homology 2 (SH2) domains, have been identified in motheaten (me) and viable motheaten (mev) mice and are associated with severe hemopoietic dysregulation. The me mutation is predicted to result in termination of the PTP1C polypeptide within the first SH2 domain, whereas the mev mutation creates an insertion or deletion in the phosphatase domain. No PTP1C RNA or protein could be detected in the hemopoietic tissues of me mice, nor could PTP1C phosphotyrosine phosphatase activity be isolated from cells homozygous for the me mutation. In contrast, mice homozygous for the less severe mev mutation expressed levels of full-length PTP1C protein comparable to those detected in wild type mice and the SH2 domains of mev PTP1C bound normally to phosphotyrosine-containing ligands in vitro. Nevertheless, the mev mutation induced a marked reduction in PTP1C activity. These observations provide strong evidence that the motheaten phenotypic results from loss-of-function mutations in the PTP1C gene and imply a critical role for PTP1C in the regulation of hemopoietic differentiation and immune function.

Abnormal chemokine-induced responses of immature and mature hematopoietic cells from motheaten mice implicate the protein tyrosine phosphatase SHP-1 in chemokine responses.

Chemokines regulate a number of biological processes, including trafficking of diverse leukocytes and proliferation of myeloid progenitor cells. SHP-1 (Src homology 2 domain tyrosine phosphatase 1), a phosphotyrosine phosphatase, is considered an important regulator of signaling for a number of cytokine receptors. Since specific tyrosine phosphorylation of proteins is important for biological activities induced by chemokines, we examined the role of SHP-1 in functions of chemokines using viable motheaten (me(v)/me(v)) mice that were deficient in SHP-1. Chemotactic responses to stromal call-derived factor 1 (SDF-1), a CXC chemokine, were enhanced with bone marrow myeloid progenitor cells as well as macrophages, T cells, and B cells from me(v)/me(v) versus wild-type (+/+) mice. SDF-1-dependent actin polymerization and activation of mitogen-activated protein kinases were also greater in me(v)/me(v) versus +/+ cells. In contrast, immature subsets of me(v)/me(v) bone marrow myeloid progenitors were resistant to effects of a number of chemokines that suppressed proliferation of +/+ progenitors. These altered chemokine responses did not appear to be due to enhanced expression of CXCR4 or lack of chemokine receptor expression. However, expression of some chemokine receptors (CCR1, CCR2, CCR3, and CXCR2) was significantly enhanced in me(v)/me(v) T cells. Our results implicate SHP-1 involvement in a number of different chemokine-induced biological activities.

[Endothelial dysfunction in children with obstructive sleep apnea syndrome].

Objective: To evaluate the endothelial function in obstructive sleep apnea syndrome(OSAS) children and to identify related factors of endothelial dysfunction. Methods: This was a cross-sectional study. Children with habitual snoring (snoring ≥3 nights per week) admitted to the ward of otolaryngology, head and neck surgery, Beijing Children's Hospital were recruited to this study between 1(st) June 2015 and 1(st) March 2016. All children aged 3 to 11 years and of them 245 were boys and 110 were girls. All subjects underwent an overnight polysomnography (PSG), as well as endothelial function testing. All subjects were grouped into primary snoring (PS) and OSAS group according to the obstructive apnea hypopnea index (OAHI). T test or Wilcoxon test were used to compare the differences in PSG results between the two groups, and univariate and multivariate correlation analyses were used to explore the relevant factors affecting the endothelial function. Results: A total of 355 subjects were enrolled and 248 had OSAS, and 107 had PS. There were no significant differences in age, gender and body mass index (BMI) Z-score between the two groups (all P>0.05). OSAS group had higher OAHI, oxgen desaturation index and respiratory related arousal index (5.2 (2.2, 13.2) vs. 0.4 (0.1, 0.7), 4.1 (2.0, 13.1) vs. 0.5 (0.1, 1.0), 2.5 (1.0, 4.8) vs. 0.4 (0.1, 0.9), Z=-14.957, -11.790, -10.378, all P<0.01), and lower minimum oxygen saturation and reactive hyperemia index (RHI) than those of PS (0.89 (0.85, 0.92) vs. 0.94 (0.91, 0.95), 1.2±0.2 vs. 1.1±0.1, Z=-9.337, t=5.354, P<0.01). Univariate regression analysis showed that RHI was linearly correlated with age (parameter estimate=0.017, P<0.01), gender (parameter estimate=0.065, P<0.01), OAHI (parameter estimate=-0.023, P<0.01), oxygen desaturation index (parameter estimate=-0.019, P<0.01), respiratory related arousal index (parameter estimate=-0.031, P<0.01), and oxygen saturation nadir (parameter estimate=0.067, P=0.045). The relationship between BMI Z-score and RHI was quadratic. Multivariate regression analysis showed that age (parameter estimate=0.015, P<0.01), BMI Z-score (parameter estimate=0.040, P<0.01), BMI Z-score quadratic form (parameter estimate=-0.010, P<0.01), respiratory related arousal index (parameter estimate=-0.020, P<0.01) were independently correlated with RHI. Conclusions: Children with OSAS have significant endothelial dysfunction compared with PS. Frequent arousals due to obstructive respiratory events during sleep may be a candidate risk factor for endothelial dysfunction in children with OSAS.

SH2-containing phosphotyrosine phosphatase as a target of protein-tyrosine kinases.

A mouse phosphotyrosine phosphatase containing two Src homology 2 (SH2) domains, Syp, was identified. Syp bound to autophosphorylated epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) receptors through its SH2 domains and was rapidly phosphorylated on tyrosine in PDGF- and EGF-stimulated cells. Furthermore, Syp was constitutively phosphorylated on tyrosine in cells transformed by v-src. This mammalian phosphatase is most closely related, especially in its SH2 domains, to the corkscrew (csw) gene product of Drosophila, which is required for signal transduction downstream of the Torso receptor tyrosine kinase. The Syp gene is widely expressed throughout embryonic mouse development and in adult tissues. Thus, Syp may function in mammalian embryonic development and as a common target of both receptor and nonreceptor tyrosine kinases.

Antiproliferative activity of a hybrid protein between interferon-gamma and tumor necrosis factor-beta.

A hybrid protein between interferon-gamma and tumor necrosis factor-beta was made by ligating the respective genes and expressing the fused genes under the control of the trp promoter in Escherichia coli. The antiproliferative activity of the hybrid protein in vitro was greatly increased compared with either interferon-gamma or tumor necrosis factor-beta alone, and both antiviral activity and cytotoxic effect were retained in the hybrid protein. The hybrid protein may have potential clinical application.

Regulation of T cell receptor signaling by tyrosine phosphatase SYP association with CTLA-4.

The absence of CTLA-4 results in uncontrolled T cell proliferation. The T cell receptor-specific kinases FYN, LCK, and ZAP-70 as well as the RAS pathway were found to be activated in T cells of Ctla-4-/- mutant mice. In addition, CTLA-4 specifically associated with the tyrosine phosphatase SYP, an interaction mediated by the SRC homology 2 (SH2) domains of SYP and the phosphotyrosine sequence Tyr-Val-Lys-Met within the CTLA-4 cytoplasmic tail. The CTLA-4-associated SYP had phosphatase activity toward the RAS regulator p52SHC. Thus, the RAS pathway and T cell activation through the T cell receptor are regulated by CTLA-4-associated SYP.

[Logistic regression analysis in observational study].

Logistic regression has been recognized as a commonly used method in epidemiological studies. However, in practice, many people only consider 'data' rather than 'study design' as important issue when working on the analysis, which may easily lead to some misleading results and conclusions. Based on the purpose of observational research during the design of the study, this paper discusses the specific ideas in logistic regression analysis, and provides references for the practical application when logistic regression method is used.

[The prevalence of snoring and its related family factors of children from 3 to 14 years old in Beijing].

Objective: To investigate the snoring status and related family factors of children from 3 to 14 years old in Beijing. Methods: From May to July, 2015, data of children from 3 to 14 years old were obtained from a status survey from 7 districts(Xicheng, Chaoyang, Changping, Shunyi, Fangshan, Huairou and Mentougou) in Beijing. A total of 11 420 children from 25 primary and middle schools were randomly selected. Pediatric Sleep Questionnaire (PSQ) and a self-administered questionnaire were carried out for the adopted children. Self-administered questionnaire included the snoring related family factors. Logistic regression was used to estimate the odd ratio(OR) with 95% confidence intervals for variables. Results: A total of 9 198 children meet the inclusion criteria and are analyzed in the study, of whom 901 (9.80%) were found with snoring behavior. The incidence of boys is higher than girls. Obese children take higher risk of snoring. Compared with younger children (≤6 years old), older children (≥12 years old) have a significantly lower risk of snoring (OR=0.464, 95%CI 0.368-0.585). There is no statistical association between full-term infants, infant feeding pattern, parental cigarette smoking and child snoring.The children with family history of snoring have a significantly higher risk of snoring occurrence. The educational background of mother is statistically related to children snoring (OR=1.241, 95%CI 1.058-1.457). Conclusions: The incidence of children snoring in Beijing is 9.80%, male gender, obesity, and young age are all risk factors for children snoring. There is a significantly statistical relationship between snoring and related family factors, such as family snoring history and education experience.

[Analysis of sleep quality and related factors among children in Beijing].

Objective: To investigate the sleep quality of children in Beijing and to analyze the related factors. Methods: The data were collected from the survey of 3-14 years old children in 7 urban districts of Beijing in 2015. By using multi-stage stratified cluster random sampling method, 26 kindergartens and primary and secondary schools in 7 districts and counties, including Xicheng, Chaoyang, Changping, Shunyi, Fangshan, Huairou and Mentougou, were randomly selected, with a total of 11 420 children. Children's sleep status was investigated with Children's Sleep Questionnaire (PSQ), and the proportion of children with sleep quality problems when the PSQ score was greater than 7. Various sleep related factors were investigated with self-made questionnaire. A multilevel model was used to analyze the relationship between PSQ score and related factors. Results: The average PSQ score of the children was 3.60±2.69. The proportion of children with sleep quality problems was 8.87%(816/9 198). Multilevel model analysis showed that the younger the children, the higher the PSQ score (<6 years old vs. 6~12 years old vs. >12 years old: 3.94±2.58 vs. 3.58±2.66 vs. 3.30±2.84, F=33.015, P<0.001); male PSQ score higher than female (3.89±2.75 vs. 3.30±2.60, t=10.560, P<0.001); and snoring, obesity, father/mother snoring, playing games before bed, surfing the internet, eating and other factors were statistically related to PSQ. Conclusions: Sleep quality of children in Beijing should not be neglected, especially preschool children with high PSQ scores. Parents should pay attention to children's snoring problems and try to reduce some pre-sleep behaviors that may affect sleep quality.

Role of Gab2 in mammary tumorigenesis and metastasis.

Overexpression of the adaptor/scaffolding protein Gab2 has been detected in primary human breast cancer cells and cell lines, although its functional significance in breast carcinogenesis is not fully understood. Here, we show a requirement for Gab2 in promoting mammary tumor metastasis. Although Gab2 expression levels were elevated in mammary tumors induced by the Neu (ErbB-2) oncogene, homozygous deletion of Gab2 in mice had only a modest effect on the initiation of Neu-induced mammary tumors. Notably, ablation of Gab2 severely suppressed lung metastasis. Gab2-deficient cancer cells displayed normal Akt activities, and their proliferative rate in vitro was similar to control cells. However, Gab2(-/-) cancer cells exhibited decreased migration and impaired Erk activation, and the defects were rescued by re-introduction of Gab2 into Gab2(-/-) cells. These findings suggest that although Gab2 overexpression may confer growth advantage to tumor cells, the functional requirement for Gab2 in mammary tumor initiation/growth may be dispensable, and that Gab2 may have a prominent role in promoting mammary tumor metastasis.

GRB2-mediated recruitment of GAB2, but not GAB1, to SF-STK supports the expansion of Friend virus-infected erythroid progenitor cells.

Friend virus induces the development of erythroleukemia in mice through the interaction of a viral glycoprotein, gp55, with a truncated form of the Stk receptor tyrosine kinase, short form-Stk (Sf-Stk), and the EpoR. We have shown previously that the ability of Sf-Stk to participate in the transformation of Friend virus-infected cells requires the kinase activity and Grb2-binding site of Sf-Stk. Here we show that Grb2 heterozygous mice exhibit decreased susceptibility to Friend erythroleukemia and that expansion of erythroid progenitors in response to infection requires the C-terminal SH3 domain of Grb2. A fusion protein in which the Grb2-binding site in Sf-Stk is replaced by Gab2, supports the growth of progenitors from mice lacking Sf-Stk, whereas a Sf-Stk/Gab1 fusion protein does not. Gab2 is expressed in spleens from Friend virus-infected mice, co-immunoprecipitates with Sf-Stk and is tyrosine phosphorylated in the presence of Sf-Stk. Mice with a targeted deletion in Gab2 are less susceptible to Friend erythroleukemia and the expansion of erythroid progenitor cells in response to infection can be rescued by expression of Gab2, but not Gab1. Taken together, these data indicate that a Sf-Stk/Grb2/Gab2 complex mediates the growth of primary erythroid progenitor cells in response to Friend virus.

The protein tyrosine phosphatase Shp-2 regulates RhoA activity.

Remodeling of filamentous actin into distinct arrangements is precisely controlled by members of the Rho family of small GTPases [1]. A well characterized member of this family is RhoA, whose activation results in reorganization of the cytoskeleton into thick actin stress fibers terminating in integrin-rich focal adhesions [2]. Regulation of RhoA is required to maintain adhesion in stationary cells, but is also critical for cell spreading and migration [3]. Despite its biological importance, the signaling events leading to RhoA activation are not fully understood. Several independent studies have implicated tyrosine phosphorylation as a critical event upstream of RhoA [4]. Consistent with this, our recent studies have demonstrated the existence of a protein tyrosine phosphatase (PTPase), sensitive to the dipeptide aldehyde calpeptin, acting upstream of RhoA [5]. Here we identify the SH2 (Src homology region 2)-containing PTPase Shp-2 as a calpeptin-sensitive PTPase, and show that calpeptin interferes with the catalytic activity of Shp-2 in vitro and with Shp-2 signaling in vivo. Finally, we show that perturbation of Shp-2 activity by a variety of genetic manipulations results in raised levels of active RhoA. Together, these studies identify Shp-2 as a PTPase acting upstream of RhoA to regulate its activity and contribute to the coordinated control of cell movement.

Phosphotyrosine phosphatases with SH2 domains: regulators of signal transduction.

Among the rapidly growing family of protein tyrosine phosphatases (PTPs), a subfamily of cytoplasmic PTPs that contain SH2 domains has been identified in both mammals and Drosophila. These PTPs each contain two tandem SH2 domains at their amino-terminus, and a single phosphatase domain. The SH2-containing PTPs appear to be downstream targets of growth factor receptor tyrosine kinases, and have been shown genetically to be required for normal development in Drosophila and in the mouse. Accumulating biochemical and genetic data therefore suggest that SH2-containing PTPs might have a physiological role in intracellular signal transduction.