Hair glucocorticoids during pregnancy in the context of trauma exposure and their predictive value for the development of childbirth-related posttraumatic stress disorder symptoms.

BACKGROUND: Childbirth-related posttraumatic stress disorder (CB-PTSD) is gaining attention as a mental disorder with negative sequela for mothers and their offspring. Maternal trauma history is a well-known vulnerability factor for CB-PTSD symptoms (CB-PTSS). Furthermore, alterations of the hypothalamus-pituitary-adrenal axis have been linked to both trauma exposure and PTSD development. Hence, we investigated whether trauma history was associated with long-term glucocorticoid (GC) levels during pregnancy and their predictive role for CB-PTSS. Further, we examined whether GCs act as a mediator in the relationship between trauma history and CB-PTSS and whether this was moderated by the subjective birth experience. METHODS: 212 women participating in the prospective cohort study DREAMHAIR provided hair samples for quantification of long-term integrated cortisol and cortisone levels prior to their anticipated birth date accompanied by measures of trauma history. CB-PTSS and subjective birth experience were assessed two months postpartum. FINDINGS: Trauma history predicted elevated hair cortisol and hair cortisone during the third trimester of pregnancy, however associations did not remain significant when Bonferroni correction due to multiple testing was applied. Trauma history also predicted higher CB-PTSS. Hair GC levels during pregnancy neither predicted CB-PTSS two months after birth nor mediated the relationship between trauma history and CB-PTSS. The subjective birth experience moderated the relationship of hair cortisol and cortisone with CB-PTSS. CONCLUSION: Our data suggest that a history of trauma contributes to a higher risk to develop CB-PTSS and elevated long-term GC levels during the third pregnancy trimester. Further, the predictive role of hair cortisol and cortisone levels for CB-PTSS may depend on subjective birth experience. This highlights the need to consider the latter in future investigations when examining the role of stress-related biomarkers in more severely affected samples.

Size matters - The olfactory bulb as a marker for depression.

BACKGROUND: Major Depression is mainly related to structural and functional alterations in brain networks involving limbic and prefrontal regions. Reduced olfactory sensitivity in depression is associated with reduced olfactory bulb (OB) volume. We determined if the OB volume reduction is a specific biomarker for depression and whether its diagnostic accuracy allows its use as a valid biomarker to support its diagnosis. METHODS: 84 in-patients with mixed mental disorders and 51 age-matched healthy controls underwent structural MR imaging with a spin-echo T2-wheighted sequence. Individual OB volume was calculated manually (interrater-reliability = .81, p < .001) and compared between groups. Multiple regression analysis with OB volume as dependent variable and Receiver Operator Characteristic analysis to obtain its diagnostic accuracy for depression were ruled out. RESULTS: Patients exhibited a 13.5% reduced OB volume. Multiple regression analysis showed that the OB volume variation was best explained by depression (ß = -.19), sex (ß = -.31) and age (ß = -.29), but not by any other mental disorder. OB volume attained a diagnostic accuracy of 68.1% for depression. LIMITATIONS: The patient group mainly contained highly comorbid patients with mostly internalizing disorders which limits the generalisability of the results of the regression analysis. CONCLUSION: The OB may serve as a marker for depression. We assume that reduced neural olfactory input to subsequent limbic and salience processing structures moderates this relation. However, the OB was in an inferior position compared to conventional questionnaires for diagnosis of depression. Combination with further structural or functional measurements is suggested.

Extended C-band tunable multi-channel InP-based coherent receiver PICs.

Fully integrated monolithic, multi-channel InP-based coherent receiver PICs and transceiver modules with extended C-band tunability are described. These PICs operate at 33 and 44 Gbaud per channel under dual polarization (DP) 16-QAM modulation. Fourteen-channel monolithic InP receiver PICs show integration and data rate scaling capability to operate at 44 Gbaud under DP 16-QAM modulation for combined 4.9 Tb/s total capacity. Six channel simultaneous operation of a commercial transceiver module at 33 Gbaud is demonstrated for a variety of modulation formats including DP 16-QAM for >1.2Tbit/s aggregate data capacity.

Sex differences of in-hospital outcome and long-term mortality in patients with Takotsubo cardiomyopathy.

BACKGROUND: Previous studies revealed that patients with Takotsubo cardiomyopathy (TTC) have a higher mortality rate than the general population. It is still unclear whether sex differences may influence long-term prognosis of TTC patients. The purpose of this study was to determine whether sex differences do influence the short- and long-term outcomes of TTC. METHODS AND RESULTS: A total of 114 patients with TTC were admitted to the University Medical Centre Mannheim from January 2003 to September 2015 and entered into the TTC database of the University Medical Centre Mannheim, and retrospectively analyzed. Patients were diagnosed by the Mayo Clinic criteria. All-cause mortality over mean follow-up of 1,529±1,121 days was revealed. Significantly more male patients died within long-term follow-up compared to female TTC patients (log-rank test; P=0.01). Most males died of noncardiac causes. In multivariate Cox regression analysis, the male sex (P=0.02, hazard ratio [HR] 2.8, 95% CI 1.1-7.2), the ejection fraction ≤35% (P=0.01, HR 3.3, 95% CI 1.2-9.2) and glomerular filtration rate <60 mL/min (P<0.01, HR 3.1, 95% CI 1.4-7.0) figured out as independent predictors of the adverse outcome. CONCLUSION: This study shows that males suffering from TTC reveal a higher long-term all-cause mortality rate than females over a 5 year follow-up period.

The intraspecies diversity of C. albicans triggers qualitatively and temporally distinct host responses that determine the balance between commensalism and pathogenicity.

The host immune status is critical for preventing opportunistic infections with Candida albicans. Whether the natural fungal diversity that exists between C. albicans isolates also influences disease development remains unclear. Here, we used an experimental model of oral infection to probe the host response to diverse C. albicans isolates in vivo and found dramatic differences in their ability to persist in the oral mucosa, which inversely correlated with the degree and kinetics of immune activation in the host. Strikingly, the requirement of interleukin (IL)-17 signaling for fungal control was conserved between isolates, including isolates with delayed induction of IL-17. This underscores the relevance of IL-17 immunity in mucosal defense against C. albicans. In contrast, the accumulation of neutrophils and induction of inflammation in the infected tissue was strictly strain dependent. The dichotomy of the inflammatory neutrophil response was linked to the capacity of fungal strains to cause cellular damage and release of alarmins from the epithelium. The epithelium thus translates differences in the fungus into qualitatively distinct host responses. Altogether, this study provides a comprehensive understanding of the antifungal response in the oral mucosa and demonstrates the relevance of evaluating intraspecies differences for the outcome of fungal-host interactions in vivo.

[Psychosomatics and psychotraumatology of refugees and migrants : A Challenge for the Internist]. / Psychosomatik und Psychotraumatologie bei Geflüchteten und Migranten : Herausforderungen für den Internisten.

Many refugees experience severely stressful events in their home countries, during migration and occasionally even after arrival in the country of destination. The individual reactions not only influence the mental health but also somatic well being. Traumatic events may have an essential impact on psychosocial functioning; moreover, the social circumstances during the integration process influence mental stability. Physicians play an important role in identifying possible traumatization and subsequently guiding towards adequate treatment; hence, the healthcare of refugees should regularly include psychosomatic and psychotraumatological aspects. Knowledge of screening instruments, trauma-informed care and interpreter-assisted communication are necessary to meet required standards.

Autocrine VEGFR1 and VEGFR2 signaling promotes survival in human glioblastoma models in vitro and in vivo.

BACKGROUND: Although the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) system has become a prime target for antiangiogenic treatment, its biological role in glioblastoma beyond angiogenesis has remained controversial. METHODS: Using neutralizing antibodies to VEGF or placental growth factor (PlGF) or the tyrosine kinase inhibitor, cediranib, or lentiviral gene silencing, we delineated autocrine signaling in glioma cell lines. The in vivo effects of VEGFR1 and VEGFR2 depletion were evaluated in orthotopic glioma xenograft models. RESULTS: VEGFR1 and VEGFR2 modulated glioma cell clonogenicity, viability, and invasiveness in vitro in an autocrine, cell-line-specific manner. VEGFR1 silencing promoted mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling, whereas VEGFR2 silencing resulted in cell-type dependent activation of the protein kinase B (PKB)/AKT and MAPK/ERK pathways. These responses may represent specific escape mechanisms from VEGFR inhibition. The survival of orthotopic glioma-bearing mice was prolonged upon VEGFR1 silencing in the LNT-229, LN-308, and U87MG models and upon VEGFR2 silencing in LN-308 and U87MG. Disruption of VEGFR1 and VEGFR2 signaling was associated with decreased tumor size, increased tumor necrosis, or loss of matrix metalloproteinase 9 (MMP9) immunoreactivity. Neutralizing VEGF and PlGF by specific antibodies was superior to either antibody treatment alone in the VEGFR1-dependent LNT-229 model. CONCLUSIONS: Differential dependence on autocrine signaling through VEGFR1 and VEGFR2 suggests a need for biomarker-stratified VEGF(R)-based therapeutic approaches to glioblastoma.

Anti-tumoral, anti-angiogenic and anti-metastatic efficacy of a tetravalent bispecific antibody (TAvi6) targeting VEGF-A and angiopoietin-2.

Vascular endothelial growth factor (VEGF)-A blockade has been validated clinically as a treatment for human cancers. Angiopoietin-2 (Ang-2) is a key regulator of blood vessel remodeling and maturation. In tumors, Ang-2 is up-regulated and an unfavorable prognostic factor. Recent data demonstrated that Ang-2 inhibition mediates anti-tumoral effects. We generated a tetravalent bispecific antibody (Ang-2-VEGF-TAvi6) targeting VEGF-A with 2 arms based on bevacizumab (Avastin®), and targeting Ang-2 with 2 arms based on a novel anti-Ang-2 antibody (LC06). The two Ang-2-targeting single-chain variable fragments are disulfide-stabilized and fused to the C-terminus of the heavy chain of bevacizumab. Treatment with Ang-2-VEGF-A-TAvi6 led to a complete abrogation of angiogenesis in the cornea micropocket assay. Metastatic spread and tumor growth of subcutaneous, orthotopic and anti-VEGF-A resistant tumors were also efficiently inhibited. These data further establish Ang-2-VEGF bispecific antibodies as a promising anti-angiogenic, anti-metastatic and anti-tumor agent for the treatment of cancer.

Mental symptoms and quality of life in lipoprotein apheresis patients in comparison to hemodialysis patients, platelet donors and normal population.

BACKGROUND: Despite the fact that extracorporeal methods such as lipoprotein apheresis (LA) and hemodialysis (HD) are highly effective in improving the physical status of patients, these treatment options may possibly harm the psychological status and the health related quality of life (HRQL). METHODS: The occurrences of anxiety, depression and the HRQL of 111 study participants treated with LA (n = 41), HD (n = 41) or undergoing plateletpheresis (PD) (n = 29) were compared to the normal population (NP), using standardized questionnaires (anxiety and depression: Hospital Anxiety and Depression Scale (HADS), heart-focused anxiety: Cardiac Anxiety Questionnaire (CAQ) and HRQL: Short-Form Health Survey (SF-12)). Additionally, the subjective mental and physical stress of study participants was evaluated. RESULTS: LA females had a significantly elevated HADS-A score compared to PD and NP. Additionally, there was a trend toward higher HADS-A scores in the LA group compared to the HD group in females. In HD males HADS-A and -D scores increased compared to PD and NP. The CAQ revealed a significant increase in the CAQ-Fear scale in LA compared to HD and PD participants. The CAQ-Avoidance score showed significantly increased scores in LA and HD patients compared to PD and NP. In the CAQ-Attention scale the LA patients also showed significantly increased scores compared to PD and NP. The increased psychological symptoms were associated with significantly lower levels of objective and subjective HRQL in LA and HD patients compared to PD and NP. CONCLUSIONS: LA and HD patients had similarly increased presence of psychological symptoms with concurrent decreased quality of life compared to PD and the normal population, which may affect the outcome of the LA patients. Therefore, early psychosomatic screening and probable psychosomatic treatment should be performed.

IL-17-mediated antifungal defense in the oral mucosa is independent of neutrophils.

Interleukin-17 (IL-17)-mediated immunity has emerged as a crucial host defense mechanism against Candida albicans infections in mucosal tissues and the skin. The precise mechanism by which the IL-17 pathway prevents fungal outgrowth has not been clarified. Neutrophils are critical for limiting fungal dissemination and IL-17 is generally thought to act by regulating neutrophil mobilization and trafficking to the site of infection. Using a mouse model of oropharyngeal candidiasis (OPC), we found that strikingly the IL-17 pathway is not required for the neutrophil response to C. albicans. Mice deficient for the IL-17 receptor subunits IL-17 receptor A (IL-17RA) or IL-17RC or mice depleted of IL-17A and IL-17F exhibited a normal granulocyte colony-stimulating factor (G-CSF) and CXC-chemokine response and displayed no defect in neutrophil recruitment or function. Instead, the inability of these mice to clear the fungus was associated with a selective defect in the induction of antimicrobial peptides (AMPs) in the epithelium that resulted in persistent fungal colonization. Importantly, this antifungal mechanism of IL-17A and IL-17F did not extend to the closely related family member IL-17C. Together, these data uncouple IL-17-dependent effector mechanisms from the neutrophil response and reveal a compartmentalization of the antifungal defense in the oral mucosa providing a new understanding of IL-17-mediated mucosal immunity against C. albicans.

Placental growth factor (PlGF)-specific uptake in tumor microenvironment of 89Zr-labeled PlGF antibody RO5323441.

UNLABELLED: Placental growth factor (PlGF) is a member of the proangiogenic vascular endothelial growth factor family, which is upregulated in many tumors. RO5323441, a humanized monoclonal antibody against PlGF, showed antitumor activity in human tumor xenografts. We therefore aimed to radiolabel RO5323441 and preclinically validate this tracer to study drug tumor uptake and organ distribution by PET imaging. (89)Zr-RO5323441 was tested for stability and immunoreactivity in vitro. METHODS: The tumor uptake and organ distribution for 10, 50, and 500 µg of (89)Zr-RO5323441 was assessed in mice bearing human PlGF-expressing hepatocellular cancer (Huh7) xenografts or human renal cell carcinoma (ACHN) xenografts without detectable human PlGF expression. The effect of pretreatment with RO5323441 (20 mg/kg) on (89)Zr-RO5323441 tumor uptake was analyzed in Huh7 xenografts. (111)In-IgG served as a control for nonspecific tumor uptake and organ distribution. Cy5-RO5323441 was injected to study the intratumor distribution of RO5323441 with fluorescence microscopy. RESULTS: (89)Zr-RO5323441 showed a time- and dose-dependent tumor accumulation. Uptake in Huh7 xenografts at 10 µg of (89)Zr-RO5323441 was 8.2% ± 1.7% injected dose (ID)/cm(3) at 144 h after injection, and in ACHN xenografts it was 5.5 ± 0.3 %ID/cm(3) (P = 0.03). RO5323441 pretreatment of Huh7 xenograft-bearing mice reduced (89)Zr-RO5323441 tumor uptake to the level of nonspecific (111)In-IgG uptake. Cy5-RO5323441 was present in the tumors mainly in the microenvironment. CONCLUSION: The findings show that RO5323441 tumor uptake is PlGF-specific and time- and dose-dependent.

A novel angiopoietin-2 selective fully human antibody with potent anti-tumoral and anti-angiogenic efficacy and superior side effect profile compared to Pan-Angiopoietin-1/-2 inhibitors.

There is increasing experimental evidence for an important role of Angiopoietin-2 (Ang-2) in tumor angiogenesis and progression. In addition, Ang-2 is up-regulated in many cancer types and correlated with poor prognosis. To investigate the functional role of Ang-2 inhibition in tumor development and progression, we generated novel fully human antibodies that neutralize specifically the binding of Ang-2 to its receptor Tie2. The selected antibodies LC06 and LC08 recognize both rodent and human Ang-2 with high affinity, but LC06 shows a higher selectivity for Ang-2 over Ang-1 compared to LC08 which can be considered an Ang-2/Ang-1 cross-reactive antibody. Our data demonstrate that Ang-2 blockade results in potent tumor growth inhibition and pronounced tumor necrosis in subcutaneous and orthotopic tumor models. These effects are attended with a reduction of intratumoral microvessel density and tumor vessels characterized by fewer branches and increased pericyte coverage. Furthermore, anti-Ang-2 treatment strongly inhibits the dissemination of tumor cells to the lungs. Interestingly, in contrast to the Ang-2/Ang-1 cross-reactive antibody LC08 that leads to a regression of physiological vessels in the mouse trachea, the inhibition with the selective anti-Ang-2 antibody LC06 appears to be largely restricted to tumor vasculature without obvious effects on normal vasculature. Taken together, these data provide strong evidence for the selective Ang-2 antibody LC06 as promising new therapeutic agent for the treatment of various cancers.

[Structure and process quality of quality-assured mamma diagnostics in Schleswig-Holstein]. / Struktur- und Prozessqualität in der qualitätsgesicherten Mammadiagnostik in Schleswig-Holstein.

PURPOSE: To demonstrate the structure and process quality of quality-assured mamma diagnostics (QuaMaDi) by means of quality indicators as defined in the European Guidelines for Quality Assurance in Breast Cancer Screening and Diagnosis and in the National Guideline on Early Detection of Cancer in Germany. Furthermore, spatial differences and changes in the chronological sequence were analyzed. MATERIALS AND METHODS: We used administrative data as documented in the time period 2006 - 2009 in QuaMaDi in Schleswig-Holstein (SH), Germany, and analyzed quality indicators as defined in the abovementioned guidelines (absolute and relative frequencies, 95 % confidence intervals). RESULTS: Each year approximately 6 % of all women age 20 or older living in SH are examined using QuaMaDi. Only minor differences regarding age and clinical data were seen between the patients in the four regions of SH. Reference values for the quality indicators are largely reached (i. e., proportion of women with breast density ACR 3 or 4 plus additional ultrasound = 96.2 %; proportion with repeated mammography = 0.2 %). Spatial differences are only minor. In the chronological sequence, quality indicators improve, if they did not reach the reference values in the beginning, or indicate a high and constant quality. CONCLUSION: With regard to those quality indicators that were computable, reference values as defined in the guidelines were reached in 9 of 12 cases. In one case the difference between the observed value and the reference values is system-immanent and in another case the difference is less than four percentage points (reference value 90 %).

Which gynecological and obstetric patients want to attend psychosomatic services?

OBJECTIVE: The aim of this study is to explore the wish of gynecological and obstetric inpatients to attend psychosomatic services. Predictors influencing this wish are evaluated. METHOD: Three groups of patients participated in the study. The groups consisted of patients diagnosed with malignant gynecological diseases (n = 175), benign gynecological diseases (n = 302), and obstetric diseases (n = 238). The following domains were assessed in a cross-sectional design: symptoms of anxiety and depression (HADS), physical complaints (GBB-24), health-related quality of life (SF-12), and the wish to attend psychosomatic services. RESULTS: 34% of the participants indicated that they wanted to attend psychosomatic services during their stay in the hospital. The group of patients diagnosed with malignant gynecological diseases had the highest proportion of women who stated that wish (43%). Multiple logistic regression models showed that former psychotherapeutic experiences as well as low psychological quality of life predicted the wish to attend psychosomatic services in patients diagnosed with malignant gynecological or obstetric diseases. CONCLUSION: It was shown that a considerable proportion of patients wanted to attend psychosomatic care during their hospitalization. Contrary to physical and sociodemographic variables, psychological factors were significant predictors of the inpatient's wish to attend psychosomatic services. This suggests that the subjective estimation of impairments is a major predictor of the wish to attend psychosomatic care.

Psychological and physical factors influencing the health-related quality of life of patients of a department of gynecology in a university hospital.

The aim of our study was to assess the physical and mental quality of life of in-patients of a Gynecological University Hospital and the factors influencing the quality of life. 715 women, who were treated in hospital with non-malignant or malignant gynecological or obstetrical diseases, took part in the study. Besides demographical data and relevant medical parameters the quality of life (SF-12), anxiety and depression (HADS) as well as physical discomforts (GBB) were assessed. The physical quality of life of the study population was significantly lower than that of the normal population (p < 0.001). Patients with obstetric diseases in comparison with patients with malignant gynecological and other gynecological diseases had the lowest physical quality of life. Regarding the mental factor, patients with malignant gynecological diseases feel most impaired, followed by those with other gynecological and obstetrical conditions. The multivariate analysis of the quality of life showed that up to 60% of the variance could be explained. The lowest variance elucidation was found in obstetrical patients in whom the physical complaints elucidated only a small part of the variance. Our results show on the one hand the high impairment of mental and especially of physical quality of life in women who are in hospital with gynecological or obstetrical diseases. On the other hand they show the great significance of the quality of life as an outcome parameter. These findings should be considered in gynecological in-patient treatments by using integrated psychosomatic care.

Age-related complaints in women and their determinants based on a representative community study.

OBJECTIVES: To determine (a) the relationship between physical and somatoform complaints, distress, life satisfaction and ageing in the female community and (b) to identify their psychosocial determinants. METHODS: Two stratified random samples of the German female population (total of 2771 women) were investigated by standardised questionnaires of complaints (MFI-20, GBB), distress (HADS) and life satisfaction (LSQ). RESULTS: When participants were divided into six age groups (18-30, 31-40, 41-50, 51-60, 61-70, >70 years), we found a continuous increase of physical, mental and general fatigue, inactivity and reduced motivation. Age-associated increases were also observed for exhaustion, cardiovascular and musculoskeletal complaints, but not for gastrointestinal complaints. This was accompanied by a reduced satisfaction with health and sexuality and increased depression and anxiety scores. Marked increases of complaints were mostly found in the sixth decade. However, depression already increased in the fourth decade, musculoskeletal complaints and reduced motivation peaked in the fifth decade, whereas mental fatigue did not increase significantly before the seventh decade followed by a rise of anxiety in women over 70 years. Most consistently, complaints were predicted by a combination of negative subjective health, higher age, lack of a partnership, and additional sociodemographic vulnerability (unemployment, low income, residence) and protective (religion) factors. CONCLUSIONS: Community data provide important reference points in evaluating the ageing female. Based on regression analyses, we could also demonstrate the contribution of psychosocial vulnerability and protective factors to the development of age-related symptoms.

A PDZ domain protein interacts with the C-terminal tail of the insulin-like growth factor-1 receptor but not with the insulin receptor.

In this study, we report on the isolation of a PDZ domain protein, here designated as IIP-1, insulin-like growth factor-1 (IGF-1) receptor-interacting protein-1, which binds to the IGF-1 receptor, but not to the related insulin receptor, and which is involved in the regulation of cell motility. The interaction between the IGF-1 receptor and IIP-1 as well as a splice variant IIP-1/p26 was demonstrated in the yeast two-hybrid system. Using co-precipitation experiments, we confirmed the interaction in transfected cells as well as in vitro. Analysis of deletion mutants indicates that the PDZ domain of IIP-1 mediates interaction with the C-terminal tail of the IGF-1 receptor (serine-threonine-cysteine). This finding demonstrates that the C terminus of the IGF-1 receptor acts as novel PDZ domain binding site. Immunofluorescence analysis revealed an overlapping localization of IIP-1 and the IGF-1 receptor in the breast cancer cell line MCF-7. A functional connection between IIP-1 and the IGF-1 receptor is further supported by the finding that the level of expression of IIP-1 and the IGF-1 receptor strongly correlates in different normal and cancer cells. Furthermore, overexpression of IIP-1 resulted in an attenuation of migration of MCF-7 cells, which is one of the biological activities mediated by the IGF-1 signaling system.

Negative regulation of Ros receptor tyrosine kinase signaling. An epithelial function of the SH2 domain protein tyrosine phosphatase SHP-1.

Male "viable motheaten" (me(v)) mice, with a naturally occurring mutation in the gene of the SH2 domain protein tyrosine phosphatase SHP-1, are sterile. Known defects in sperm maturation in these mice correlate with an impaired differentiation of the epididymis, which has similarities to the phenotype of mice with a targeted inactivation of the Ros receptor tyrosine kinase. Ros and SHP-1 are coexpressed in epididymal epithelium, and elevated phosphorylation of Ros in the epididymis of me(v) mice suggests that Ros signaling is under control of SHP-1 in vivo. Phosphorylated Ros strongly and directly associates with SHP-1 in yeast two-hybrid, glutathione S-transferase pull-down, and coimmunoprecipitation experiments. Strong binding of SHP-1 to Ros is selective compared to six other receptor tyrosine kinases. The interaction is mediated by the SHP-1 NH(2)-terminal SH2 domain and Ros phosphotyrosine 2267. Overexpression of SHP-1 results in Ros dephosphorylation and effectively downregulates Ros-dependent proliferation and transformation. We propose that SHP-1 is an important downstream regulator of Ros signaling.

Src homology 2-containing inositol 5-phosphatase 1 binds to the multifunctional docking site of c-Met and potentiates hepatocyte growth factor-induced branching tubulogenesis.

Hepatocyte growth factor (HGF)/scatter factor is a multifunctional cytokine that induces mitogenesis, motility, and morphogenesis in epithelial, endothelial, and neuronal cells. The receptor for HGF/scatter factor was identified as c-Met tyrosine kinase, and activation of the receptor induces multiple signaling cascades. To gain further insight into c-Met-mediated multiple events at a molecular level, we isolated several signaling molecules including a novel binding partner of c-Met, SH2 domain-containing inositol 5-phosphatase 1 (SHIP-1). Western blot analysis revealed that SHIP-1 is expressed in the epithelial cell line, Madin-Darby canine kidney (MDCK) cells. SHIP-1 binds at phosphotyrosine 1356 at the multifunctional docking site. Because a number of signaling molecules such as Grb2, phosphatidylinositol 3-kinase, and Gab1 bind to the multifunctional docking site, we further performed an in vitro competition study using glutathione S-transferase- or His-tagged signaling molecules with c-Met tyrosine kinase. Our binding study revealed that SHIP-1, Grb2, and Gab1 bound preferentially over phosphatidylinositol 3-kinase. Surprisingly, MDCK cells that overexpress SHIP-1 demonstrated branching tubulogenesis within 2 days after HGF treatment, whereas wild-type MDCK cells showed tubulogenesis only after 6 days following treatment without altering cell scattering or cell growth potency. Furthermore, overexpression of a mutant SHIP-1 lacking catalytic activity impaired HGF-mediated branching tubulogenesis.