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Mariko Hatakeyama

Publications and source records attributed to Mariko Hatakeyama.

12 recordsLinked to original sources
PubMed2006

Quantitative transcriptional control of ErbB receptor signaling undergoes graded to biphasic response for cell differentiation.

ErbB receptor ligands, epidermal growth factor (EGF) and heregulin (HRG), induce dose-dependent transient and sustained intracellular signaling, proliferation, and differentiation of MCF-7 breast cancer cells, respectively. In an effort to delineate the ligand-specific cell determination mechanism, we investigated time course gene expressions induced by EGF and HRG that induce distinct cellular phenotypes in MCF-7 cells. To analyze independently the effects of ligand dosage and time for gene expression, we developed a statistical method for estimating the two effects. Our results indicated that signal transduction pathways convey quantitative properties of the dose-dependent activation of ErbB receptor to early transcription. The results also implied that moderate changes in the expression levels of a number of genes, not the predominant regulation of a few specific genes, might cooperatively work at the early stage of the transcription for determining cell fate. However, the EGF- and HRG-induced distinct signal durations resulted in the ligand-oriented biphasic induction of proteins after 20 min. The selected gene list and HRG-induced prolonged signaling suggested that transcriptional feedback to the intracellular signaling results in a graded to biphasic response in the cell determination process and that each ErbB receptor is inextricably responsible for the control of amplitude and duration of cellular biochemical reactions.

Cell Differentiation↗
PubMed2006

Expression of the ErbB4 receptor causes reversal regulation of PP2A in the Shc signal transduction pathway in human cancer cells.

Expression of ErbB4 receptor is correlated with the incidence of non-metastatic types of human cancers, whereas the overexpression of other ErbB receptor families (ErbB1/EGFR, ErbB2 and ErbB3) is correlated to the formation of metastatic tumors. However, the molecular mechanism underlying this phenomenon has been unclear. Earlier, we demonstrated that okadaic acid (OA), an inhibitor of a serine/threonine phosphatase PP2A, stimulated the growth hormone-induced ERK phosphorylation in the wild type Chinese hamster ovary (CHO) cells and the cells expressing ErbB1 receptor, but suppressed ERK activation in CHO cells that express ErbB4 receptor. PP2A had been understood as a negative regulator of the growth hormone-stimulated signal transduction pathways, however, this observation suggested that expression of ErbB4 receptor reversed the regulation of PP2A in the ErbB4 signalling pathway. In this study, we found that OA suppressed phosphorylation of Shc at Tyr317, therefore it down-regulated ERK phosphorylation in the ErbB4 expressing CHO cells. Accordingly, basal PP2A contributed to the phosphorylation of Shc Tyr317 in ErbB4 expressing CHO cells, nevertheless it had been reported that PP2A negatively regulates Shc tyrosine phosphorylation in the EGF- or IGF-I-induced signalling pathways. By testing OA for human cancer cell lines that express different types of ErbB receptors, we found that ErbB4 receptor expression was accompanied with positive regulation of PP2A for phosphorylation of Shc Tyr317 and its downstream ERK phosphorylation in MCF-7 and SK-OV-3 cell lines, but not in LNCaP and PC-3 cells. Thus, PP2A regulates the ERK activity in a cell-specific manner, and it is speculated that distinct regulation of PP2A in the ErbB4 receptor signalling pathway may cause a difference in progression of cancer phenotypes.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Compensation effect of the MAPK cascade on formation of phospho-protein gradients.

The signal-transfer process in the mitogen-activated protein kinase (MAPK) cascade is formulated as a reaction-diffusion system describing the complete three-step phospho-protein reactions and the diffusion process in the direction from the cell membrane to the nucleus. The simulation analysis of the model demonstrates that MAPK cascade can work as a signal amplifier so as to compensate the signal attenuation due to formation of phospho-protein gradients. It also is found to be attainable for eukaryotic cells that a steep gradient of phosphorylated MAPK is not formed in a certain range of the system parameter values. One of the distinctive features in the formation of phospho-protein gradients is revealed to be its high sensitivity to a change in parameter values such as diffusion distance, diffusion coefficients and enzymatic activities of the phosphatases, suggesting that these parameters may act as the key factors for regulation of the signal transduction systems.

Animals↗
PubMed2004

Novel mechanism of interaction of p85 subunit of phosphatidylinositol 3-kinase and ErbB3 receptor-derived phosphotyrosyl peptides.

Ligand-activated and tyrosine-phosphorylated ErbB3 receptor binds to the SH2 domain of the p85 subunit of phosphatidylinositol 3-kinase and initiates intracellular signaling. Here, we studied the interactions between the N- (N-SH2) and C- (C-SH2) terminal SH2 domains of the p85 subunit of the phosphatidylinositol 3-kinase and eight ErbB3 receptor-derived phosphotyrosyl peptides (P-peptides) by using molecular dynamics, free energy, and surface plasmon resonance (SPR) analyses. In SPR analysis, these P-peptides showed no binding to the C-SH2 domain, but P-peptides containing a phospho-YXXM or a non-phospho-YXXM motif did bind to the N-SH2 domain. The N-SH2 domain has two phosphotyrosine binding sites in its N- (N1) and C- (N2) terminal regions. Interestingly, we found that P-peptides of pY1180 and pY1241 favored to bind to the N2 site, although all other P-peptides showed favorable binding to the N1 site. Remarkably, two phosphotyrosines, pY1178 and pY1243, which are just 63 amino acids apart from the pY1241 and pY1180, respectively, showed favorable binding to the N1 site. These findings indicate a possibility that the pair of phosphotyrosines, pY1178-pY1241 or pY1243-pY1180, will fold into an appropriate configuration for binding to the N1 and N2 sites simultaneously. Our model structures of the cytoplasmic C-terminal domain of ErbB3 receptor also strongly supported the speculation. The calculated binding free energies between the N-SH2 domain and P-peptides showed excellent qualitative agreement with SPR data with a correlation coefficient of 0.91. The total electrostatic solvation energy between the N-SH2 domain and P-peptide was the dominant factor for its binding affinity.

Amino Acid Motifs↗
PubMed2004

Inference of S-system models of genetic networks using a cooperative coevolutionary algorithm.

MOTIVATION: To resolve the high-dimensionality of the genetic network inference problem in the S-system model, a problem decomposition strategy has been proposed. While this strategy certainly shows promise, it cannot provide a model readily applicable to the computational simulation of the genetic network when the given time-series data contain measurement noise. This is a significant limitation of the problem decomposition, given that our analysis and understanding of the genetic network depend on the computational simulation. RESULTS: We propose a new method for inferring S-system models of large-scale genetic networks. The proposed method is based on the problem decomposition strategy and a cooperative coevolutionary algorithm. As the subproblems divided by the problem decomposition strategy are solved simultaneously using the cooperative coevolutionary algorithm, the proposed method can be used to infer any S-system model ready for computational simulation. To verify the effectiveness of the proposed method, we apply it to two artificial genetic network inference problems. Finally, the proposed method is used to analyze the actual DNA microarray data.

Algorithms↗
PubMed2004

OBIYagns: a grid-based biochemical simulator with a parameter estimator.

UNLABELLED: OBIYagns (yet another gene network simulator) is a biochemical system simulator that comprises a multiple-user Web-based graphical interface, an ordinary differential equation solver and a parameter estimators distributed over an open bioinformatics grid (OBIGrid). This grid-based biochemical simulation system can achieve high performance and provide a secure simulation environment for estimating kinetic parameters in an acceptable time period. OBIYagns can be applied to larger system biology-oriented simulation projects. AVAILABILITY: OBIYagns example models, methods and user guide are available at https://access.obigrid.org/yagns/ SUPPLEMENTARY INFORMATION: Please refer to Bioinformatics online.

Algorithms↗
PubMed2003

Tyr-317 phosphorylation increases Shc structural rigidity and reduces coupling of domain motions remote from the phosphorylation site as revealed by molecular dynamics simulations.

Activated receptor tyrosine kinases bind the Shc adaptor protein through its N-terminal phosphotyrosine-binding (PTB) and C-terminal Src homology 2 (SH2) domains. After binding, Shc is phosphorylated within the central collagen-homology (CH) linker region on Tyr-317, a residue remote to both the PTB and SH2 domains. Shc phosphorylation plays a pivotal role in the initiation of mitogenic signaling through the Ras/Raf/MEK/ERK pathway, but it is unclear if Tyr-317 phosphorylation affects Shc-receptor interactions through the PTB and SH2 domains. To investigate the structural impact of Shc phosphorylation, molecular dynamics simulations were carried out using special-purpose Molecular Dynamics Machine-Grape computers. After a 1-nanosecond equilibration, atomic motions in the structures of unphosphorylated Shc and Shc phosphorylated on Tyr-317 were calculated during a 2-nanosecond period. The results reveal larger phosphotyrosine-binding domain fluctuations and more structural flexibility of unphosphorylated Shc compared with phosphorylated Shc. Collective motions between the PTB-SH2, PTB-CH, and CH-SH2 domains were highly correlated only in unphosphorylated Shc. Dramatic changes in domain coupling and structural rigidity, induced by Tyr-317 phosphorylation, may alter Shc function, bringing about marked differences in the association of unphosphorylated and phosphorylated Shc with its numerous partners, including activated membrane receptors.

Adaptor Proteins, Signal Transducing↗
PubMed2003

A computational model on the modulation of mitogen-activated protein kinase (MAPK) and Akt pathways in heregulin-induced ErbB signalling.

ErbB tyrosine kinase receptors mediate mitogenic signal cascade by binding a variety of ligands and recruiting the different cassettes of adaptor proteins. In the present study, we examined heregulin (HRG)-induced signal transduction of ErbB4 receptor and found that the phosphatidylinositol 3'-kinase (PI3K)-Akt pathway negatively regulated the extracellular signal-regulated kinase (ERK) cascade by phosphorylating Raf-1 on Ser(259). As the time-course kinetics of Akt and ERK activities seemed to be transient and complex, we constructed a mathematical simulation model for HRG-induced ErbB4 receptor signalling to explain the dynamics of the regulation mechanism in this signal transduction cascade. The model reflected well the experimental results observed in HRG-induced ErbB4 cells and in other modes of growth hormone-induced cell signalling that involve Raf-Akt cross-talk. The model suggested that HRG signalling is regulated by protein phosphatase 2A as well as Raf-Akt cross-talk, and protein phosphatase 2A modulates the kinase activity in both the PI3K-Akt and MAPK (mitogen-activated protein kinase) pathways.

Animals↗
PubMed2003

Molecular dynamics, free energy, and SPR analyses of the interactions between the SH2 domain of Grb2 and ErbB phosphotyrosyl peptides.

We studied the interactions between the SH2 domain of growth factor receptor binding protein 2 (Grb2) and ErbB receptor-derived phosphotyrosyl peptides using molecular dynamics, free energy calculations, and surface plasmon resonance (SPR) analysis. Binding free energies for nine phosphotyrosyl peptides were calculated using the MM-PBSA continuum solvent method, and excellent qualitative agreement with the SPR experimental data, with a correlation coefficient of 0.92, was obtained. Consistent with previous experimental findings, phosphotyrosyl peptides with the consensus sequence pYXNX showed favorable binding affinity for the Grb2. Unexpectedly, phosphotyrosyl peptides with the consensus sequence pYQQD, which had not shown any specific binding affinity for the Grb2 in earlier studies, also showed favorable binding affinity for the Grb2 in our experimental and computational analyses. Component analysis of the calculated binding free energies revealed that van der Waals interaction between the Grb2 and the phosphotyrosyl peptide was the dominant factor for specificity and binding affinity. These results indicate that current methods of estimating binding free energies are efficient for obtaining important information about protein-protein interactions, which are essential for the transmission of signals in cellular signaling pathways.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Comparison of the characteristic of estrogenic action patterns of beta-HCH and heregulin beta1 in MCF-7 human breast cancer cells.

In this study, we compared the estrogenic action pattern of beta-HCH to another ErbB2 activating agent, heregulin beta1 (HRG), along with 17beta-estradiol and epidermal growth factor, to understand the similarities and differences of their action mechanisms. Not surprisingly, most of the initial test results indicated that the two agents, beta-HCH and HRG, are remarkably similar in several estrogenicity tests. However, in-depth biochemical studies revealed that there are some distinct differences between these two compounds in affecting ErbB2 and ErbB3 at early stages of their action. Immunocoprecipitation and Western blot studies indicated that beta-HCH mainly promotes dimerization of ErbB2 and ErbB3 at early time points, whereas HRG causes their dimerization with a rapid and significant rise in their tyrosine phosphorylation levels. These results indicate that, while both beta-HCH and HRG act through ErbB2, their initial actions differ. To understand the long-term consequence of such differential actions of these two agents, we tested the effect of a number of standard pathway specific inhibitors on their actions to induce foci formation after 2 weeks of exposure. The most conspicuous difference between beta-HCH and HRG in MCF-7 foci formation test was their response to 4-hydroxytamoxifen and LY294002, a PI3K inhibitor, i.e., the action of beta-HCH was inhibited by 4-hydroxytamoxifen but stimulated by LY294002, whereas that of heregulin was suppressed by LY294002 but stimulated by 4-hydroxytamoxifen. It appears, therefore, that the action of the latter relies more heavily on the PI3K route as compared to that of the former which has been shown to mainly act through p42/44 MAPK. These differences may account for their differential sensitivities to 4-hydroxytamoxifen.

Blotting, Western↗
PubMed2002

Coronary artery bypass surgery in patients with abdominal aortic aneurysm: detection and treatment of concomitant coronary artery disease.

OBJECTIVES: Complication due to coronary artery disease (CAD) is a major cause of mortality in the surgical treatment of abdominal aortic aneurysm (AAA). The purpose was to show 1) the incidence of patients who required coronary artery bypass grafting (CABG), and 2) risk factors for the necessity of CABG in patients with AAA. METHODS: Subjects were consecutive 159 patients (132 males and 27 females) undergoing elective repair of non-ruptured AAA between May 1993 and March 2002. Most patients (n=145) underwent routine preoperative coronary angiography (CAG) and received coronary revascularization when necessary. Clinical atherosclerotic risk factors were subjected to univariate and multivariate analysis to determine predictors for the necessity of CABG. RESULTS: Of 43 patients (27.0%) with significant coronary stenosis, 7 patients (4.4%) underwent CABG concomitantly (n=1) or prior to the AAA repair (n=6) in the same admission. Other patients received percutaneous transluminal coronary angioplasty (PTCA) (n=14) and isolated medical treatment (n=22). Overall mortality of 159 patients undergoing AAA repair was 2.5% and there were no deaths in 7 patients undergoing CABG. Univariate and multivariate analysis indicated only the history of angina as significant for the necessity of CABG in patients with AAA. Of 155 survivors, 5 patients underwent CABG later in the follow-up period. CONCLUSIONS: The incidence of patients who required CABG in the treatment of AAA was 4.4% in our institute. It was difficult to predict the necessity of CABG without conducting CAG in patients with asymptomatic myocardial ischemia. These results may justify the routine enforcement of preoperative CAG in patients with AAA.

Aged↗