Summary Activation of ErbB receptors by epidermal growth factor (EGF) or heregulin (HRG) determines distinct cell fate decisions, although signals propagate through shared pathways. Using modeling and experiments, we unravel how EGF and HRG generate distinct, all-or-none responses of the phosphorylated transcription factor c-Fos. In the cytosol, EGF induces transient and HRG induces sustained ERK activation. In the nucleus, however, ERK activity and c-fos mRNA expression are transient for both ligands. Knockdown of dual-specificity phosphatases extends HRG-stimulated nuclear ERK activation, but not c-fos mRNA expression, implying the existence of a HRG-induced repressor of c-fos transcription. Further experiments confirmed that this repressor is mainly induced by HRG, but not EGF, and requires new protein synthesis. We show how a spatially distributed, signaling-transcription cascade robustly discriminates between transient and sustained ERK activities at the c-Fos system level. The proposed control mechanisms are general and operate in different cell types, stimulated by various ligands.
The different kinetics displayed by extracellular signal-regulated kinase (ERK) 3 activation often results in distinct cellular phenotypes of mammalian cells. In PC12 cells, the epidermal growth factor (EGF)-stimulated transient activation of ERK induces cell proliferation, whereas a nerve growth factor-stimulated sustained activation of ERK induces differentiation (1, 2). Similarly, different growth factor ligands cause distinct kinetics of ERK activation in human breast cancer cells (3, 4). ERK and Akt/protein kinase B are deterministic kinases that control the activation of nuclear transcription factors (5-7); therefore, it is expected that the activation kinetics of these kinases might affect the following gene expression profiles. However, the question concerning gene expression dynamics induced by kinetically different kinase activities and its effect on cell determination mechanisms remains unsolved.In this study we focused on the dose-dependent time course analysis of early transcription induced by two ligands of the ErbB family receptor, EGF and heregulin (HRG), which induce distinct kinase activity patterns and phenotypes of MCF-7 cells. Although many studies attempted to delineate the biochemical characteristics of ErbB ligands and receptors, no systematic study has been reported concerning the analysis of ErbB receptor-mediated cell fate control.MCF-7 cells endogenously express all family members of the ErbB protein-tyrosine kinase receptors (EGFR/ErbB1, ErbB2, ErbB3, and ErbB4 receptors). EGF preferably binds to an EGFR, whereas HRG first binds to either the ErbB3 or ErbB4 receptor and then induces trans-activation of ErbB2 (8). ErbB receptors tend to form heterodimers in response to ligand binding when different ErbB receptors are co-expressed in the same cell. In particular, ErbB2 is the preferred heterodimerization partner among the receptor family (9), and it functions as an oncogenic unit through heterodimer formation with ErbB3 (10). EGFR activation induces selfdown-regulation of the receptor by recruitment of the Cbl ubiquitin ligase (11,12), and the activation of ErbB3 strongly evokes phosphatidylinositol 3Ј-kinase (PI3K) activation (13,14). Activation of ErbB receptor is often accompanied by activation of Shc-ERK and PI3K-Akt pathways. These two pathways often cross-talk or inhibit each other (15, 16) thereby resulting in distinct activity patterns pertaining to intracellular signaling that activate various types of transcription factors (17-19). In addition, many studies attempted to identify specific gene expression induced by different ErbB ligands that show signaling diversities and distinct biological outcomes (20, 21); however, earlier results using platelet-derived growth factor (PDGF)- receptor mutants indicated that diverse signaling pathways induce broadly overlapping transcription (22).
The graph in Fig. 2D that was meant to represent EGF:phospho-Akt quantification was incorrect. The correct graph is shown below. This correction does not affect the interpretation of the results or the conclusions.
Research on so-called "chemical artificial intelligence" (CAI) is an emerging field with the aim of constructing information-processing systems with learning capabilities based on chemical methodologies. This can be regarded as an attempt to reconstruct Cybernetics using molecular based systems. Many chemical reaction systems with computational abilities are proposed, but most are fixed functions that deliver molecular output for a given molecular input. On the other hand, chemical AI is a system with learning capability; namely, the output should be variable and gradually change upon repeated molecular inputs. In this paper, a compartmentalization approach for implementing cellular chemical AI using liposomes is discussed. The existing studies in terms of the methods used for assembling systems consisting of many liposomes with different functions, methods for achieving recursiveness and plasticity in chemical reaction systems, and methods for reconfiguring the network topology by liposome deformation are reviewed. Issues that must be addressed in order to realize chemical AI are also identified.
This paper addresses the longitudinal traction control problem of vehicles. A nonlinear control law at the torque level is shown to cope with the unknown tyre reaction force. From a physical consideration of a vehicle, a decoupling controller design is considered, which enables us to make the controller design straightforward. A parameter estimator is introduced to adaptive control of the system with uncertain frictional coefficient. The proposed controller indicates the better control performance than that of a non-adaptive or a conventional PI controller as evaluated in numerical simulation.
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