Biomedical subjects

Takuji Tanoue

Publications and source records attributed to Takuji Tanoue.

8 recordsLinked to original sources

PubMed2007

Temporal and spatial expression profiles of the Fat3 protein, a giant cadherin molecule, during mouse development.

Cadherins constitute a superfamily of cell-cell interaction molecules that participate in morphogenetic processes of animal development. Fat cadherins are the largest members of this superfamily, with 34 extracellular cadherin repeats. Classic Fat, identified in Drosophila, is known to regulate cell proliferation and planar cell polarity. Although 4 subtypes of Fat cadherin, Fat1, Fat2, Fat3, and Fat4/Fat-J, have been identified in vertebrates, their protein localization remains largely unknown. Here we describe the mRNA and protein distributions of Fat3 during mouse development. We found that Fat3 expression was restricted to the nervous system. In the brain, Fat3 was expressed in a variety of regions and axon fascicles. However, its strongest expression was observed in the olfactory bulb and retina. Detailed analysis of Fat3 in the developing olfactory bulb revealed that Fat3 mRNA was mainly expressed by mitral cells and that its proteins were densely localized along the dendrites of these cells as well as in their axons to some extent. Fat3 transcripts in the retina were expressed by amacrine and ganglion cells, and its proteins were concentrated in the inner plexiform layer throughout development. Based on these observations, we suggest that Fat3 plays a role in the interactions between neurites derived from specific subsets of neurons during development.

Animals↗

PubMed2005

New insights into Fat cadherins.

Cell-cell adhesion is fundamental to multicellular architecture. Several classes of adhesion molecule are used to achieve this, and cadherins represent a major family of such molecules. The cadherin family has multiple subfamilies. Members of the Fat cadherin subfamily, which is conserved across species, have an extraordinarily large extracellular region, comprising 34 repeated domains, making them the largest cadherin molecules. Classic Fat, identified in Drosophila, is known to regulate cell proliferation and planar cell polarity. Recent studies of one of its mammalian homologs, Fat1, have revealed novel functions of this molecule. Fat1 binds to Ena/VASP proteins and regulates actin dynamics at both cell-cell contacts and leading edges. These observations suggest that Fat1 is an important regulator of actin dynamics and controls cell-cell interactions through this activity.

Actins↗

PubMed2005

Requirement of the MAP kinase signaling pathways for mouse preimplantation development.

Mammalian preimplantation development involves several crucial events, such as compaction and blastocyst formation, but little is known about essential genes that regulate this developmental process. Here, we have focused on MAP kinase signaling pathways as potential regulatory pathways for the process. Our results show that inhibition of the JNK pathway or of the p38 MAP kinase pathway, but not of the ERK pathway, results in inhibition of cavity formation, and that JNK and p38 are active during mouse preimplantation development. Our subsequent microarray analyses show that, of about 39,000 transcripts analyzed, the number of those genes whose expression level is sensitive to the inhibition of the JNK or the p38 pathway, but insensitive to the inhibition of the ERK pathway, is only 156. Moreover, of the 156 genes, expression of 10 genes (two genes upregulated and eight genes downregulated) is sensitive to either inhibition of the JNK or p38 pathways. These 10 genes include several genes known for their function in axis and pattern formation. Downregulation of some of the 10 genes simultaneously using siRNA leads to abnormality in cavity formation. Thus, this study has successfully narrowed down candidate genes of interest, detailed analysis of which will probably lead to elucidation of the molecular mechanism of preimplantation development.

Animals↗

PubMed2004

Mammalian Fat1 cadherin regulates actin dynamics and cell-cell contact.

Fat cadherins form a distinct subfamily of the cadherin gene superfamily, and are featured by their unusually large extracellular domain. In this work, we investigated the function of a mammalian Fat cadherin. Fat1 was localized at filopodial tips, lamellipodial edges, and cell-cell boundaries, overlapping with dynamic actin structures. RNA interference-mediated knockdown of Fat1 resulted in disorganization of cell junction-associated F-actin and other actin fibers/cables, disturbance of cell-cell contacts, and also inhibition of cell polarity formation at wound margins. Furthermore, we identified Ena/vasodilator-stimulated phosphoproteins as a potential downstream effector of Fat1. These results suggest that Fat1 regulates actin cytoskeletal organization at cell peripheries, thereby modulating cell contacts and polarity.

Actin Cytoskeleton↗

PubMed2003

Molecular recognitions in the MAP kinase cascades.

The mitogen-activated protein kinase (MAPK) cascades play a pivotal role in many aspects of cellular functions, and are evolutionarily conserved from yeast to mammals. In mammals, there are four subfamily members in the MAPKs. Each MAPK has its own activators, substrates and inactivators. In order to achieve normal cellular functions, the MAPK cascades should transduce signals with high efficiency and fidelity. However, the molecular basis for the mechanism underlying the specific reactions in the MAPK cascades has not been fully understood. The MAPKs form a globular structure without a distinct domain specific for protein-protein interactions. Recent studies revealed two mechanisms regulating the signalling, the docking interaction and the scaffolding. The docking interaction is achieved through the common docking domain (the CD domain) on MAPKs, and is different from a transient enzyme-substrate interaction through the active centre of the enzymes. Almost all the MAPK-interacting molecules have a conserved motif interacting with the CD domain. The scaffolding usually utilizes a third molecule to tether several components of the MAPK cascades. Both of them are thought to regulate the enzymatic specificity and efficiency.

Amino Acid Motifs↗

PubMed2002

Identification of the Anti-proliferative protein Tob as a MAPK substrate.

Mitogen-activated protein kinases (MAPKs) regulate a wide variety of cellular functions by phosphorylating their specific substrates. Here we have identified Tob as a novel substrate of MAPK. Tob, a member of the Tob and B-cell translocation gene anti-proliferative protein family, is shown to negatively regulate the proliferation of osteoblasts and T cells. In this study, our two-hybrid screening has identified Tob as an ERK2-interacting protein. Biochemical analyses have then shown that ERK MAPK (ERK2) and JNK/SAPK (JNK2) bind to and phosphorylate Tob in vitro. ERK catalyzes the phosphorylation more efficiently than JNK. When the ERK pathway is activated in cells, phosphorylation of Tob is induced. An ERK-binding or -docking site locates in the N-terminal portion of Tob, and phosphorylation sites reside in the C-terminal stretch region. The docking is crucial for efficient phosphorylation. Mutant forms of Tob, in which serines are replaced by glutamic acids to mimic phosphorylation, show a much reduced ability to inhibit the cell cycle progression to S phase from G(0)/G(1) phase, as compared with wild-type Tob, indicating that ERK phosphorylation negatively regulates the anti-proliferative function of Tob.

Amino Acid Sequence↗

PubMed2002

Modular structure of a docking surface on MAPK phosphatases.

Mitogen-activated protein kinases (MAPKs) must be precisely inactivated to achieve proper functions in the cells. Ten members of dual specificity phosphatases specifically acting on MAPKs, termed MAPK phosphatases (MKPs), have been reported. Each member has its own substrate specificity that should be tightly regulated. However, the molecular mechanism underlying the regulation of the specificity is largely unknown. In the MAPK signaling pathways, docking interactions, which are different from transient enzyme-substrate interaction, are known to regulate the enzymatic specificity. Here we have identified and characterized a docking surface of MKPs. Our results show that a docking surface is composed of a tandem alignment of three subregions (modules): a cluster of positively charged amino acids, a cluster of hydrophobic amino acids, and a cluster of positively charged amino acids (positive-hydrophobic-positive). This modular structure well fits the docking groove on MAPKs that we have previously identified and may contribute to regulating the docking specificity of the MKP family. The position, number, and species of charged amino acids in each module including the central hydrophobic subregion are important factors in regulation of docking to specific MAPKs. This modular structure in the docking interaction may define a novel model of protein-protein interaction that would also regulate other systems.

Amino Acid Sequence↗

PubMedDate not supplied

Docking interactions in the mitogen-activated protein kinase cascades.

Regulation of cellular functions and responses utilizes a number of the signal transduction pathways. Each pathway should transduce signals with high efficiency and fidelity to avoid unnecessary crosstalks. The mitogen-activated protein kinase (MAPK) cascades regulate a wide variety of cellular functions, including cell proliferation, differentiation, and stress responses. MAPK is activated by MAPK kinase; phosphorylates various targets, including transcription factors and MAPK-activated protein kinases; and is inactivated by several phosphatases. Recent studies have provided a cue to understand the molecular mechanism underlying the signal transduction through the MAPK cascades. In the MAPK cascades, docking interactions, which are achieved through a site outside the catalytic domain of MAPKs, regulate the efficiency and specificity of the enzymatic reactions. The docking interaction is different from a transient enzyme-substrate interaction through the active center. It has been shown that activators, substrates, and inactivators of MAPKs utilize a common site on MAPKs in the docking interaction. Then, the docking interaction may regulate not only the efficiency and specificity of the cascades, but also the ordered and integrated signaling.

Animals↗