Biomedical subjects

Naruhisa Ota

Publications and source records attributed to Naruhisa Ota.

3 recordsLinked to original sources

PubMed2006

Vav1 acidic region tyrosine 174 is required for the formation of T cell receptor-induced microclusters and is essential in T cell development and activation.

Vav proteins are multidomain signaling molecules critical for mediating signals downstream of several surface receptors, including the antigen receptors of T and B lymphocytes. The catalytic guanine nucleotide exchange factor (GEF) activity of the Vav Dbl homology (DH) domain is thought to be controlled by an intramolecular autoinhibitory mechanism involving an N-terminal extension and phosphorylation of tyrosine residues in the acidic region (AC). Here, we report that the sequences surrounding the Vav1 AC: Tyr(142), Tyr(160), and Tyr(174) are evolutionarily conserved, conform to consensus SH2 domain binding motifs, and bind several proteins implicated in TCR signaling, including Lck, PI3K p85alpha, and PLCgamma1, through direct interactions with their SH2 domains. In addition, the AC tyrosines regulate tyrosine phosphorylation of Vav1. We also show that Tyr(174) is required for the maintenance of TCR-signaling microclusters and for normal T cell development and activation. In this regard, our data demonstrate that while Vav1 Tyr(174) is essential for maintaining the inhibitory constraint of the DH domain in both developing and mature T cells, constitutively activated Vav GEF disrupts TCR-signaling microclusters and leads to defective T cell development and proliferation.

Cell Proliferation↗

PubMed2004

N-domain-dependent nonphosphorylated STAT4 dimers required for cytokine-driven activation.

The N-terminal protein interaction domain (N-domain) of the signal transducer and activator of transcription-4 (STAT4) is believed to stabilize interactions between two phosphorylated STAT4 dimers to form STAT4 tetramers. Here, we show that nonphosphorylated STAT4 dimers form in vivo before cytokine receptor-driven activation. Mutations in the N-domain dimerization interface abolished assembly of nonphosphorylated STAT4 dimers and prevented STAT4 phosphorylation mediated by cytokine receptors. In addition, N-domain dimerization occurred for other STAT family members but was homotypic in character. This implies a conserved role for N-domain dimerization, which might include influencing interactions with cytokine receptors, favoring homodimer formation or accelerating formation of the phosphorylated STAT dimer.

Animals↗

PubMed2004

Issues in T-helper 1 development--resolved and unresolved.

T-helper 1 cell (Th1) development participates in immunity to many pathogens in part by providing a source of interferon (IFN)-gamma that contributes numerous protective effects. The process of Th1 development involves signals provided by antigen-presenting cells and cytokines produced in response to pathogens, with IFN-gamma itself, interleukin (IL)-12, and IL-18 each promoting the process in some way. Despite the rapid progress into mechanisms of Th1 development in recent years, there are still a number of important unresolved issues in this area. The precise sequence of effector and cellular mechanisms represents a relatively recent avenue of research but is still the subject of current debate, as is the basis of mechanisms that may stabilize a Th1 response. Another unresolved issue is the role of type I IFNs in substituting for IL-12-mediated activation of signal transducer and activator of transcription 4 (Stat4) and induction of IFN-gamma in either murine or human T cells. It is now clear that Th1 cells acquire the property of being capable of nonantigen-dependent activation through the coordinate signaling of IL-12 and IL-18, but the precise order of intracellular signaling events and the uniqueness of this pathway's reliance on the p38 mitogen-activated protein kinase (MAPK) pathway are still issues in need of resolution. Finally, the process of verifying the effects of Stat4 mutations on functional responses has led to the recognition of an unexpected action of the STAT N-domain that may apply generally to other STAT proteins as well. None of these areas is static or resolved fully, and they likely will remain topics of rapid progress.

Animals↗