Biomedical subjects

Stephan Philipp

Publications and source records attributed to Stephan Philipp.

4 recordsLinked to original sources

PubMed2005

Modulation of Ca2+ signaling by Na+/Ca2+ exchangers in mast cells.

Mast cells rely on Ca(2+) signaling to initiate activation programs leading to release of proinflammatory mediators. The interplay between Ca(2+) release from internal stores and Ca(2+) entry through store-operated Ca(2+) channels has been extensively studied. Using rat basophilic leukemia (RBL) mast cells and murine bone marrow-derived mast cells, we examine the role of Na(+)/Ca(2+) exchangers. Calcium imaging experiments and patch clamp current recordings revealed both K(+)-independent and K(+)-dependent components of Na(+)/Ca(2+) exchange. Northern blot analysis indicated the predominant expression of the K(+)-dependent sodium-calcium exchanger NCKX3. Transcripts of the exchangers NCX3 and NCKX1 were additionally detected in RBL cells with RT-PCR. The Ca(2+) clearance via Na(+)/Ca(2+) exchange represented approximately 50% of the total clearance when Ca(2+) signals reached levels > or =200 nM. Ca(2+) signaling and store-operated Ca(2+) entry were strongly reduced by inverting the direction of Na(+)/Ca(2+) exchange, indicating that Na(+)/Ca(2+) exchangers normally extrude Ca(2+) ions from cytosol and prevent the Ca(2+)-dependent inactivation of store-operated Ca(2+) channels. Working in the Ca(2+) efflux mode, Na(+)/Ca(2+) exchangers such as NCKX3 and NCX3 might, therefore, play a role in the Ag-induced mast cell activation by controlling the sustained phase of Ca(2+) mobilization.

Animals↗

PubMed2004

Np9 protein of human endogenous retrovirus K interacts with ligand of numb protein X.

We have recently identified Np9 as a novel nuclear protein produced by the human endogenous retrovirus K and were able to document the exclusive presence of np9 transcript in tumors and transformed cells. With the aim of studying whether Np9 has a role in tumorigenesis, a systematic search for interacting proteins was performed. Here, we identify the RING-type E3 ubiquitin ligase LNX (ligand of Numb protein X) as an Np9-interacting partner. We furthermore show that the interaction involves N- and C-terminal domains of both proteins and can affect the subcellular localization of LNX. LNX has been reported to target the cell fate determinant and Notch antagonist Numb for proteasome-dependent degradation, thereby causing an increase in transactivational activity of Notch. We document that LNX-interacting Np9, like Numb, is unstable and degraded via the proteasome pathway and that ectopic Numb can stabilize recombinant Np9. Combined, these findings point to the possibility that Np9 affects tumorigenesis through the LNX/Numb/Notch pathway.

Animals↗

PubMed2004

TRPC4 and TRPC4-deficient mice.

TRP proteins, in most cases, provide localized Ca2+ increases for spatially defined signal transduction processes. They are activated by as yet unclear mechanisms, many involving the complex phospholipase C and phosphatidylinositol pathways. In mouse endothelial cells at least seven TRPs are expressed, including TRPC1, TRPC2, TRPC3, TRPC4, TRPC6, TRPV4 and TRPM4. As shown previously, TRPC4 is an indispensable component of agonist-induced Ca2+ entry channels in native endothelial cells which essentially contributes to agonist-induced vessel relaxation and microvascular endothelial permeability, although, it is still open, whether TRPC4 acts as channel-forming subunit and/or essential constituent for channel activation. Utilizing the mouse model is one way to address this question and to provide novel insights for the biological functions of TRPC4. Here we review recent results on heterologously expressed TRPC4 and summarize what is known on the phenotype of the TRPC4-/- mice generated in our laboratory.

Amino Acid Sequence↗

PubMed2003

TRPC3 mediates T-cell receptor-dependent calcium entry in human T-lymphocytes.

Stimulation of the T-cell receptor (TCR) activates Ca2+ entry across the plasma membrane, which is a key triggering event for the T-cell-associated immune response. We show that TRPC3 channels are important for the TCR-dependent Ca2+ entry pathway. The TRPC3 gene was found to be damaged in human T-cell mutants defective in Ca2+ influx. Mutations of the TRPC3 gene were accompanied by changes of TRPC3 gene expression. Introduction of the complete human TRPC3 cDNA into those mutants rescued Ca2+ currents as well as TCR-dependent Ca2+ signals. Our data provide the initial step toward understanding the molecular nature of endogenous Ca2+ channels participating in T-cell activation and put forward TRPC3 as a new target for modulating the immune response.

Barium↗