Biomedical subjects

Edward A Clark

Publications and source records attributed to Edward A Clark.

24 records · Page 2Linked to original sources

PubMed2003

Branches of the B cell antigen receptor pathway are directed by protein conduits Bam32 and Carma1.

Adaptor proteins act as conduits to channel upstream signals into downstream effector branches. Two B cell-associated adaptors, Bam32 and Carma1, regulate the ERK, JNK, and NF-kappaB branches of the BCR signaling pathway. Recent studies of Bam32-/- and Carma1-/- mice suggest that each adaptor controls a distinct conduit regulating either only proliferation (Bam32) or both the proliferation and survival of B cells (Carma1).

Adaptor Proteins, Signal Transducing↗

PubMed2003

The dual-function CD150 receptor subfamily: the viral attraction.

The CD150 subfamily within the CD2 family is a growing group of dual-function receptors that have within their cytoplasmic tails a characteristic signaling motif. The ITSM (immunoreceptor tyrosine-based switch motif) enables these receptors to bind to and be regulated by small SH2 domain adaptor proteins, including SH2D1A (SH2-containing adaptor protein SH2 domain protein 1A) and EAT-2 (EWS-activated transcript 2). A major signaling pathway through the prototypic receptor in this subfamily, CD150, leads to the activation of interferon-gamma, a key cytokine for viral immunity. As a result, many viruses have designed strategies to usurp or alter CD150 functions. Measles virus uses CD150 as a receptor and Molluscum contagiosum virus encodes proteins that are homologous to CD150. Thus, viruses use CD150 subfamily receptors to create a favorable environment to elude detection and destruction. Understanding the CD150 subfamily may lead to new strategies for vaccine development and antiviral therapies.

Animals↗

PubMed2002

Dendritic cell-associated lectin-1: a novel dendritic cell-associated, C-type lectin-like molecule enhances T cell secretion of IL-4.

We have characterized dendritic cell (DC)-associated lectin-1 (DCAL-1), a novel, type II, transmembrane, C-type lectin-like protein. DCAL-1 has restricted expression in hemopoietic cells, in particular, DCs and B cells, but T cells and monocytes do not express it. The DCAL-1 locus is within a cluster of C-type lectin-like loci on human chromosome 12p12-13 just 3' to the CD69 locus. The consensus sequence of the DCAL-1 gene was confirmed by RACE-PCR; however, based on sequence alignment with genomic DNA and with various human expressed sequence tags, we predict that DCAL-1 has two splice variants. C-type lectins share a common sequence motif of 14 invariable and 18 highly conserved aa residues known as the carbohydrate recognition domain. DCAL-1, however, is missing three of the cysteine residues required to form the standard carbohydrate recognition domain. DCAL-1 mRNA and protein expression are increased upon the differentiation of monocytes to CD1a(+) DCs. B cells also express high levels of DCAL-1 on their cell surface. Using a DCAL-1 fusion protein we identified a population of CD4(+) CD45RA(+) T cells that express DCAL-1 ligand. Coincubation with soluble DCAL-1 enhanced the proliferation of CD4(+) T cells in response to CD3 ligation and significantly increased IL-4 secretion. In contrast, coincubation with soluble DC-specific ICAM-3-grabbing nonintegrin (CD209) fusion protein as a control had no effect on CD4(+) T cell proliferation or IL-4 and IFN-gamma secretion. Therefore, the function of DCAL-1 on DCs and B cells may act as a T cell costimulatory molecule, which skews CD4(+) T cells toward a Th2 response by enhancing their secretion of IL-4.

Adjuvants, Immunologic↗

PubMed2002

FDC-SP, a novel secreted protein expressed by follicular dendritic cells.

To define better the molecular basis for follicular dendritic cell (FDC) function, we used PCR-based cDNA subtraction to identify genes specifically expressed in primary FDC isolated from human tonsils. In this work we report the discovery of a novel gene encoding a small secreted protein, which we term FDC-SP (FDC secreted protein). The FDC-SP gene lies on chromosome 4q13 adjacent to clusters of proline-rich salivary peptides and C-X-C chemokines. Human and mouse FDC-SP proteins are structurally unique and contain a conserved N-terminal charged region adjacent to the leader peptide. FDC-SP has a very restricted tissue distribution and is expressed by activated FDCs from tonsils and TNF-alpha-activated FDC-like cell lines, but not by B cell lines, primary germinal center B cells, or anti-CD40 plus IL-4-activated B cells. Strikingly, FDC-SP is highly expressed in germinal center light zone, a pattern consistent with expression by FDC. In addition, FDC-SP is expressed in leukocyte-infiltrated tonsil crypts and by LPS- or Staphylococcus aureus Cowan strain 1-activated leukocytes, suggesting that FDC-SP can also be produced in response to innate immunity signals. We provide evidence that FDC-SP is posttranslationally modified and secreted and can bind to the surface of B lymphoma cells, but not T lymphoma cells, consistent with a function as a secreted mediator acting upon B cells. Furthermore, we find that binding of FDC-SP to primary human B cells is markedly enhanced upon activation with the T-dependent activation signals such as anti-CD40 plus IL-4. Together our data identify FDC-SP as a unique secreted peptide with a distinctive expression pattern within the immune system and the ability to specifically bind to activated B cells.

Amino Acid Sequence↗

PubMed2002

The B lymphocyte adaptor molecule of 32 kD (Bam32) regulates B cell antigen receptor signaling and cell survival.

The B lymphocyte-associated adaptor protein 32 kD in size (Bam32) is expressed at high levels in germinal center (GC) B cells. It has an NH(2)-terminal src homology 2 (SH2) domain which binds phospholipase C (PLC)gamma 2, and a COOH-terminal pleckstrin homology (PH) domain. Thus, Bam32 may function to integrate protein tyrosine kinase (PTK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways in B cells. To further define the role Bam32 plays in B cells, we generated Bam32-deficient DT40 cells. These Bam32(-/-) cells exhibited lower levels of B cell antigen receptor (BCR)-induced calcium mobilization with modest decreases in tyrosine phosphorylation of phospholipase C (PLC)gamma 2. Moreover, BCR-induced activation of extracellular signal-regulated kinase (ERK), c-jun NH2-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) pathways was impaired in Bam32(-/-) cells but not the activation of Akt-related pathways. Activation of downstream transcription factors such as nuclear factor of activated T cells (NF-AT) and nuclear factor of kappa binding (NF-kappa B) was also impaired in Bam32(-/-) cells. Furthermore, Bam32(-/-) cells were more susceptible to BCR-induced death. Taken together, these findings suggest that Bam32 functions to regulate BCR-induced signaling and cell survival most likely in germinal centers.

Animals↗

PubMed2002

Regulation of B-cell fate by antigen-receptor signals.

Recent evidence indicates that B cells are instructed continuously by B-cell receptor (BCR) signals to make crucial cell-fate decisions at several checkpoints during their development. Targeted disruption of BCR signalling components leads to distinct blocks in B-cell maturation, which indicates that key kinases and adaptors fine-tune BCR signalling to direct appropriate cell fates. Recent progress in unravelling the molecular mechanisms of the BCR signalling pathways has helped to clarify how BCR signals regulate the proliferation, survival and apoptosis of developing B cells.

Animals↗