Negative signaling in health and disease

Abstract

Signal transduction induced by receptors can elicit intracellular biochemical events that either support or inhibit cell activation. Induction of the latter has been termed "negative signaling" and can be triggered by receptors on immune cells that are distinct from activating receptors while other growth-promoting receptors induce both positive and negative signaling events. Here, the biochemistry leading to cell activation or inhibition and induced by receptors on immune cells are reviewed. Furthermore, recent experimental evidence is reviewed that indicates an important contribution of negative signaling to the intracellular survival of infectious pathogens.

Myeloid Cell IL-10 Production in Response to Leishmania Involves Inactivation of Glycogen Synthase Kinase-3β Downstream of Phosphatidylinositol-3 Kinase

“…To ensure their survival, leishmania in particular have the capacity to inhibit numerous macrophage functions and to prevent cell activation (3,42,48). The activation states of mononuclear phagocytes are under the influence of the ambient concentrations of both stimulatory and in-FIGURE 7.…”

Inhibition of EGFR-mediated phosphoinositide-3-OH kinase (PI3-K) signaling and glioblastoma phenotype by Signal-Regulatory Proteins (SIRPs)

“…Observations in hematopoietic cells showing that signaling from receptor tyrosine kinases (RTKs) could be attenuated by association with phosphotyrosine phosphatases led to the identi®cation of distinct families of inhibitory receptors (reviewed in Cambier, 1997;Coggeshall, 1999). Most of the inhibitory receptors are monomeric proteins that contain multiple immunoglobin super-family (IgSF) domains in their extracellular regions (Cambier, 1997).…”

“…Phosphorylation of the tyrosine in ITIM triggers binding and activation of SHP1 and SHP2 and, in some cases, the phosphatidylinositol (3,4,5)P 3 5' inositol phosphatase, SHIP (Cambier, 1997;Coggeshall, 1999). Mutation of the I/V position disrupts binding of SHP1 and SHP2 (Vely et al, 1997).…”

“…In many systems, the binding of SH2 domain-containing phosphatases appears to be critical to the function of inhibitory receptors and PTPs may represent the e ectors of inhibitory receptors. It is likely that distinct di erences in the primary sequence Oncogene (2000) 19, 3999 ± 4010 ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00 www.nature.com/onc surrounding the phosphotyrosine residue underlies di erential recruitment of SH2 domain-containing proteins between positive and negative signaling receptors (Cambier, 1997;Coggeshall, 1999). Investigation of mechanisms of PTP binding to ITIM motifs may shed light on PTP functional regulation, since little is known regarding the recruitment and activation of PTPs under physiologic conditions.…”

First evidence of Okadaic acid acyl-derivative and Dinophysistoxin-3 in mussel samples collected in Chiloe Island, Southern Chile

“…The PP2A appears to play a key role in the regulation of most major cell metabolic pathways, as well as translation, transcription and control of transition from G2 to the M phase of the cell cycle. Moreover, this Phosphatase may function as either tumor promoter or tumor suppressor depending on the cell type or the transforming agent (Coggeshall, 1999;Milward et al, 1999).…”