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Activation of Vav and Ras through the nerve growth factor and B cell receptors by different kinases
1Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, Colorado, 80206, USA.
Abstract:
Engagement of the B-cell antigen receptor (BCR) or the nerve growth factor receptor (NGFR/TrkA) induces activation of multiple tyrosine kinases, resulting in phosphorylation of numerous intracellular substrates. We show that addition of NGF or anti-IgM antibody leads to the early tyrosine phosphorylation of p95(vav), which is expressed exclusively in hematopoietic cells; NGF, similar to crosslinking the BCR, also results in the rapid activation of Ras. The phosphorylation of Vav and activation of Ras triggered by NGF is mediated through Trk tyrosine kinase, whereas signaling through the BCR uses a different tyrosine kinase. We also show that NGF induces tyrosine phosphorylation of Shc and its association with Grb2. Vav and Ras with the adaptor proteins Shc and Grb2 appear to serve as a link between different receptor-mediated signaling pathways and, in human B cells, may play an important regulatory role in neuroimmune interactions.
Insights
Nerve growth factor (NGF) and B-cell receptor (BCR) signaling activate similar pathways, including Vav and Ras activation. These pathways link neuroimmune interactions in human B cells.
Area of Science:
- Immunology
- Neuroscience
- Cell Signaling
Background:
- B-cell antigen receptor (BCR) and nerve growth factor receptor (NGFR/TrkA) engagement activate tyrosine kinases.
- These receptors initiate intracellular signaling cascades involving substrate phosphorylation.
Purpose of the Study:
- To investigate the signaling pathways downstream of NGFR/TrkA and BCR.
- To elucidate the role of Vav and Ras in mediating these signaling events.
- To explore the connection between neuroimmune interactions in B cells.
Main Methods:
- Stimulation of cells with NGF or anti-IgM antibody.
- Analysis of tyrosine phosphorylation of p95(vav), Shc, and Grb2.
- Assessment of Ras activation.
Main Results:
- Both NGF and anti-IgM induced early tyrosine phosphorylation of p95(vav).
- NGF and BCR crosslinking both led to rapid Ras activation.
- NGF-induced signaling involved Trk tyrosine kinase, distinct from BCR signaling.
- NGF triggered tyrosine phosphorylation and association of Shc with Grb2.
Conclusions:
- Vav, Ras, Shc, and Grb2 act as crucial links between receptor-mediated signaling pathways.
- These signaling molecules may play a significant role in regulating neuroimmune interactions within human B cells.