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Inhibition of tyrosine phosphorylation potentiates substrate-induced neurite growth
1Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Florida 33136.
Abstract:
Protein tyrosine kinases (PTKs) have major roles in signal transduction and growth control. There are several lines of evidence implicating PTKs in the regulation of axon growth, and this has led to the suggestion that they are centrally involved in the transduction of neuronal growth signals. To test this idea, we assayed the effect of the compounds genistein and lavendustin, specific inhibitors of PTKs, on neurite growth. We find that genistein greatly reduces phosphotyrosine in neurons, as expected from its action on other cells. Surprisingly, administration of genistein or lavendustin potentiated substrate-induced neurite growth in at least several different neuronal types. Stimulation of neurite growth by genistein was abolished by vanadate, providing additional evidence that inhibition of PTKs is responsible for this effect. The potentiation of growth is rather general, in that it occurs on several different extracellular matrix substrates and on two different cell adhesion molecules. Both the initiation of neurite growth and the rate of neurite elongation appear to be potentiated. Our results do not provide evidence for models of substrate-induced signal transduction that involve PTKs as a positive and necessary step, but suggest that such kinases play a regulatory role in neurite elongation.
Insights
Protein tyrosine kinases (PTKs) regulate axon growth. Inhibiting PTKs with genistein or lavendustin surprisingly enhanced neurite growth, suggesting a regulatory role rather than a necessary one in neuronal signaling.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Protein tyrosine kinases (PTKs) are crucial for signal transduction and cellular growth.
- Evidence suggests PTKs regulate axon growth and neuronal signaling.
- The precise role of PTKs in substrate-induced neurite outgrowth remains unclear.
Purpose of the Study:
- To investigate the role of PTKs in neurite growth.
- To determine if PTK inhibition affects substrate-induced neurite outgrowth.
Main Methods:
- Assayed the effect of PTK inhibitors genistein and lavendustin on neurite growth.
- Measured phosphotyrosine levels in neurons.
- Examined neurite growth on various extracellular matrix substrates and cell adhesion molecules.
Main Results:
- Genistein significantly reduced neuronal phosphotyrosine levels.
- Genistein and lavendustin potentiated substrate-induced neurite growth across multiple neuronal types.
- Vanadate abolished genistein-induced growth potentiation, confirming PTK inhibition's role.
- Growth potentiation occurred on diverse substrates and cell adhesion molecules, affecting both initiation and elongation.
Conclusions:
- PTK inhibition potentiates, rather than inhibits, substrate-induced neurite growth.
- PTKs are not a necessary positive step in substrate-induced signal transduction for neurite growth.
- PTKs appear to play a regulatory role in neurite elongation.