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Growth factor-stimulated phosphorylation cascades: activation of growth factor-stimulated MAP kinase
N G Ahn1, R Seger, R L Bratlien
1Department of Biochemistry, University of Washington, Seattle 98185.
Abstract:
Protein phosphorylation is an important mechanism in the response of cells to growth factors by which signals can be conveyed from cell surface receptors to intracellular targets. In addition to stimulation of protein tyrosine phosphorylation, activation of growth factor receptors having protein tyrosine kinase activity leads to dramatic alterations in the levels of protein serine/threonine phosphorylation. Several growth factor-stimulated serine/threonine-specific kinases have been identified as potential mediators of such signalling. MAP (microtubule-associated protein) kinase has emerged as a very interesting member of this group, because it activates a separate kinase, pp90rsk, which is also growth factor-stimulated. MAP kinase itself appears to be regulated by protein phosphorylation, because it can be inactivated by protein phosphatases. We have identified two 60 kDa proteins that promote the phosphorylation and full activation of MAP kinase in a manner paralleling its activation by growth factors in intact cells. These 'MAP kinase activators' are themselves stimulated by growth factors, suggesting that they function as intermediates between the MAP kinase and cell surface receptors in a growth factor-stimulated kinase cascade. Identification of the components of this protein kinase cascade reveals a mechanism by which at least some of the effects of receptor tyrosine kinases can be mediated through serine/threonine phosphorylation.
Insights
Growth factors trigger cell signaling via protein phosphorylation. Researchers identified two novel proteins that activate MAP kinase, revealing a key step in growth factor-stimulated signaling pathways.
Area of Science:
- Cellular signaling pathways
- Molecular biology
- Biochemistry
Background:
- Protein phosphorylation is crucial for cellular responses to growth factors.
- Growth factor receptors with tyrosine kinase activity modulate both tyrosine and serine/threonine phosphorylation.
- Serine/threonine kinases mediate growth factor signaling, with MAP kinase being a key player.
Purpose of the Study:
- To identify novel components involved in growth factor-mediated intracellular signaling.
- To elucidate the mechanism by which growth factors activate MAP kinase.
- To understand the role of serine/threonine phosphorylation in signal transduction.
Main Methods:
- Investigated protein phosphorylation in response to growth factors.
- Identified and characterized proteins that activate MAP kinase.
- Studied the regulation of MAP kinase activity by phosphorylation and dephosphorylation.
Main Results:
- Discovered two 60 kDa proteins that enhance MAP kinase phosphorylation and activation.
- Demonstrated that these 'MAP kinase activators' are stimulated by growth factors.
- Showed that these activators act as intermediates in a growth factor-stimulated kinase cascade.
Conclusions:
- Identified novel intermediates in the growth factor signaling pathway.
- Proposed a mechanism involving MAP kinase activators and serine/threonine phosphorylation.
- Highlighted the role of receptor tyrosine kinases in mediating cellular effects through serine/threonine phosphorylation.