J Biol Chem 1999,
PMID: 10066754
Sutor, S L; Vroman, B T; Armstrong, E A; Abraham, R T; Karnitz, L M
Cytokines trigger the rapid assembly of multimolecular signaling complexes that direct the activation of downstream protein kinase cascades. Two protein kinases that have been linked to growth factor-regulated proliferation and survival are mitogen-activated protein/ERK kinase (MEK) and its downstream target Erk, a member of the mitogen-activated protein kinase family. Using complementary pharmacological and genetic approaches, we demonstrate that MEK and Erk activation requires a phosphatidylinositol 3-kinase (PI3-K)-generated signal in an interleukin (IL)-3-dependent myeloid progenitor cell line. Analysis of the upstream pathway leading to MEK activation revealed that inhibition of PI3-K did not block c-Raf activation, whereas MEK activation was effectively blocked under these conditions. Furthermore, agents that elevated cAMP suppressed IL-3-induced c-Raf activation but did not inhibit MEK activation. Because c-Raf activation and MEK activation were inversely affected by PI3-K- and cAMP-dependent pathways, we examined whether IL-3 activated the alternative Raf isoforms A-Raf and B-Raf. Although IL-3 did not activate B-Raf, A-Raf was activated by the cytokine. Moreover, A-Raf activation, like MEK activation, was blocked by inhibition of PI3-K but was insensitive to cAMP. Experiments with dominant negative mutants of the Raf isoforms showed that overexpression of dominant negative c-Raf did not prevent MEK activation. However, dominant negative A-Raf effectively blocked MEK activation, suggesting that activation of the MEK-Erk signaling cascade is mediated through A-Raf. Taken together, these results suggest that IL-3 receptors engage and activate both c-Raf and A-Raf in hemopoietic cells. However, these intermediates are differentially regulated by upstream signaling cascades and selectively coupled to downstream signaling pathways.
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Text Mining Data
c-Raf → PI3-K: "
Analysis of the upstream pathway leading to MEK activation revealed that inhibition of
PI3-K did not
block c-Raf activation, whereas MEK activation was effectively blocked under these conditions
"
c-Raf → IL-3: "
Furthermore, agents that elevated cAMP suppressed IL-3 induced c-Raf activation but did not inhibit MEK activation
"
c-Raf — PI3-K-: "
Because c-Raf activation and MEK activation were inversely affected by PI3-K- and cAMP dependent pathways, we examined whether IL-3 activated the alternative Raf isoforms A-Raf and B-Raf
"
B-Raf → IL-3: "
Although IL-3 did not activate B-Raf , A-Raf was activated by the cytokine
"
A-Raf ⊣ PI3-K: "
Moreover, A-Raf activation , like MEK activation, was blocked by inhibition of PI3-K but was insensitive to cAMP
"
A-Raf → IL-3: "
Taken together, these results suggest that IL-3 receptors engage and activate both c-Raf and A-Raf in hemopoietic cells
"
c-Raf → IL-3: "
Taken together, these results suggest that IL-3 receptors engage and activate both c-Raf and A-Raf in hemopoietic cells
"
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