Abstract
The protein kinases Raf-1, A-Raf and B-Raf connect receptor stimulation with intracellular signaling pathways and function as a central intermediate in many signaling pathways. Gain-of-function experiments shed light on the pleiotropic biological activities of these enzymes. Expression experiments involving constitutively active Raf revealed the essential functions of Raf in controlling proliferation, differentiation and cell death in a cell-type specific manner.
Highlights
All three Raf isoenzymes are cytosolic serine/threonine protein kinases that exhibit a high degree of sequence similarity
The activated protein kinases ERK1/2 are able to translocate into the nucleus and change the gene expression pattern via phosphorylation of gene regulatory proteins
Activation of Raf is essential for activating the Raf/mitogen-activated protein kinase (MAP) kinase (MEK)/extracellular signal-regulated protein kinase (ERK) signaling pathway and many functions attributed to Raf activation are executed by the subsequent activation of MEK and ERK
Summary
All three Raf isoenzymes are cytosolic serine/threonine protein kinases that exhibit a high degree of sequence similarity. Expression of the hormone-regulated form of Raf-1, ΔRaf-1:ER, induced cell proliferation in NIH 3T3 fibroblasts that was accompanied by an upregulation of cyclin D1 and a repression of p27KIP, a cyclin-dependent protein kinase inhibitor [16]. The Raf-MEK-ERK signaling pathway is activated, leading to further synthesis of EGF growth factors [2,18]. Expression of ΔRaf-1:ER in small lung cancer cells induced a growth inhibitory pathway that is accompanied by the induction of the cyclin-dependent protein kinase inhibitor p27KIP and a decrease in cdc protein kinase activity [20]. Activation of ΔRaf-1:ER induced expression of the cyclin-dependent protein kinase inhibitor p21KIP and an accumulation of the cells in G1, leading to growth suppression [21]. Experiments using HT22 immortalized neurons derived from the hippocampal region of the CNS showed that stimulation with BDNF rescues the cells from serum withdrawal-induced cell death when the BDNF receptor TrkB
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