Sandbox Reserved 707: Difference between revisions
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[[Image:The RAS RAF MEK ERK pathway.jpg|400px|thumb| Diagram of the RAS-RAF-MEK-ERK pathway<ref>PMID:17208430</ref>.]] | [[Image:The RAS RAF MEK ERK pathway.jpg|400px|thumb| Diagram of the RAS-RAF-MEK-ERK pathway<ref>PMID:17208430</ref>.]] | ||
The regulation of RAF Kinases involves protein-protein interactions, phosphorylations, dephosphorylations and conformational changes<ref>PMID:15520807</ref>. <br /> | The regulation of RAF Kinases involves protein-protein interactions, phosphorylations, dephosphorylations and conformational changes<ref>PMID:15520807</ref>. <br /> | ||
RAF kinases participate in the RAS-RAF-MEK-ERK signal transduction cascade, which is sometimes denoted as the mitogen-activated protein kinase (MAPK) cascade<ref>PMID:12471243</ref>. Growth factors bind to receptor tyrosine kinases (RTKs), resulting in RAS activation. RAF proteins are one of a family of effector proteins activated by RAS, and they in turn stimulate the activation of MEK, which subsequently stimulates ERK activity. ERK phosphorylates both cytosolic and nuclear proteins, thereby mediating the cellular responses cells make when this pathway is activated.<br /> | RAF kinases participate in the RAS-RAF-MEK-ERK signal transduction cascade, which is sometimes denoted as the mitogen-activated protein kinase (MAPK) cascade<ref>PMID:12471243</ref>. Growth factors bind to receptor tyrosine kinases (RTKs), resulting in RAS activation. RAF proteins are one of a family of effector proteins activated by RAS, and they in turn stimulate the activation of MEK, which subsequently stimulates [[ERK]] activity. ERK phosphorylates both cytosolic and nuclear proteins, thereby mediating the cellular responses cells make when this pathway is activated.<br /> | ||
=== Structural implication on the MAP Kinase Pathway === | === Structural implication on the MAP Kinase Pathway === | ||
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RAF kinase inhibitors effectively block MEK and ERK phosphorylation. | RAF kinase inhibitors effectively block MEK and ERK phosphorylation. | ||
However the B-RAF specific inhibitor 885-A produces an unexpected increase in ERK phosphorylation in human melanoma cell lines. How can a RAF kinase inhibitor lead to the paradoxical increase in RAF kinase activity and ERK phosphorylation? Two additional studies noted below address this issue, and the common finding is that the binding of inhibitors to RAF kinases promotes RAS-dependent C-RAF homo- or heterodimerization and C-RAF activation. <br /> | However the B-RAF specific inhibitor 885-A produces an unexpected increase in ERK phosphorylation in human melanoma cell lines. How can a RAF kinase inhibitor lead to the paradoxical increase in RAF kinase activity and ERK phosphorylation? Two additional studies noted below address this issue, and the common finding is that the binding of inhibitors to RAF kinases promotes RAS-dependent C-RAF homo- or heterodimerization and C-RAF activation. <br /> | ||
<Structure load='3omv' size='400' frame='true' align='left' caption='3D View of C-RAF' scene='Insert optional scene name here' /> | |||
=== First Study === | === First Study === | ||
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These studies indicate that the binding of an inhibitor to C-RAF leads to the formation of a C-RAF homodimer and C-RAF activation resulting in downstream MEK-ERK activation. Another possible, but not mutually exclusive, mechanism is that binding of an inhibitor to B-RAF leads to the formation of a B-RAF–C-RAF heterodimer and C-RAF activation. That RAF-kinase-induced paradoxical activation occurs in B-RAF -/- mouse embryonic fibroblasts does not rule out the possibility that B-RAF–C-RAF heterodimers play a role in paradoxical activation. A recent study showed that A-RAF acts as a Scaffold to stabilize the heterodimers of B-RAF and C-RAF<ref>PMID:22927515</ref>. | These studies indicate that the binding of an inhibitor to C-RAF leads to the formation of a C-RAF homodimer and C-RAF activation resulting in downstream MEK-ERK activation. Another possible, but not mutually exclusive, mechanism is that binding of an inhibitor to B-RAF leads to the formation of a B-RAF–C-RAF heterodimer and C-RAF activation. That RAF-kinase-induced paradoxical activation occurs in B-RAF -/- mouse embryonic fibroblasts does not rule out the possibility that B-RAF–C-RAF heterodimers play a role in paradoxical activation. A recent study showed that A-RAF acts as a Scaffold to stabilize the heterodimers of B-RAF and C-RAF<ref>PMID:22927515</ref>. | ||
== B-RAF in cancers == | == B-RAF in cancers == | ||
