1uwj: Difference between revisions

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==Overview==

Over 30 mutations of the B-RAF gene associated with human cancers have, been identified, the majority of which are located within the kinase, domain. Here we show that of 22 B-RAF mutants analyzed, 18 have elevated, kinase activity and signal to ERK in vivo. Surprisingly, three mutants, have reduced kinase activity towards MEK in vitro but, by activating C-RAF, in vivo, signal to ERK in cells. The structures of wild type and oncogenic, V599EB-RAF kinase domains in complex with the RAF inhibitor BAY43-9006, show that the activation segment is held in an inactive conformation by, association with the P loop. The clustering of most mutations to these two, regions suggests that disruption of this interaction converts B-RAF into, its active conformation. The high activity mutants signal to ERK by, directly phosphorylating MEK, whereas the impaired activity mutants, stimulate MEK by activating endogenous C-RAF, possibly via an allosteric, or transphosphorylation mechanism.

Over 30 mutations of the B-RAF gene associated with human cancers have been identified, the majority of which are located within the kinase domain. Here we show that of 22 B-RAF mutants analyzed, 18 have elevated kinase activity and signal to ERK in vivo. Surprisingly, three mutants have reduced kinase activity towards MEK in vitro but, by activating C-RAF in vivo, signal to ERK in cells. The structures of wild type and oncogenic V599EB-RAF kinase domains in complex with the RAF inhibitor BAY43-9006 show that the activation segment is held in an inactive conformation by association with the P loop. The clustering of most mutations to these two regions suggests that disruption of this interaction converts B-RAF into its active conformation. The high activity mutants signal to ERK by directly phosphorylating MEK, whereas the impaired activity mutants stimulate MEK by activating endogenous C-RAF, possibly via an allosteric or transphosphorylation mechanism.

==Disease==

Line 16:

[[Category: Homo sapiens]]

[[Category: Single protein]]

[[Category: Transferred entry: 2.7.11.1]]

[[Category: Transferred entry: 2 7.11 1]]

[[Category: Barford, D.]]

[[Category: Roe, S.M.]]

[[Category: Roe, S M.]]

[[Category: Wan, P.T.C.]]

[[Category: Wan, P T.C.]]

[[Category: BAX]]

[[Category: kinase]]

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[[Category: threonine-protein kinase]]

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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:29:06 2008''

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@@ Line 4: / Line 4: @@
 ==Overview==
-Over 30 mutations of the B-RAF gene associated with human cancers have, been identified, the majority of which are located within the kinase, domain. Here we show that of 22 B-RAF mutants analyzed, 18 have elevated, kinase activity and signal to ERK in vivo. Surprisingly, three mutants, have reduced kinase activity towards MEK in vitro but, by activating C-RAF, in vivo, signal to ERK in cells. The structures of wild type and oncogenic, V599EB-RAF kinase domains in complex with the RAF inhibitor BAY43-9006, show that the activation segment is held in an inactive conformation by, association with the P loop. The clustering of most mutations to these two, regions suggests that disruption of this interaction converts B-RAF into, its active conformation. The high activity mutants signal to ERK by, directly phosphorylating MEK, whereas the impaired activity mutants, stimulate MEK by activating endogenous C-RAF, possibly via an allosteric, or transphosphorylation mechanism.
+Over 30 mutations of the B-RAF gene associated with human cancers have been identified, the majority of which are located within the kinase domain. Here we show that of 22 B-RAF mutants analyzed, 18 have elevated kinase activity and signal to ERK in vivo. Surprisingly, three mutants have reduced kinase activity towards MEK in vitro but, by activating C-RAF in vivo, signal to ERK in cells. The structures of wild type and oncogenic V599EB-RAF kinase domains in complex with the RAF inhibitor BAY43-9006 show that the activation segment is held in an inactive conformation by association with the P loop. The clustering of most mutations to these two regions suggests that disruption of this interaction converts B-RAF into its active conformation. The high activity mutants signal to ERK by directly phosphorylating MEK, whereas the impaired activity mutants stimulate MEK by activating endogenous C-RAF, possibly via an allosteric or transphosphorylation mechanism.
 ==Disease==
@@ Line 16: / Line 16: @@
 [[Category: Homo sapiens]]
 [[Category: Single protein]]
-[[Category: Transferred entry: 2.7.11.1]]
+[[Category: Transferred entry: 2 7.11 1]]
 [[Category: Barford, D.]]
-[[Category: Roe, S.M.]]
+[[Category: Roe, S M.]]
-[[Category: Wan, P.T.C.]]
+[[Category: Wan, P T.C.]]
 [[Category: BAX]]
 [[Category: kinase]]
@@ Line 25: / Line 25: @@
 [[Category: threonine-protein kinase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Feb  3 10:08:42 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:29:06 2008''