The C-terminus of Raf-1 acts as a 14-3-3-dependent activation switch

Dhillon, Amardeep S.; Yip, Yan Yan; Grindlay, Guillermo; Pakay, Julian L.; Dangers, Marc; Hillmann, Meike; Clark, William; Pitt, Andrew R.; Mischak, Harald; Kölch, Walter

doi:10.1016/j.cellsig.2009.07.001

Cited by 45 publications

(45 citation statements)

References 38 publications

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“…Intramolecular autophosphorylation at this site stabilizes CRAF and maintains its kinase activity (70,71). Hence, the phosphorylationdeficient CRAF S621A mutant is unstable (70) and kinetically inactive (69,72) even in the yeast system (data not shown).…”

Section: Stability Of Folded Craf Is Insensitive To Hsp90mentioning

confidence: 99%

Bipartite Role of Heat Shock Protein 90 (Hsp90) Keeps CRAF Kinase Poised for Activation

Mitra

Ghosh

Gayen

et al. 2016

Journal of Biological Chemistry

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Edited by Velia FowlerCRAF kinase maintains cell viability, growth, and proliferation by participating in the MAPK pathway. Unlike BRAF, CRAF requires continuous chaperoning by Hsp90 to retain MAPK signaling. However, the reason behind the continuous association of Hsp90 with CRAF is still elusive. In this study, we have identified the bipartite role of Hsp90 in chaperoning CRAF kinase. Hsp90 facilitates Ser-621 phosphorylation of CRAF and prevents the kinase from degradation. Co-chaperone Cdc37 assists in this phosphorylation event. However, after folding, the stability of the kinase becomes insensitive to Hsp90 inhibition, although the physical association between Hsp90 and CRAF remains intact. We observed that overexpression of Hsp90 stimulates MAPK signaling by activating CRAF. The interaction between Hsp90 and CRAF is substantially increased under an elevated level of cellular Hsp90 and in the presence of either active Ras (Ras V12 ) or EGF. Surprisingly, enhanced binding of Hsp90 to CRAF occurs prior to the Ras-CRAF association and facilitates actin recruitment to CRAF for efficient Ras-CRAF interaction, which is independent of the ATPase activity of Hsp90. However, monomeric CRAF (CRAF R401H ) shows abrogated interaction with both Hsp90 and actin, thereby affecting Hsp90-dependent CRAF activation. This finding suggests that stringent assemblage of Hsp90 keeps CRAF kinase equipped for participating in the MAPK pathway. Thus, the role of Hsp90 in CRAF maturation and activation acts as a limiting factor to maintain the function of a strong client like CRAF kinase.

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Section: Stability Of Folded Craf Is Insensitive To Hsp90mentioning

confidence: 99%

Bipartite Role of Heat Shock Protein 90 (Hsp90) Keeps CRAF Kinase Poised for Activation

Mitra

Ghosh

Gayen

et al. 2016

Journal of Biological Chemistry

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“…There is a suggestion that upregulation of 14-3-3 proteins may be protective in atherosclerosis, although assignment of specific roles for the different isoforms is difficult (218,1052). Remarkably, however, phosphorylation of S621 on Raf1 creates a binding site for 14-3-3 which is mandatory for Raf1 activity (by providing a binding site for ATP and a shield against S621 dephosphorylation) (419). Once active, Raf1 phosphorylates MEK1 or MEK2 which can then phosphorylate and activate the terminal MAPK, ERK1, or ERK2.…”

Section: Activation Of Raf1 a Prototypical Map3k And Other Activatomentioning

confidence: 99%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

389

344

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At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-␣ and related family members leading to activation of NF-B; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

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“…Stat3 signaling activity is tightly regulated by its interacting proteins and multiple signaling cascades and its prolonged activation is associated with various malignancies, including OSCC (Yu et al, 2007). Many studies have indicated that 14-3-3 proteins are involved in various steps regulating Stat3 activity, including PKC , Raf1 (Dhillon et al, 2009), MEK1/2 (Fanger et al, 1998), and PP2A (Sun et al, 2007). Moreover, 14-3-3 may serve as a molecular stabilizer, which contributes to serine phosphorylation and converts Stat3 from the form with lower activity to that with higher activity .…”

Section: Discussionmentioning

confidence: 99%