Negative Regulation of the Serine/Threonine Kinase B-Raf by Akt

Guan, Kun‐Liang; Figueroa, Claudia; Brtva, Teresa R.; Zhu, Tianquan; Taylor, Jennifer; Barber, Theodore D.; Vojtek, Anne B.

doi:10.1016/s0021-9258(19)61518-8

Cited by 208 publications

(36 citation statements)

References 21 publications

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“…Nevertheless, recent cryo-electron microscopy (cryo-EM) and crystal structures of BRAF have shed light on these complexes, providing visual context to the knowledge obtained through biochemical and cell biological approaches 13,23,24 . For example, the published cryo-EM structure of an autoinhibited, monomeric BRAF complex confirmed that a 14-3-3 dimer can bind simultaneously to the BRAF pS365 and pS729 sites and that the CRD makes critical contacts with both the RAF catalytic domain and the 14-3-3 dimer in the autoinhibited state 13 , consistent with previous studies implicating the CRD and 14-3-3 as key regulators of RAF autoinhibition 10,12,25,26 . Binding of the 14-3-3 dimer was also found to occlude both the membrane/ligand binding region of the CRD and the dimer interface of the kinase domain 13 , thus preventing spurious CRD-membrane contact as well as RAF dimer formation.…”

Section: Introductionsupporting

confidence: 87%

Structural insights into the BRAF monomer-to-dimer transition mediated by RAS binding

et al. 2021

Preprint

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An unresolved issue in RAF kinase signaling is how binding of autoinhibited RAF monomers to activated RAS initiates the conformational changes required to form active RAF dimers. Here, we present cryo-electron microscopy structures of full-length BRAF complexes derived from mammalian cells: autoinhibited monomeric BRAF:14-3-32:MEK and BRAF:14-3-32 complexes and an inhibitor-bound, dimeric BRAF2:14-3-32 complex, at 3.7, 4.1, and 3.9 Å resolution, respectively. The RAS binding domain (RBD) of BRAF is resolved in the autoinhibited structures, and we find that neither MEK nor ATP binding is required to stabilize the autoinhibited complexes. Notably, the RBD was found to interact extensively with the 14-3-3 protomer bound to the BRAF C-terminal site. Moreover, through structure-guided mutational studies, our findings indicate that RAS-RAF binding is a dynamic process and that RBD residues at the 14-3-3 interface have a dual function, first stabilizing RBD orientation in the autoinhibited state and then contributing to full RAS contact.

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Section: Introductionsupporting

confidence: 87%

Structural insights into the BRAF monomer-to-dimer transition mediated by RAS binding

et al. 2021

Preprint

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“…Another example is A727, which is within a 14-3-3 binding site C-terminal to the kinase domain (Figure 2); it is not clear how its mutation to valine activates B-RAF. Finally, K438 and T439 are outside the kinase domain in a region of B-RAF that is implicated in negative regulation by protein kinase B (Figure 2) (Guan et al, 2000). Presumably, some of the mutants destabilize the inactive conformation through alternative mechanisms, possibly by disrupting intramolecular interactions, or by affecting negative regulation by other pathways, demonstrating that B-RAF can be activated by multiple mechanisms, some of which are not fully understood.…”

Section: A Molecular Understanding Of B-raf Mutationsmentioning

confidence: 99%

Guilty as charged

2004

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RAF proteins are components of a conserved signaling pathway that regulates cellular responses to extracellular signals. Despite over 20 years of research into the regulation and function of the RAF proteins, it was only realized recently that the B-RAF isoform is mutated at a high frequency in human cancer. Here we review the rapid progress made in our understanding of B-RAF as an oncogene and of its role in cancer.

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“…We found that short-term PI3Ki treatment of wild-type mice led to pERK upregulation in the DESC, T-A, and ameloblast regions. PI3K is an upstream regulator of ERK in the mouse laCL, and previous studies have shown crosstalk between the MAPK and PI3K pathways through AKT inhibition of Raf (Guan et al 2000; Reusch et al 2001; Mabuchi et al 2002; El-Naggar et al 2009). Additionally, PI3K inhibitors have been shown to activate MEK and ERK signaling in cancer models (reviewed in Rozengurt et al 2014).…”

Section: Discussionmentioning

confidence: 97%

Ras Signaling Regulates Stem Cells and Amelogenesis in the Mouse Incisor

et al. 2017

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The role of Ras signaling during tooth development is poorly understood. Ras proteins-which are activated by many upstream pathways, including receptor tyrosine kinase cascades-signal through multiple effectors, such as the mitogen-activated protein kinase (MAPK) and PI3K pathways. Here, we utilized the mouse incisor as a model to study how the MAPK and PI3K pathways regulate dental epithelial stem cells and amelogenesis. The rodent incisor-which grows continuously throughout the life of the animal due to the presence of epithelial and mesenchymal stem cells-provides a model for the study of ectodermal organ renewal and regeneration. Utilizing models of Ras dysregulation as well as inhibitors of the MAPK and PI3K pathways, we found that MAPK and PI3K regulate dental epithelial stem cell activity, transit-amplifying cell proliferation, and enamel formation in the mouse incisor.

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Negative Regulation of the Serine/Threonine Kinase B-Raf by Akt

Cited by 208 publications

References 21 publications

Structural insights into the BRAF monomer-to-dimer transition mediated by RAS binding

Structural insights into the BRAF monomer-to-dimer transition mediated by RAS binding

Guilty as charged

Ras Signaling Regulates Stem Cells and Amelogenesis in the Mouse Incisor

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