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  1. Article ; Online: Regulation of RAF family kinases: new insights from recent structural and biochemical studies.

    Spencer-Smith, Russell / Morrison, Deborah K

    Biochemical Society transactions

    2024  

    Abstract: The RAF kinases are required for signal transduction through the RAS-RAF-MEK-ERK pathway, and their activity is frequently up-regulated in human cancer and the RASopathy developmental syndromes. Due to their complex activation process, developing drugs ... ...

    Abstract The RAF kinases are required for signal transduction through the RAS-RAF-MEK-ERK pathway, and their activity is frequently up-regulated in human cancer and the RASopathy developmental syndromes. Due to their complex activation process, developing drugs that effectively target RAF function has been a challenging endeavor, highlighting the need for a more detailed understanding of RAF regulation. This review will focus on recent structural and biochemical studies that have provided 'snapshots' into the RAF regulatory cycle, revealing structures of the autoinhibited BRAF monomer, active BRAF and CRAF homodimers, as well as HSP90/CDC37 chaperone complexes containing CRAF or BRAFV600E. In addition, we will describe the insights obtained regarding how BRAF transitions between its regulatory states and examine the roles that various BRAF domains and 14-3-3 dimers play in both maintaining BRAF as an autoinhibited monomer and in facilitating its transition to an active dimer. We will also address the function of the HSP90/CDC37 chaperone complex in stabilizing the protein levels of CRAF and certain oncogenic BRAF mutants, and in serving as a platform for RAF dephosphorylation mediated by the PP5 protein phosphatase. Finally, we will discuss the regulatory differences observed between BRAF and CRAF and how these differences impact the function of BRAF and CRAF as drivers of human disease.
    Language English
    Publishing date 2024-05-02
    Publishing country England
    Document type Journal Article
    ZDB-ID 184237-7
    ISSN 1470-8752 ; 0300-5127
    ISSN (online) 1470-8752
    ISSN 0300-5127
    DOI 10.1042/BST20230552
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  2. Article ; Online: A Structure is Worth a Thousand Words: New Insights for RAS and RAF Regulation.

    Simanshu, Dhirendra K / Morrison, Deborah K

    Cancer discovery

    2022  Volume 12, Issue 4, Page(s) 899–912

    Abstract: The RAS GTPases are frequently mutated in human cancer, with KRAS being the predominant tumor driver. For many years, it has been known that the structure and function of RAS are integrally linked, as structural changes induced by GTP binding or ... ...

    Abstract The RAS GTPases are frequently mutated in human cancer, with KRAS being the predominant tumor driver. For many years, it has been known that the structure and function of RAS are integrally linked, as structural changes induced by GTP binding or mutational events determine the ability of RAS to interact with regulators and effectors. Recently, a wealth of information has emerged from structures of specific KRAS mutants and from structures of multiprotein complexes containing RAS and/or RAF, an essential effector of RAS. These structures provide key insights regarding RAS and RAF regulation as well as promising new strategies for therapeutic intervention.
    Significance: The RAS GTPases are major drivers of tumorigenesis, and for RAS proteins to exert their full oncogenic potential, they must interact with the RAF kinases to initiate ERK cascade signaling. Although binding to RAS is typically a prerequisite for RAF to become an activated kinase, determining the molecular mechanisms by which this interaction results in RAF activation has been a challenging task. A major advance in understanding this process and RAF regulation has come from recent structural studies of various RAS and RAF multiprotein signaling complexes, revealing new avenues for drug discovery.
    MeSH term(s) Humans ; MAP Kinase Signaling System ; Oncogenes ; Proto-Oncogene Proteins c-raf/genetics ; Proto-Oncogene Proteins c-raf/metabolism ; Signal Transduction ; raf Kinases/genetics ; raf Kinases/metabolism ; ras Proteins/metabolism
    Chemical Substances Proto-Oncogene Proteins c-raf (EC 2.7.11.1) ; raf Kinases (EC 2.7.11.1) ; ras Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2022-01-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
    ZDB-ID 2625242-9
    ISSN 2159-8290 ; 2159-8274
    ISSN (online) 2159-8290
    ISSN 2159-8274
    DOI 10.1158/2159-8290.CD-21-1494
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 6916: Show issues Location:
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  3. Article ; Online: Protocol for measuring BRAF autoinhibition in live cells using a proximity-based NanoBRET assay.

    Spencer-Smith, Russell / Morrison, Deborah K

    STAR protocols

    2023  Volume 4, Issue 3, Page(s) 102461

    Abstract: BRAF is frequently activated via mutation in human cancer and the RASopathy syndromes; however, for BRAF activation to occur, autoinhibitory interactions between the regulatory and catalytic domains must be relieved. Here, we present a proximity-based ... ...

    Abstract BRAF is frequently activated via mutation in human cancer and the RASopathy syndromes; however, for BRAF activation to occur, autoinhibitory interactions between the regulatory and catalytic domains must be relieved. Here, we present a proximity-based NanoBRET (bioluminescence resonance energy transfer) assay for real-time measurement of BRAF autoinhibition in live cells. We describe steps for seeding, transfecting, and replating cells. We then detail procedures for reading the NanoBRET emissions and confirming protein expression. For complete details on the use and execution of this protocol, please refer to Spencer-Smith et al. (2022).
    MeSH term(s) Humans ; Proto-Oncogene Proteins B-raf/genetics ; Biological Assay ; Mutation
    Chemical Substances Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; BRAF protein, human (EC 2.7.11.1)
    Language English
    Publishing date 2023-08-16
    Publishing country United States
    Document type Journal Article
    ISSN 2666-1667
    ISSN (online) 2666-1667
    DOI 10.1016/j.xpro.2023.102461
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Protocol for measuring BRAF autoinhibition in live cells using a proximity-based NanoBRET assay

    Russell Spencer-Smith / Deborah K. Morrison

    STAR Protocols, Vol 4, Iss 3, Pp 102461- (2023)

    2023  

    Abstract: Summary: BRAF is frequently activated via mutation in human cancer and the RASopathy syndromes; however, for BRAF activation to occur, autoinhibitory interactions between the regulatory and catalytic domains must be relieved. Here, we present a proximity- ...

    Abstract Summary: BRAF is frequently activated via mutation in human cancer and the RASopathy syndromes; however, for BRAF activation to occur, autoinhibitory interactions between the regulatory and catalytic domains must be relieved. Here, we present a proximity-based NanoBRET (bioluminescence resonance energy transfer) assay for real-time measurement of BRAF autoinhibition in live cells. We describe steps for seeding, transfecting, and replating cells. We then detail procedures for reading the NanoBRET emissions and confirming protein expression.For complete details on the use and execution of this protocol, please refer to Spencer-Smith et al. (2022).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.
    Keywords Cell Biology ; Cell-based Assays ; Cancer ; Signal Transduction ; Protein Biochemistry ; Science (General) ; Q1-390
    Language English
    Publishing date 2023-09-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Using Comic-Based Concussion Discharge Instructions to Address Caregiver Health Literacy in the Emergency Department.

    Pham, Tom N / Morrison, Andrea K / Menard, Michael S / Martinez, Deborah / Thomas, Danny G

    Journal of emergency nursing

    2023  Volume 49, Issue 2, Page(s) 236–243

    Abstract: Introduction: This study compared the effectiveness of comic-based with text-based concussion discharge instructions on improving caregiver knowledge. This study also examined the role of social determinants of health on comprehension instructions.: ... ...

    Abstract Introduction: This study compared the effectiveness of comic-based with text-based concussion discharge instructions on improving caregiver knowledge. This study also examined the role of social determinants of health on comprehension instructions.
    Methods: This was an observational study of the caregivers of pediatric concussion patients. Caregivers' health literacy and demographics related socioeconomic factors were obtained. After the patients' evaluation in the emergency department, caregivers were given printed comic-based concussion discharge instructions. Caregivers were contacted 3 days later and tested overall knowledge of discharge instructions' content. These survey results were compared with historical controls who received text-based instructions.
    Results: A total of 120 participants were recruited, and 86 participants completed follow-up procedures. When comparing the caregivers' recall ability with a comic-based vs traditional text-based instructions, caregivers with comic-based content were more likely to accurately recall overall discharge instructions (77.5% vs 44%, P < .001), particularly physical rest and activity restrictions (86.5% vs 63%, P < .001). Caregivers also were less likely to misidentify a red flag symptom (7.5% vs 19%, P < .04). Comic-based instructions did not increase recall of cognitive rest instructions or postconcussive symptoms. When examining demographic factors, caregivers who could not recall 3 postconcussive symptoms were more likely to be Hispanic or Black, less likely to be college educated, and more likely to have low health literacy.
    Discussion: Novel methods should be explored to adequately prepare caregivers for continuing postconcussive care at home. Discharge instructions must be tailored to address caregivers' baseline health literacy and how caregivers digest and retain information.
    MeSH term(s) Humans ; Child ; Patient Discharge ; Caregivers ; Health Literacy ; Brain Concussion ; Emergency Service, Hospital
    Language English
    Publishing date 2023-01-04
    Publishing country United States
    Document type Observational Study ; Journal Article
    ZDB-ID 604632-0
    ISSN 1527-2966 ; 0099-1767
    ISSN (online) 1527-2966
    ISSN 0099-1767
    DOI 10.1016/j.jen.2022.12.006
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  6. Article ; Online: Ras-Mediated Activation of the Raf Family Kinases.

    Terrell, Elizabeth M / Morrison, Deborah K

    Cold Spring Harbor perspectives in medicine

    2019  Volume 9, Issue 1

    Abstract: The extracellular signal-regulated kinase (ERK) cascade comprised of the Raf, MEK, and ERK protein kinases constitutes a key effector cascade used by the Ras GTPases to relay signals regulating cell growth, survival, proliferation, and differentiation. ... ...

    Abstract The extracellular signal-regulated kinase (ERK) cascade comprised of the Raf, MEK, and ERK protein kinases constitutes a key effector cascade used by the Ras GTPases to relay signals regulating cell growth, survival, proliferation, and differentiation. Of the ERK cascade components, the regulation of the Raf kinases is by far the most complex, involving changes in subcellular localization, protein and lipid interactions, as well as alterations in the Raf phosphorylation state. The Raf kinases interact directly with active, membrane-localized Ras, and this interaction is often the first step in the Raf activation process, which ultimately results in ERK activation and the downstream phosphorylation of cellular targets that will specify a particular biological response. Here, we will examine our current understanding of how Ras promotes Raf activation, focusing on the molecular mechanisms that contribute to the Raf activation/inactivation cycle.
    MeSH term(s) Animals ; Cell Proliferation ; Dimerization ; Germ-Line Mutation ; Humans ; MAP Kinase Signaling System ; Signal Transduction ; raf Kinases/metabolism
    Chemical Substances raf Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2019-01-02
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 2157-1422
    ISSN (online) 2157-1422
    DOI 10.1101/cshperspect.a033746
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Structural insights into the BRAF monomer-to-dimer transition mediated by RAS binding.

    Martinez Fiesco, Juliana A / Durrant, David E / Morrison, Deborah K / Zhang, Ping

    Nature communications

    2022  Volume 13, Issue 1, Page(s) 486

    Abstract: RAF kinases are essential effectors of RAS, but how RAS binding initiates the conformational changes needed for autoinhibited RAF monomers to form active dimers has remained unclear. Here, we present cryo-electron microscopy structures of full-length ... ...

    Abstract RAF kinases are essential effectors of RAS, but how RAS binding initiates the conformational changes needed for autoinhibited RAF monomers to form active dimers has remained unclear. Here, we present cryo-electron microscopy structures of full-length BRAF complexes derived from mammalian cells: autoinhibited, monomeric BRAF:14-3-3
    MeSH term(s) 14-3-3 Proteins/chemistry ; 14-3-3 Proteins/metabolism ; Animals ; Cell Line ; Cryoelectron Microscopy/methods ; Humans ; Mice ; Mutation ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/pathology ; Protein Conformation ; Protein Multimerization ; Proto-Oncogene Proteins B-raf/chemistry ; Proto-Oncogene Proteins B-raf/metabolism ; Proto-Oncogene Proteins p21(ras)/chemistry ; Proto-Oncogene Proteins p21(ras)/metabolism
    Chemical Substances 14-3-3 Proteins ; KRAS protein, human ; YWHAZ protein, human ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
    Language English
    Publishing date 2022-01-25
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Intramural
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-022-28084-3
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  8. Article ; Online: RAS signaling: Divide and conquer.

    Holderfield, Matthew / Morrison, Deborah K

    Nature chemical biology

    2016  Volume 13, Issue 1, Page(s) 7–8

    MeSH term(s) Allosteric Site ; Signal Transduction
    Language English
    Publishing date 2016-10-29
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 2202962-X
    ISSN 1552-4469 ; 1552-4450
    ISSN (online) 1552-4469
    ISSN 1552-4450
    DOI 10.1038/nchembio.2264
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  9. Article ; Online: Structural insights into the BRAF monomer-to-dimer transition mediated by RAS binding

    Juliana A. Martinez Fiesco / David E. Durrant / Deborah K. Morrison / Ping Zhang

    Nature Communications, Vol 13, Iss 1, Pp 1-

    2022  Volume 14

    Abstract: RAF kinases are essential for RAS protein signalling but how RAS binding regulates dimerization and activation of RAF has remained unclear. Here, the authors report cryoEM structures that provide mechanistic insights into the RAS-mediated monomer-to- ... ...

    Abstract RAF kinases are essential for RAS protein signalling but how RAS binding regulates dimerization and activation of RAF has remained unclear. Here, the authors report cryoEM structures that provide mechanistic insights into the RAS-mediated monomer-to-dimer transition of full-length BRAF.
    Keywords Science ; Q
    Language English
    Publishing date 2022-01-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
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  10. Article ; Online: MAP kinase pathways.

    Morrison, Deborah K

    Cold Spring Harbor perspectives in biology

    2012  Volume 4, Issue 11

    MeSH term(s) Cell Death/physiology ; Cell Differentiation/physiology ; Cell Proliferation ; Enzyme Activation/physiology ; Mitogen-Activated Protein Kinases/metabolism ; Mitogen-Activated Protein Kinases/physiology ; Models, Biological ; Phosphorylation ; Signal Transduction/physiology
    Chemical Substances Mitogen-Activated Protein Kinases (EC 2.7.11.24)
    Language English
    Publishing date 2012-11-01
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 1943-0264
    ISSN (online) 1943-0264
    DOI 10.1101/cshperspect.a011254
    Database MEDical Literature Analysis and Retrieval System OnLINE

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