Molecular analyses of the C-terminal CRAF variants associated with cardiomyopathy reveal their opposing impacts on the active conformation of the kinase domain

Nakhaei‐Rad, Saeideh; Janati-Fard, Fatemeh; Dvorský, Radovan; Ahmadian, Mohammad Réza; Housaindokht, Mohammad Reza

doi:10.1080/07391102.2023.2187221

Cited by 2 publications

(2 citation statements)

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“…C-RAF (often also called RAF1) belongs to the RAF kinase family (A-RAF, B-RAF, and C-RAF), which transfers proliferative and growth signals to downstream activation of MEK/ERK kinases. These RAF paralogs share several structural properties ( Rezaei Adariani et al, 2018 ; Nakhaei-Rad et al, 2023b ), yet they differ in terms of activity levels and functional roles ( Desideri et al, 2015 ). Among them, C-RAF exhibits moderate activity, less than B-RAF, but more than A-RAF, and is associated with cancer and developmental disorders ( Blasco et al, 2011 ; Karreth et al, 2011 ; Gelb et al, 2015 ; Degirmenci et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

SIRT4 as a novel interactor and candidate suppressor of C-RAF kinase in MAPK signaling

Mehrabipour,

Nakhaei-Rad,

Dvorsky

et al. 2024

Life Sci. Alliance

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Cellular responses leading to development, proliferation, and differentiation depend on RAF/MEK/ERK signaling, which integrates and amplifies signals from various stimuli for downstream cellular responses. C-RAF activation has been reported in many types of tumor cell proliferation and developmental disorders, necessitating the discovery of potential C-RAF protein regulators. Here, we identify a novel and specific protein interaction between C-RAF among the RAF kinase paralogs, and SIRT4 among the mitochondrial sirtuin family members SIRT3, SIRT4, and SIRT5. Structurally, C-RAF binds to SIRT4 through the N-terminal cysteine-rich domain, whereas SIRT4 predominantly requires the C-terminus for full interaction with C-RAF. Interestingly, SIRT4 specifically interacts with C-RAF in a pre-signaling inactive (serine 259–phosphorylated) state. Consistent with this finding, the expression of SIRT4 in HEK293 cells results in an up-regulation of pS259-C-RAF levels and a concomitant reduction in MAPK signaling as evidenced by strongly decreased phospho-ERK signals. Thus, we propose an additional extra-mitochondrial function of SIRT4 as a cytosolic tumor suppressor of C-RAF-MAPK signaling, besides its metabolic tumor suppressor role of glutamate dehydrogenase and glutamate levels in mitochondria.

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Section: Introductionmentioning

confidence: 99%

SIRT4 as a novel interactor and candidate suppressor of C-RAF kinase in MAPK signaling

Mehrabipour,

Nakhaei-Rad,

Dvorsky

et al. 2024

Life Sci. Alliance

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show abstract

“…C-RAF (often also called RAF1) belongs to the RAF kinases family (A-RAF, B-RAF, and C-RAF) which transfer proliferative and growth signals to downstream activation of MEK/ERK kinases. These RAF paralogs share several structural properties (1,2), yet they differ in terms of activity levels and functional roles (3). Among them, C-RAF exhibits moderate activity, less than B-RAF, but more than A-RAF, and is associated with cancer and developmental disorders (4–7).…”

Section: Introductionmentioning

confidence: 99%

Identification of SIRT4 as a novel paralog-specific interactor and candidate suppressor of C-RAF kinase in MAPK signaling

Mehrabipour,

Dvorsky,

Nakhaei-Rad

et al. 2023

Preprint

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Cellular responses leading to development, proliferation, and differentiation rely on RAF/MEK/ERK signaling that integrates and amplifies signals from various stimuli to cellular downstream responses. The clinical significance of C-RAF activation has been reported in many types of tumor cell proliferation and developmental disorders, which requires the discovery of potential C-RAF protein regulators. Here, we identify a novel and specific protein interaction between C-RAF, among the RAF kinase paralogs, and SIRT4 among the mitochondrial sirtuin family members SIRT3, SIRT4, and SIRT5. Structurally, C-RAF binds to SIRT4 through the N-terminal cysteine-rich domain (CRD; a.a. 136-187), and on the other side, SIRT4 requires predominantly the C-terminus (a.a. 255-314) for full interaction with C-RAF. Interestingly, SIRT4 interacts specifically with C-RAF in a pre-signaling inactive (serine 259 phosphorylated) state. Consistent with this finding, ectopic expression of SIRT4 in HEK293 cells results in upregulation of pS259-C-RAF levels and concomitant reduction of MAPK signaling as evidenced by strongly decreased phospho-ERK signals. Thus, our findings propose another extra-mitochondrial role of SIRT4 and suggest that SIRT4 functions as a cytosolic tumor suppressor of C-RAF-MAPK signaling, besides its known metabolic tumor suppressor role towards glutamate dehydrogenase and glutamine levels in mitochondria.

show abstract

Molecular analyses of the C-terminal CRAF variants associated with cardiomyopathy reveal their opposing impacts on the active conformation of the kinase domain

Cited by 2 publications

References 49 publications

SIRT4 as a novel interactor and candidate suppressor of C-RAF kinase in MAPK signaling

SIRT4 as a novel interactor and candidate suppressor of C-RAF kinase in MAPK signaling

Identification of SIRT4 as a novel paralog-specific interactor and candidate suppressor of C-RAF kinase in MAPK signaling

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