The 14-3-3 Proteins as Important Allosteric Regulators of Protein Kinases

Obšilová, Veronika; Obšil, Tomáš

doi:10.3390/ijms21228824

Cited by 64 publications

(44 citation statements)

References 114 publications

(186 reference statements)

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“…In the inactive state, 14-3-3 binds to both the C-terminus and the CR2 site in the intervening hinge motifs of a single Raf molecule. [128][129][130][131]. To facilitate 14-3-3 binding, the CR2 site is phosphorylation by several different enzymes, including protein kinase A (PKA) [23,132], AKT [133,134], AMPK [135][136][137] serum/glucocorticoid regulated kinase (SGK) [128] and LATS1 [138].…”

Section: Activation and Regulation Of Raf Proteinmentioning

confidence: 99%

“…[128][129][130][131]. To facilitate 14-3-3 binding, the CR2 site is phosphorylation by several different enzymes, including protein kinase A (PKA) [23,132], AKT [133,134], AMPK [135][136][137] serum/glucocorticoid regulated kinase (SGK) [128] and LATS1 [138]. All parts of this inactivating bundle are oriented by the CRD domain at the center of the complex.…”

Section: Activation and Regulation Of Raf Proteinmentioning

confidence: 99%

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Progress on Ras/MAPK Signaling Research and Targeting in Blood and Solid Cancers

Dillon

López

Lin

et al. 2021

Cancers

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The mitogen-activated protein kinase (MAPK) pathway, consisting of the Ras-Raf-MEK-ERK signaling cascade, regulates genes that control cellular development, differentiation, proliferation, and apoptosis. Within the cascade, multiple isoforms of Ras and Raf each display differences in functionality, efficiency, and, critically, oncogenic potential. According to the NCI, over 30% of all human cancers are driven by Ras genes. This dysfunctional signaling is implicated in a wide variety of leukemias and solid tumors, both with and without viral etiology. Due to the strong evidence of Ras-Raf involvement in tumorigenesis, many have attempted to target the cascade to treat these malignancies. Decades of unsuccessful experimentation had deemed Ras undruggable, but recently, the approval of Sotorasib as the first ever KRas inhibitor represents a monumental breakthrough. This advancement is not without novel challenges. As a G12C mutant-specific drug, it also represents the issue of drug target specificity within Ras pathway; not only do many drugs only affect single mutational profiles, with few pan-inhibitor exceptions, tumor genetic heterogeneity may give rise to drug-resistant profiles. Furthermore, significant challenges in targeting downstream Raf, especially the BRaf isoform, lie in the paradoxical activation of wild-type BRaf by BRaf mutant inhibitors. This literature review will delineate the mechanisms of Ras signaling in the MAPK pathway and its possible oncogenic mutations, illustrate how specific mutations affect the pathogenesis of specific cancers, and compare available and in-development treatments targeting the Ras pathway.

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Section: Activation and Regulation Of Raf Proteinmentioning

confidence: 99%

Section: Activation and Regulation Of Raf Proteinmentioning

confidence: 99%

Progress on Ras/MAPK Signaling Research and Targeting in Blood and Solid Cancers

Dillon

López

Lin

et al. 2021

Cancers

View full text Add to dashboard Cite

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“…The family of 14-3-3 adaptor and chaperon proteins interact with signal-transduction molecules to change their activity and the subcellular localization. This kind of molecule participates in the regulation of several cellular pathways [ 47 ]. The P. falciparum protein 14-3-3 (PF3D7_0818200) has been observed interacting with Pf CDPK1 and was proposed as a target for malaria treatment [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

The search for molecular mimicry in proteins carried by extracellular vesicles secreted by cells infected with Plasmodium falciparum

Armijos-Jaramillo

Mosquera

Rojas

et al. 2021

Communicative & Integrative Biology

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Red blood cells infected with Plasmodium falciparum secrete extracellular vesicles in order to facilitate the survival and infection of human cells. Various researchers have studied the composition of these extracellular vesicles and identified the proteins contained inside. In this work, we used that information to detect potential P. falciparum molecules that could be imitating host proteins. We carried out several searches to detect sequences and structural similarities between the parasite and host. Additionally, the possibility of functional mimicry was explored in line with the potential role that each candidate can perform for the parasite inside the host. Lastly, we determined a set of eight sequences (mainly moonlighting proteins) with a remarkable resemblance to human proteins. Due to the resemblance observed, this study proposes the possibility that certain P. falciparum molecules carried by extracellular vesicles could be imitating human proteins to manipulate the host cell's physiology.

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“…Its activity is sustained by various molecules to acquire more stability, a prolonged half-life and, consequently, increased biochemical activity. In particular 14-3-3 proteins, which are molecular chaperones that interact with many proteins that are involved in signal transduction, are likely the most important [ 29 ]. Their binding during the interphase induces a conformational change at the N-terminal domain of Wee1, hiding its site for degradation.…”

Section: Wee1 Familymentioning

confidence: 99%

Wee1 Kinase: A Potential Target to Overcome Tumor Resistance to Therapy

Esposito¹,

Giuffrida²,

Raciti³

et al. 2021

IJMS

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During the cell cycle, DNA suffers several lesions that need to be repaired prior to entry into mitosis to preserve genome integrity in daughter cells. Toward this aim, cells have developed complex enzymatic machinery, the so-called DNA damage response (DDR), which is able to repair DNA, temporarily stopping the cell cycle to provide more time to repair, or if the damage is too severe, inducing apoptosis. This DDR mechanism is considered the main source of resistance to DNA-damaging therapeutic treatments in oncology. Recently, cancer stem cells (CSCs), which are a small subset of tumor cells, were identified as tumor-initiating cells. CSCs possess self-renewal potential and persistent tumorigenic capacity, allowing for tumor re-growth and relapse. Compared with cancer cells, CSCs are more resistant to therapeutic treatments. Wee1 is the principal gatekeeper for both G2/M and S-phase checkpoints, where it plays a key role in cell cycle regulation and DNA damage repair. From this perspective, Wee1 inhibition might increase the effectiveness of DNA-damaging treatments, such as radiotherapy, forcing tumor cells and CSCs to enter into mitosis, even with damaged DNA, leading to mitotic catastrophe and subsequent cell death.

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The 14-3-3 Proteins as Important Allosteric Regulators of Protein Kinases

Cited by 64 publications

References 114 publications

Progress on Ras/MAPK Signaling Research and Targeting in Blood and Solid Cancers

Progress on Ras/MAPK Signaling Research and Targeting in Blood and Solid Cancers

The search for molecular mimicry in proteins carried by extracellular vesicles secreted by cells infected with Plasmodium falciparum

Wee1 Kinase: A Potential Target to Overcome Tumor Resistance to Therapy

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