Regulation of protein prenylation

Jung, Dominik; Bachmann, Hagen S.

doi:10.1016/j.biopha.2023.114915

Cited by 11 publications

(9 citation statements)

References 224 publications

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“…In particular, farnesyl moieties are of great importance, which are attached at the C-terminal CAAX-box of Ras proteins by farnesyl transferases (FTases). FTases (Zn 2+ and Mg 2+ -dependent enzymes) recognize the CAAX-box of Ras and Rho proteins, remove the terminal AAX residues, methylate the C-terminus (methyl ester), and activate the terminal Ras cysteine, which reacts with farnesyl pyrophosphate to form farnesyl thioethers [41]. The hydrophobic C-terminus with the farnesyl moiety efficiently interacts with the lipid bilayers of membranes.…”

Section: Receptor Tyrosine Kinases and Ras/mapk/erk Signalingmentioning

confidence: 99%

Role and Function of Receptor Tyrosine Kinases in BRAF Mutant Cancers

Biersack,

Tahtamouni,

Höpfner

2024

Receptors

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The development of potent BRAF inhibitors has revolutionized the treatment of BRAF mutant cancers, in particular, melanomas. However, BRAF mutant cancers of other entities, e.g., colorectal cancers, display distinctly reduced responses to BRAF inhibitors. In addition, the emergence of cancer resistance to BRAF inhibitor treatment poses a severe problem. The reactivation of MAPK/ERK signaling was identified as an important mode of BRAF inhibitor resistance. Receptor tyrosine kinases (RTKs), which are prominent anticancer drug targets in their own right, play a crucial role in the development of drug resistance to BRAF inhibitors and the reactivation of MAPK/ERK signal transduction, as well as the establishment of bypassing signaling pathways. MAPK reactivation can occur via increased expression of RTKs, altered RTK signaling, and post-translational processes, among others. This review summarizes the influence of pertinent RTKs on BRAF mutant cancers and BRAF inhibitor resistance and outlines possible and proven ways to circumvent BRAF-associated resistance mechanisms.

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Section: Receptor Tyrosine Kinases and Ras/mapk/erk Signalingmentioning

confidence: 99%

Role and Function of Receptor Tyrosine Kinases in BRAF Mutant Cancers

Biersack,

Tahtamouni,

Höpfner

2024

Receptors

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“…Protein prenylation (lipid PTM) is particularly interesting for drug target research, as prenyltransferases (PTases) are involved in many physiological and pathological processes in various species of eukaryotes, including malaria parasites [ 161 , 172 , 173 ]. Prenylation is catalyzed by the soluble PTases farnesyltransferase (FT or FTase) and geranylgeranyltransferase (GGT).…”

Section: Protein Ptms In Plasmodium Parasite Growt...mentioning

confidence: 99%

“…The use of farnesyltransferase inhibitors (e.g., THQ class inhibitor BMS-386914) abolished FCP prenylation and led to its cytosolic mislocalization [ 9 , 179 ]. Interestingly, the activity of protein prenylation enzymes PTases is modulated, in turn, by phosphorylation [ 173 ]. Thus, P.f.…”

Section: Protein Ptms In Plasmodium Parasite Growt...mentioning

confidence: 99%

Post-Translational Modifications of Proteins of Malaria Parasites during the Life Cycle

Schwarzer,

Skorokhod

2024

IJMS

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Post-translational modifications (PTMs) are essential for regulating protein functions, influencing various fundamental processes in eukaryotes. These include, but are not limited to, cell signaling, protein trafficking, the epigenetic control of gene expression, and control of the cell cycle, as well as cell proliferation, differentiation, and interactions between cells. In this review, we discuss protein PTMs that play a key role in the malaria parasite biology and its pathogenesis. Phosphorylation, acetylation, methylation, lipidation and lipoxidation, glycosylation, ubiquitination and sumoylation, nitrosylation and glutathionylation, all of which occur in malarial parasites, are reviewed. We provide information regarding the biological significance of these modifications along all phases of the complex life cycle of Plasmodium spp. Importantly, not only the parasite, but also the host and vector protein PTMs are often crucial for parasite growth and development. In addition to metabolic regulations, protein PTMs can result in epitopes that are able to elicit both innate and adaptive immune responses of the host or vector. We discuss some existing and prospective results from antimalarial drug discovery trials that target various PTM-related processes in the parasite or host.

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“…The modulation of PPT activity can be achieved at two distinct levels: either by an extension of protein substrates used specifically by an enzyme or by using alternative prenyl diphosphate substrates to modify the protein. The CaaX consensus motif (containing three variable residues) is by definition not very stringent and has over the years constantly extended and reevaluated [ 19 ]. A further degree of flexibility, especially in plants, is achieved by the use of the second substrate, prenyl diphosphate.…”

Section: Introductionmentioning

confidence: 99%

Methyl-Jasmonate Functions as a Molecular Switch Promoting Cross-Talk between Pathways for the Biosynthesis of Isoprenoid Backbones Used to Modify Proteins in Plants

Chevalier,

Huchelmann,

Debié

et al. 2024

Plants

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In plants, the plastidial mevalonate (MVA)-independent pathway is required for the modification with geranylgeranyl groups of CaaL-motif proteins, which are substrates of protein geranylgeranyltransferase type-I (PGGT-I). As a consequence, fosmidomycin, a specific inhibitor of 1-deoxy-d-xylulose (DX)-5 phosphate reductoisomerase/DXR, the second enzyme in this so-called methylerythritol phosphate (MEP) pathway, also acts as an effective inhibitor of protein prenylation. This can be visualized in plant cells by confocal microscopy by expressing GFP-CaM-CVIL, a prenylation sensor protein. After treatment with fosmidomycin, the plasma membrane localization of this GFP-based sensor is altered, and a nuclear distribution of fluorescence is observed instead. In tobacco cells, a visual screen of conditions allowing membrane localization in the presence of fosmidomycin identified jasmonic acid methyl esther (MeJA) as a chemical capable of gradually overcoming inhibition. Using Arabidopsis protein prenyltransferase loss-of-function mutant lines expressing GFP-CaM-CVIL proteins, we demonstrated that in the presence of MeJA, protein farnesyltransferase (PFT) can modify the GFP-CaM-CVIL sensor, a substrate the enzyme does not recognize under standard conditions. Similar to MeJA, farnesol and MVA also alter the protein substrate specificity of PFT, whereas DX and geranylgeraniol have limited or no effect. Our data suggest that MeJA adjusts the protein substrate specificity of PFT by promoting a metabolic cross-talk directing the origin of the prenyl group used to modify the protein. MVA, or an MVA-derived metabolite, appears to be a key metabolic intermediate for this change in substrate specificity.

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Regulation of protein prenylation

Cited by 11 publications

References 224 publications

Role and Function of Receptor Tyrosine Kinases in BRAF Mutant Cancers

Role and Function of Receptor Tyrosine Kinases in BRAF Mutant Cancers

Post-Translational Modifications of Proteins of Malaria Parasites during the Life Cycle

Methyl-Jasmonate Functions as a Molecular Switch Promoting Cross-Talk between Pathways for the Biosynthesis of Isoprenoid Backbones Used to Modify Proteins in Plants

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