Targeting protein prenylation for cancer therapy

Berndt, Norbert; Hamilton, Andrew D.; Sebti, Saı̈d M.

doi:10.1038/nrc3151

Cited by 501 publications

(513 citation statements)

References 202 publications

(197 reference statements)

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“…ICMT is the only cellular enzyme known to methylate prenylcysteine substrates; methylation is important for their biological functions, including the membrane localisations and subsequent activities of Ras 1 , prelamin A 3 , and Rab 4 . ICMT inhibition has potential for combating progeria 3 and cancer 5–8 . Here we present an X-ray structure of ICMT, at 2.3 Å resolution, in complex with its cofactor, an ordered lipid molecule and a monobody inhibitor.…”

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confidence: 99%

Atomic structure of the eukaryotic intramembrane RAS methyltransferase ICMT

Diver

Pedi

Koide

et al. 2018

Nature

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The maturation of Ras GTPases, and ~200 other cellular CaaX proteins, involves three enzymatic steps: addition of a farnesyl or geranylgeranyl prenyl lipid to the cysteine (C) in the C-terminal CaaX motif, proteolytic cleavage of the aaX residues, and methylation of the exposed prenylcysteine residue at its terminal carboxylate1. This final step is catalyzed by isoprenylcysteine carboxyl methyltransferase (ICMT), a eukaryotic-specific integral membrane enzyme of the endoplasmic reticulum (ER)2. ICMT is the only cellular enzyme known to methylate prenylcysteine substrates; methylation is important for their biological functions, including the membrane localisations and subsequent activities of Ras1, prelamin A3, and Rab4. ICMT inhibition has potential for combating progeria3 and cancer5–8. Here we present an X-ray structure of ICMT, at 2.3 Å resolution, in complex with its cofactor, an ordered lipid molecule and a monobody inhibitor. The active site spans cytosolic and membrane-exposed regions, indicating distinct entry routes for its cytosolic methyl donor, S-adenosyl-L-methionine (AdoMet), and for prenylcysteine substrates, which are associated with the ER membrane. The structure suggests how ICMT overcomes the topographical challenge and unfavourable energetics of bringing two reactants that have different cellular localisations together in a membrane environment – a relatively uncharacterized, but defining feature of many integral membrane enzymes.

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confidence: 99%

Atomic structure of the eukaryotic intramembrane RAS methyltransferase ICMT

Diver

Pedi

Koide

et al. 2018

Nature

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“…The TSC1/2 complex is an established mTORC1 suppressor, and its protein destabilization via extracellular-signalregulated kinase (ERK) activates mTORC1 (2). Because the GTPbound form of Ras interacts with and activates PI3K and ERK, Ras is also an activator of mTORC1 (3).…”

mentioning

confidence: 99%

Loss of mTOR complex 1 induces developmental blockage in early T-lymphopoiesis and eradicates T-cell acute lymphoblastic leukemia cells

Hoshii

Kasada

Hatakeyama

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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mTOR is an evolutionarily conserved kinase that plays a critical role in sensing and responding to environmental determinants. Recent studies have shown that fine-tuning of the activity of mTOR complexes contributes to organogenesis and tumorigenesis. Although rapamycin, an allosteric mTOR inhibitor, is an effective immunosuppressant, the precise roles of mTOR complexes in early T-cell development remain unclear. Here we show that mTORC1 plays a critical role in the development of both early T-cell progenitors and leukemia. Deletion of Raptor, an essential component of mTORC1, produced defects in the earliest development of T-cell progenitors in vivo and in vitro. Deficiency of Raptor resulted in cell cycle abnormalities in early T-cell progenitors that were associated with instability of the Cyclin D2/D3-CDK6 complexes; deficiency of Rictor, an mTORC2 component, did not have the same effect, indicating that mTORC1 and -2 control T-cell development in different ways. In a model of myeloproliferative neoplasm and T-cell acute lymphoblastic leukemia (T-ALL) evoked by Kras activation, Raptor deficiency dramatically inhibited the cell cycle in oncogenic Kras-expressing T-cell progenitors, but not myeloid progenitors, and specifically prevented the development of T-ALL. Although rapamycin treatment significantly prolonged the survival of recipient mice bearing T-ALL cells, rapamycin-insensitive leukemia cells continued to propagate in vivo. In contrast, Raptor deficiency in the T-ALL model resulted in cell cycle arrest and efficient eradication of leukemia. Thus, understanding the cell-contextdependent role of mTORC1 illustrates the potential importance of mTOR signals as therapeutic targets.

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“…Prenylated proteins have important and diverse roles in eukaryotic biology, as exemplified by small GTPases such as K/H/Ras in cell growth (2), Rabfamily proteins in membrane trafficking (3), and lamin isoforms in nuclear matrix homeostasis (4). Because aberrant expression or mutation of prenylated proteins like K-Ras and lamin A are major drivers of human diseases like cancer or progeria, respectively, prenyltransferase inhibitors that interfere with lipidation of these proteins and their function are under clinical development (5,6). In addition to cellular proteins, virulence factors from viruses (7)(8)(9)(10) and bacterial pathogens (11)(12)(13)(14) can be S-prenylated by host enzymes to enhance microbial infection.…”

mentioning

confidence: 99%

Prenylome profiling reveals S-farnesylation is crucial for membrane targeting and antiviral activity of ZAP long-isoform

Charron

MacDonald

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

111

159

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S-prenylation is an important lipid modification that targets proteins to membranes for cell signaling and vesicle trafficking in eukaryotes. As S-prenylated proteins are often key effectors for oncogenesis, congenital disorders, and microbial pathogenesis, robust proteomic methods are still needed to biochemically characterize these lipidated proteins in specific cell types and disease states. Here, we report that bioorthogonal proteomics of macrophages with an improved alkyne-isoprenoid chemical reporter enables large-scale profiling of prenylated proteins, as well as the discovery of unannotated lipidated proteins such as isoform-specific S-farnesylation of zinc-finger antiviral protein (ZAP). Notably, S-farnesylation was crucial for targeting the long-isoform of ZAP (ZAPL/PARP-13.1/zc3hav1) to endolysosomes and enhancing the antiviral activity of this immune effector. These studies demonstrate the utility of isoprenoid chemical reporters for proteomic analysis of prenylated proteins and reveal a role for protein prenylation in host defense against viral infections.

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Targeting protein prenylation for cancer therapy

Cited by 501 publications

References 202 publications

Atomic structure of the eukaryotic intramembrane RAS methyltransferase ICMT

Atomic structure of the eukaryotic intramembrane RAS methyltransferase ICMT

Loss of mTOR complex 1 induces developmental blockage in early T-lymphopoiesis and eradicates T-cell acute lymphoblastic leukemia cells

Prenylome profiling reveals S-farnesylation is crucial for membrane targeting and antiviral activity of ZAP long-isoform

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