Depalmitoylated Ras traffics to and from the Golgi complex via a nonvesicular pathway

Goodwin, J. Shawn; Drake, Kimberly R.; Rogers, Carl E.; Wright, Latasha; Lippincott‐Schwartz, Jennifer; Philips, Mark R.; Kenworthy, Anne K.

doi:10.1083/jcb.200502063

Cited by 264 publications

(286 citation statements)

References 76 publications

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“…2). [25,26] Non-palmitoylated K-Ras4B also traffics back and forth from the PM, although by other mechanisms: phosphorylation of K-Ras4B by PKC promotes its release from the PM and its transfer to mitochondria. [27] Calmodulin binding to K-Ras4B also dislodges it from the PM, facilitating its translocation to the GC and to early endosomes.…”

Section: Ras: An Actor On Many Stagesmentioning

confidence: 99%

The Ras‐ERK pathway: Understanding site‐specific signaling provides hope of new anti‐tumor therapies

2010

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Recent discoveries have suggested the concept that intracellular signals are the sum of multiple, site-specified subsignals, rather than single, homogeneous entities. In the context of cancer, searching for compounds that selectively block subsignals essential for tumor progression, but not those regulating ''house-keeping'' functions, could help in producing drugs with reduced side effects compared to compounds that block signaling completely. The Ras-ERK pathway has become a paradigm of how space can differentially shape signaling. Today, we know that Ras proteins are found in different plasma membrane microdomains and endomembranes. At these localizations, Ras is subject to site-specific regulatory mechanisms, distinctively engaging effector pathways and switching-on diverse genetic programs to generate different biological responses. The Ras effector pathway leading to ERKs activation is also under strict, space-related regulatory processes. These findings may open a gate for aiming at the Ras-ERK pathway in a spatially restricted fashion, in our quest for new anti-tumor therapies.

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Section: Ras: An Actor On Many Stagesmentioning

confidence: 99%

The Ras‐ERK pathway: Understanding site‐specific signaling provides hope of new anti‐tumor therapies

2010

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“…The importance of Ras palmitoylation has also been recently highlighted in studies on the regulation of its localization and activity [65][66][67][68] . Some of these studies used semisynthetic proteins, whereas others used fluorescently labeled proteins 67 .…”

Section: Palmitoylation Of Prenylated Proteinsmentioning

confidence: 99%

“…The complex also shows substrate selectivity for the C terminus of Ras proteins, which suggests that it is a human ortholog of the yeast palmitoyltransferase. The localization of the protein complex in the Golgi suggests that it is an important contributor to the control of Ras palmitoylation in vivo.The importance of Ras palmitoylation has also been recently highlighted in studies on the regulation of its localization and activity [65][66][67][68] . Some of these studies used semisynthetic proteins, whereas others used fluorescently labeled proteins 67 .…”

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confidence: 99%

Therapeutic intervention based on protein prenylation and associated modifications

et al. 2006

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In eukaryotic cells, a specific set of proteins are modified by C-terminal attachment of 15-carbon farnesyl groups or 20-carbon geranylgeranyl groups that function both as anchors for fixing proteins to membranes and as molecular handles for facilitating binding of these lipidated proteins to other proteins. Additional modification of these prenylated proteins includes C-terminal proteolysis and methylation, and attachment of a 16-carbon palmitoyl group; these modifications augment membrane anchoring and alter the dynamics of movement of proteins between different cellular membrane compartments. The enzymes in the protein prenylation pathway have been isolated and characterized. Blocking protein prenylation is proving to be therapeutically useful for the treatment of certain cancers, infection by protozoan parasites and the rare genetic disease Hutchinson-Gilford progeria syndrome.Isoprenoids are lipids made of five-carbon blocks, and they constitute one of the main classes of natural products. A subset of isoprenoids called prenyl groups are found on a variety of biological substances, including proteins. Prenylated proteins and peptides are found in most (if not all) eukaryotes. They arise from the post-translational attachment of 15-carbon farnesyl or 20-carbon geranylgeranyl groups to the C-terminal segment of proteins. Protein prenyl groups not only are hydrophobic elements that bind proteins to membranes, but, at least in some cases, they also function as molecular handles that bind to hydrophobic grooves on the surface of soluble protein factors; these factors then remove the prenylated protein from the membrane in a regulated manner. NIH Public Access Author ManuscriptNat Chem Biol. Author manuscript; available in PMC 2010 June 28. Published in final edited form as:Nat Chem Biol. 2006 October ; 2(10): 518-528. doi:10.1038/nchembio818. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptProtein prenylation has been vigorously studied over the past ~15 years because it is found on several signaling proteins (including heterotrimeric G proteins) that connect cell surface receptors to intracellular effectors, and also on Ras proteins, one of the most common oncoproteins found in human tumors. Ras proteins serve as molecular switches at cellular membranes to control propagation of growth signals from cell surface receptors to nuclear transcription factors. Because Ras mutations are important in many human cancers, there has been extensive focus on Ras prenylation. Discovery of protein prenyl groups and structural varietiesThe first reports of prenylated proteins and peptides described the secreted pheromone peptides from jelly fungi 1,2 , whose structure resembles that of the well-known a-factor mating pheromone from baker's yeast (Saccharomyces cerevisiae), which contains a cysteine methylester farnesylated at the C terminus 3 . In the 1980s, studies on the timing of cholesterol biosynthesis with respect to the cell cycle in human cells led to the discovery that a compound deriv...

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“…The palmitoylation-depalmitoylation cycle allows them to shuttle between the plasma membrane and the endomembranes of the Golgi apparatus and Endoplasmic Reticulum. 22 K-Ras4B, on the other hand, lacks palmitoyl groups in its HVR. Instead, a polylysine patch in the K-Ras4B HVR, in addition to the farnesyl group, assists in binding the membrane.…”

Section: Interaction Of Ras Gtpases With Different Membrane Microdomainsmentioning

confidence: 99%

Plasma membrane regulates Ras signaling networks

et al. 2015

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Depalmitoylated Ras traffics to and from the Golgi complex via a nonvesicular pathway

Cited by 264 publications

References 76 publications

The Ras‐ERK pathway: Understanding site‐specific signaling provides hope of new anti‐tumor therapies

The Ras‐ERK pathway: Understanding site‐specific signaling provides hope of new anti‐tumor therapies

Therapeutic intervention based on protein prenylation and associated modifications

Plasma membrane regulates Ras signaling networks

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