The Autodepalmitoylating Activity of APT Maintains the Spatial Organization of Palmitoylated Membrane Proteins

Vartak, Nachiket; Papke, Bjoern; Grecco, Hernán E.; Roßmannek, Lisaweta; Waldmann, Herbert; Hedberg, Christian; Bastiaens, Philippe I. H.

doi:10.1016/j.bpj.2013.11.024

Cited by 79 publications

(78 citation statements)

References 41 publications

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“…1G, H). However, ectopic expression of a catalytically inactive mutant form of APT1, in Ser 119 in the catalytic domain is mutated to Ala (APT1 S119A ) (40, 41), failed to rescue asymmetric Numb and β-catenin localization (fig. S1B; Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Using human cancer cell lines derived from malignant tumors that exhibit high cellular heterogeneity, such as triple receptor–negative breast cancers and osteosarcomas (34–38), we found that the depalmitoylating enzyme acyl-protein thioesterase 1 (APT1) (39–41), directs the asymmetric localization of Numb and β-catenin. Additionally, we found that APT1 activity during mitosis restricted Notch-, Wnt-, and Sox2-dependent transcription to one daughter cell.…”

Section: Introductionmentioning

confidence: 99%

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The depalmitoylase APT1 directs the asymmetric partitioning of Notch and Wnt signaling during cell division

2018

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Asymmetric cell division results in two distinctly fated daughter cells. A molecular hallmark of asymmetric division is the unequal partitioning of cell fate determinants. We have previously established that growth factor signaling promotes protein depalmitoylation to foster polarized protein localization, which in turns drives migration and metastasis. Here, we report protein palmitoylation as a key mechanism for the asymmetric partitioning of the cell fate determinants Numb and β-catenin through the activity of the depalmitoylating enzyme APT1. Using point mutations, we show specific palmitoylated residues on Numb are required for asymmetric localization. By live-cell imaging, we show that reciprocal interactions between APT1 and the Rho-family GTPase CDC42 promote the asymmetric localization of Numb and β-catenin to the plasma membrane. This in turn restricts Notch- and Wnt-responsive transcriptional activity to one daughter cell. Moreover, we show altering APT1 expression changes the transcriptional signatures of MDA-MB-231 triple receptor–negative breast cancer cells similarly to changes in Notch and β-catenin–mediated Wnt signaling. We also show that loss of APT1 depletes a specific subpopulation of tumorigenic cells in colony formation assays. Together, our findings demonstrate that APT1-mediated depalmitoylation is a major mechanism of asymmetric cell division maintaining Notch and Wnt-associated protein dynamics, gene expression, and cellular functions.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The depalmitoylase APT1 directs the asymmetric partitioning of Notch and Wnt signaling during cell division

2018

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“…This process is facilitated by acyl protein thioesterase 1 (APT1, also known as lysophospholipase 1, LYPLA1) and possibly also APT2, which are themselves reversibly S-acylated (73). The existence of APT in both palmitoylated Golgi-bound and nonpalmitoylated cytosolic pools (74) due to autodepalmitoylating activity of APTs (74) may explain how cytosolic (nonpalmitoylated) APT can promote cycling of palmitoylatable isoforms of RAS proteins to and from membranes, ultimately resulting in enrichment of the palmitoylated forms at the PM and Golgi (72,74). These features provide the rationale for development of APT1/2 inhibitors as potential anti-RAS agents.…”

Section: Targeting Ras Trafficking By Disrupting Depalmitoylation: Apmentioning

confidence: 99%

Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?

Cox

Der

Philips

2015

Clinical Cancer Research

323

292

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RAS proteins require membrane association for their biological activity, making this association a logical target for anti-RAS therapeutics. Lipid modification of RAS proteins by a farnesyl isoprenoid is an obligate step in that association, and is an enzymatic process. Accordingly, farnesyltransferase inhibitors (FTIs) were developed as potential anti-RAS drugs. The lack of efficacy of FTIs as anti-cancer drugs was widely seen as indicating that blocking RAS membrane association was a flawed approach to cancer treatment. However, a deeper understanding of RAS modification and trafficking has revealed that this was an erroneous conclusion. In the presence of FTIs, KRAS and NRAS, which are the RAS isoforms most frequently mutated in cancer, become substrates for alternative modification, can still associate with membranes, and can still function. Thus, FTIs failed not because blocking RAS membrane association is an ineffective approach, but because FTIs failed to accomplish that task. Recent findings regarding RAS isoform trafficking and the regulation of RAS subcellular localization have rekindled interest in efforts to target these processes. In particular, improved understanding of the palmitoylation/depalmitoylation cycle that regulates RAS interaction with the plasma membrane, endomembranes and cytosol, and of the potential importance of RAS chaperones, have led to new approaches. Efforts to validate and target other enzymatically regulated post-translational modifications are also ongoing. In this review, we revisit lessons learned, describe the current state of the art, and highlight challenging but promising directions to achieve the goal of disrupting RAS membrane association and subcellular localization for anti-RAS drug development.

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“…APT1 can also depalmitoylate itself as well as APT2, promoting membrane to cytosol shuttling. An alternative view proposes that the soluble, non-palmitoylated forms of APT are responsible for depalmitoylation of membrane-bound substrates and that this serves to remove non-specifically adsorbed Ras proteins from all internal membranes and enable them to be concentrated on the plasma membrane[82]. …”

Section: Protein Palmitoylationmentioning

confidence: 99%

Fatty acylation of proteins: The long and the short of it

Resh

2016

Progress in Lipid Research

238

235

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Long, short and medium chain fatty acids are covalently attached to hundreds of proteins. Each fatty acid confers distinct biochemical properties, enabling fatty acylation to regulate intracellular trafficking, subcellular localization, protein-protein and protein-lipid interactions. Myristate and palmitate represent the most common fatty acid modifying groups. New insights into how fatty acylation reactions are catalyzed, and how fatty acylation regulates protein structure and function continue to emerge. Myristate is typically linked to an N-terminal glycine, but recent studies reveal that lysines can also be myristoylated. Enzymes that remove N-terminal myristoyl-glycine or myristate from lysines have now been identified. DHHC proteins catalyze S-palmitoylation, but the mechanisms that regulate substrate recognition by individual DHHC family members remain to be determined. New studies continue to reveal thioesterases that remove palmitate from S-acylated proteins. Another area of rapid expansion is fatty acylation of the secreted proteins Hedgehog, Wnt and Ghrelin, by Hhat, Porcupine and GOAT, respectively. Understanding how these membrane bound O-acyl transferases recognize their protein and fatty acyl CoA substrates is an active area of investigation, and is punctuated by the finding that these enzymes are potential drug targets in human diseases.

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The Autodepalmitoylating Activity of APT Maintains the Spatial Organization of Palmitoylated Membrane Proteins

Cited by 79 publications

References 41 publications

The depalmitoylase APT1 directs the asymmetric partitioning of Notch and Wnt signaling during cell division

The depalmitoylase APT1 directs the asymmetric partitioning of Notch and Wnt signaling during cell division

Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?

Fatty acylation of proteins: The long and the short of it

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