The Lyn kinase C-lobe mediates Golgi export of Lyn through conformation-dependent ACSL3 association

Obata, Yuichi; Fukumoto, Yasunori; Nakayama, Yuji; Kuga, Tetsurō; Dohmae, Naoshi; Yamaguchi, Naoto

doi:10.1242/jcs.066266

Cited by 40 publications

(24 citation statements)

References 68 publications

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“…ACSL3 also interacts with the Src-family tyrosine kinase Lyn in the Golgi of HeLa and COS-1 cells and allows Lyn to be transported to the plasma membrane (149). Because a mutant of ACSL3 that lacks the AMP/ATP-binding motif can still function for Lyn transport, it was concluded that ACSL activity was not required for this role, however, enzyme activity was not measured (149).…”

Section: Long-chain Acyl-coa Synthetasesmentioning

confidence: 99%

“…Because a mutant of ACSL3 that lacks the AMP/ATP-binding motif can still function for Lyn transport, it was concluded that ACSL activity was not required for this role, however, enzyme activity was not measured (149). Although mammalian synthesis of 4 and 16-carbon acyl-CoAs for protein acylation have not been described, in Xenopus, triacsin C-mediated inhibition of ACSL activity blocks the palmitoylation of Gα (197).…”

Section: Long-chain Acyl-coa Synthetasesmentioning

confidence: 99%

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Acyl-CoA Metabolism and Partitioning

Grevengoed¹,

Klett

Coleman³

2014

Annu. Rev. Nutr.

365

330

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Long-chain fatty acyl-CoAs are critical regulatory molecules and metabolic intermediates. The initial step in their synthesis is the activation of fatty acids by one of 13 long-chain acyl-CoA synthetase isoforms. These isoforms are regulated independently and have different tissue expression patterns and subcellular locations. Their acyl-CoA products regulate metabolic enzymes and signaling pathways, become oxidized to provide cellular energy, and are incorporated into acylated proteins and complex lipids like triacylglycerol, phospholipids, and cholesterol esters. Their differing metabolic fates are determined by a network of proteins that channel the acyl-CoAs towards or away from specific metabolic pathways and serve as the basis for partitioning. This review evaluates the evidence for acyl-CoA partitioning by reviewing experimental data on proteins that are believed to contribute to acyl-CoA channeling, the metabolic consequences of loss of these proteins, and the potential role of maladaptive acyl-CoA partitioning in the pathogenesis of metabolic disease and carcinogenesis.

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Section: Long-chain Acyl-coa Synthetasesmentioning

confidence: 99%

Section: Long-chain Acyl-coa Synthetasesmentioning

confidence: 99%

Acyl-CoA Metabolism and Partitioning

Grevengoed¹,

Klett

Coleman³

2014

Annu. Rev. Nutr.

365

330

View full text Add to dashboard Cite

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“…Immunofluorescence staining was performed as described112955. In brief, cells were fixed with 4% paraformaldehyde in phosphate-buffered saline (PBS) for 20 min, and permeabilized with 0.2% Triton X-100 in PBS for 5 min.…”

Section: Methodsmentioning

confidence: 99%

“…To detect tyrosine phosphorylation of proteins, cell lysates were prepared with SDS-sample buffer containing 10 mM sodium orthovanadate, 20 mM ß-glycerophosphate, and 50 mM NaF. Immunodetection was performed by enhanced chemiluminescence and examined using an image analyzer ChemiDoc XRSplus (Bio-Rad) as reported previously1150. Sequential reprobing of membranes with various antibodies was performed after the removal of antibodies from the membranes or inactivation of HRP by 0.1% NaN 3 , according to the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

“…Lyn, a mono-myristoylated and mono-palmitoylated Src-family kinase, contains glycine-2 for myristoylation and cysteine-3 for palmitoylation in the SH4 domain, both of which are necessary for membrane anchorage of Lyn56. We showed that Lyn is exocytosed toward the plasma membrane via the Golgi region along the secretory pathway following its biosynthesis in the cytoplasm7891011. In addition, palmitoylation of Lyn, Lck, and Fyn at cysteine-3 is important for their membrane localization and trafficking5610121314.…”

mentioning

confidence: 91%

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Protective role for lipid modifications of Src-family kinases against chromosome missegregation

Honda

Soeda

Tsuda

et al. 2016

Sci Rep

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Src-family tyrosine kinases, which are expressed in various cell types, play critical roles in cell signalling at the cytoplasmic side of the plasma membrane through their lipid modifications. Src-family kinases are cotranslationally myristoylated and posttranslationally palmitoylated in the amino-terminal region. The Src-family member Lyn contains a myristoylation site at glycine-2 and a palmitoylation site at cysteine-3, whereas c-Src has a myristoylation site at glycine-2 but not any palmitoylation sites. However, little is known about the role for lipid modifications of Src-family kinases in cell division. Here, we show that non-lipid-modified Lyn and c-Src, Lyn(G2A/C3A) and c-Src(G2A), are delocalized from membranes to the cytoplasm and the nucleus, which gives rise to a significant increase in the rate of chromosome missegregation, such as chromosome lagging and anaphase chromosome bridging, in a tyrosine kinase activity-dependent manner. Treatment with the Src inhibitor PP2 shows that the kinase activity of non-lipid-modified, non-membrane-bound Src during M phase is critical for giving rise to chromosome missegregation. Given that only a fraction of Src-family kinases fails in lipid modifications during biosynthesis, these results suggest that Src’s membrane anchorage through their lipid modifications from prophase to anaphase plays a protective role against induction of chromosome missegregation.

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Src family kinases maintain the balance between replication stress and the replication checkpoint

Miura

Fukumoto

Morii

et al. 2015

Cell Biology International

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Progression of DNA replication is tightly controlled by replication checkpoints to ensure the accurate and rapid duplication of genetic information. Upon replication stress, the replication checkpoint slows global DNA replication by inhibiting the late-firing origins and by slowing replication fork progression. Activation of the replication checkpoint has been studied in depth; however, little is known about the termination of the replication checkpoint. Here, we show that Src family kinases promote the recovery from replication checkpoints. shRNA knockdown of a Src family kinase, Lyn, and acute chemical inhibition of Src kinases prevented inactivation of Chk1 after removal of replication stress. Consistently, Src inhibition slowed resumption of DNA replication, after the removal of replication blocks. The effect of Src inhibition was not observed in the presence of an ATM/ATR inhibitor caffeine. These data indicate that Src kinases promote the resumption of DNA replication by suppressing ATR-dependent replication checkpoints. Surprisingly, the resumption of replication was delayed by caffeine. In addition, Src inhibition delayed recovery from replication fork collapse. We propose that Src kinases maintain the balance between replication stress and the activity of the replication checkpoint.

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The Lyn kinase C-lobe mediates Golgi export of Lyn through conformation-dependent ACSL3 association

Cited by 40 publications

References 68 publications

Acyl-CoA Metabolism and Partitioning

Acyl-CoA Metabolism and Partitioning

Protective role for lipid modifications of Src-family kinases against chromosome missegregation

Src family kinases maintain the balance between replication stress and the replication checkpoint

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