Dual myristylation and palmitylation of Src family member p59fyn affects subcellular localization

Alland, Leila; Peseckis, Steven M.; Atherton, R. E.; Berthiaume, Luc G.; Resh, Marilyn D.

doi:10.1016/s0021-9258(19)89447-4

Cited by 196 publications

(40 citation statements)

References 20 publications

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“…The Src-family kinases FYN and LCK are critical for proximal TCR signaling and are anchored to the plasma membrane by acylation of the unique N-terminal SH4 domains. FYN is myristoylated at Gly2, followed by palmitoylation at Cys3 19 . IL-17 dependent recruitment of TRAF3IP2 to the plasma membrane initiates signaling downstream of TRAF3IP2.…”

Section: Resultsmentioning

confidence: 99%

Fusion transcripts FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T-cell lymphoma, not otherwise specified

et al. 2021

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Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas with poor prognosis. Up to 30% of PTCL lack distinctive features and are classified as PTCL, not otherwise specified (PTCL-NOS). To further improve our understanding of the genetic landscape and biology of PTCL-NOS, we perform RNA-sequencing of 18 cases and validate results in an independent cohort of 37 PTCL cases. We identify FYN-TRAF3IP2, KHDRBS1-LCK and SIN3A-FOXO1 as new in-frame fusion transcripts, with FYN-TRAF3IP2 as a recurrent fusion detected in 8 of 55 cases. Using ex vivo and in vivo experiments, we demonstrate that FYN-TRAF3IP2 and KHDRBS1-LCK activate signaling pathways downstream of the T cell receptor (TCR) complex and confer therapeutic vulnerability to clinically available drugs.

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Section: Resultsmentioning

confidence: 99%

Fusion transcripts FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T-cell lymphoma, not otherwise specified

et al. 2021

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“…Signaling pathways, like Ca 2ϩ , Ras, and Rac pathways, These results are similar to those obtained in mutagenemight be initiated through recruiting of PLC-␥1, Vav, and Grb2 into GEMs. sis studies of Lck and Fyn (Alland et al, 1994; Kabouridis observed that many more proteins such as Cbl, Syk, Transient and stable transfection of Jurkat cells were performed as described . For labeling with [ 3 H]palmitate, 2 ϫ Vav, ZAP-70, PLC-␥1, TCR chains, and others are en-10 7 Jurkat cells were removed from culture and resuspended in 1 riched in GEMs.…”

Section: Discussionmentioning

confidence: 99%

“…Many palmitoylated proteins, such as the Src family kinases Lck and Fyn, are targeted into GEMs of the plasma membrane (Alland et al, 1994;Shenoy-Scaria et al, 1994). GEMs are operationally characterized by resistance to Triton extraction at 4ЊC and are found in low-density fractions of a sucrose gradient (Simons and Ikonen, 1997).…”

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confidence: 99%

LAT Palmitoylation

1998

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The linker molecule LAT is a critical substrate of the tyrosine kinases activated upon TCR engagement. Phosphorylated LAT binds Grb2, PLC-gamma1, and other signaling molecules. We demonstrate that human LAT is palmitoylated and that palmitoylated LAT predominantly localizes into glycolipid-enriched microdomains (GEMs). Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. LAT palmitoylation is necessary for its tyrosine phosphorylation. After T cell activation, most tyrosine-phosphorylated LAT molecules and a fraction of PLC-gamma1 and other signaling molecules are present in GEMs. LAT is central to T cell activation and is a novel linker molecule shown to require targeting to membrane microdomains for signaling.

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“…In addition to N-myristoylation, several proteins, such as the ␣-subunit of G-protein and Src family kinases, are S-palmitoylated (33)(34)(35). Multiple S-palmitoylations controlled by both palmitoyl acyl-transferases and thioesterases regulate dynamic cellular processes, including membrane trafficking, lipid raft targeting, and intracellular signaling cascades, through modulation of the protein hydrophobicity (7).…”

Section: Tg-a Is Also Modified By S-palmitoylationmentioning

confidence: 99%

Drosophila TG-A transglutaminase is secreted via an unconventional Golgi-independent mechanism involving exosomes and two types of fatty acylations

Shibata¹,

Hadano²,

Kawasaki³

et al. 2017

Journal of Biological Chemistry

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Transglutaminases (TGs) play essential intracellular and extracellular roles by covalently cross-linking many proteins. TG is encoded by one gene and has two alternative splicing-derived isoforms, TG-A and TG-B, which contain distinct N-terminal 46- and 38-amino acid sequences, respectively. The TGs identified to date do not have a typical endoplasmic reticulum (ER)-signal peptide, and the molecular mechanisms of their secretion under physiologic conditions are unclear. Immunocytochemistry revealed that TG-A localizes to multivesicular-like structures, whereas TG-B localizes to the cytosol. We also found that TG-A, but not TG-B, was modified concomitantly bymyristoylation and -palmitoylation, andmyristoylation was a pre-requisite for palmitoylation. Moreover, TG-A, but not TG-B, was secreted in response to calcium signaling induced by Ca ionophores and uracil, a pathogenic bacteria-derived substance. Brefeldin A and monensin, inhibitors of the ER/Golgi-mediated conventional pathway, did not suppress TG-A secretion, whereas inhibition of -palmitoylation by 2-bromopalmitate blocked TG-A secretion. Ultracentrifugation, electron microscopy analyses, and treatments with inhibitors of multivesicular body formation revealed that TG-A was secreted via exosomes together with co-transfected mammalian CD63, an exosomal marker, and the secreted TG-A was taken up by other cells. The 8-residue N-terminal fragment of TG-A containing the fatty acylation sites was both necessary and sufficient for the exosome-dependent secretion of TG-A. In conclusion, TG-A is secreted through an unconventional ER/Golgi-independent pathway involving two types of fatty acylations and exosomes.

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Dual myristylation and palmitylation of Src family member p59fyn affects subcellular localization

Cited by 196 publications

References 20 publications

Fusion transcripts FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T-cell lymphoma, not otherwise specified

Fusion transcripts FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T-cell lymphoma, not otherwise specified

LAT Palmitoylation

Drosophila TG-A transglutaminase is secreted via an unconventional Golgi-independent mechanism involving exosomes and two types of fatty acylations

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