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SIRT2 and lysine fatty acylation regulate the transforming activity of K-Ras4a.

eLife | 2017

Ras proteins play vital roles in numerous biological processes and Ras mutations are found in many human tumors. Understanding how Ras proteins are regulated is important for elucidating cell signaling pathways and identifying new targets for treating human diseases. Here we report that one of the K-Ras splice variants, K-Ras4a, is subject to lysine fatty acylation, a previously under-studied protein post-translational modification. Sirtuin 2 (SIRT2), one of the mammalian nicotinamide adenine dinucleotide (NAD)-dependent lysine deacylases, catalyzes the removal of fatty acylation from K-Ras4a. We further demonstrate that SIRT2-mediated lysine defatty-acylation promotes endomembrane localization of K-Ras4a, enhances its interaction with A-Raf, and thus promotes cellular transformation. Our study identifies lysine fatty acylation as a previously unknown regulatory mechanism for the Ras family of GTPases that is distinct from cysteine fatty acylation. These findings highlight the biological significance of lysine fatty acylation and sirtuin-catalyzed protein lysine defatty-acylation.

Pubmed ID: 29239724 RIS Download

Associated grants

  • Agency: NIGMS NIH HHS, United States
    Id: R01 GM121540
  • Agency: NIH HHS, United States
    Id: S10 OD017992
  • Agency: NCRR NIH HHS, United States
    Id: S10 RR025502

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.

This is a list of tools and resources that we have found mentioned in this publication.


GE Healthcare (tool)

RRID:SCR_000004

A commercial antibody supplier and provider of various services.

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ATCC (tool)

RRID:SCR_001672

Global nonprofit biological resource center (BRC) and research organization that provides biological products, technical services and educational programs to private industry, government and academic organizations. Its mission is to acquire, authenticate, preserve, develop and distribute biological materials, information, technology, intellectual property and standards for the advancement and application of scientific knowledge. The primary purpose of ATCC is to use its resources and experience as a BRC to become the world leader in standard biological reference materials management, intellectual property resource management and translational research as applied to biomaterial development, standardization and certification. ATCC characterizes cell lines, bacteria, viruses, fungi and protozoa, as well as develops and evaluates assays and techniques for validating research resources and preserving and distributing biological materials to the public and private sector research communities.

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Thermo Fisher Scientific (tool)

RRID:SCR_008452

Commercial vendor and service provider of laboratory reagents and antibodies. Supplier of scientific instrumentation, reagents and consumables, and software services.

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Cell Signaling Technology (tool)

RRID:SCR_004431

Privately held company that develops and produces antibodies, ELISA kits, ChIP kits, proteomic kits, and other related reagents used to study cell signaling pathways that impact human health.

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Thermo Xcalibur (tool)

RRID:SCR_014593

A software which acquires and processes data sets, primarily through the Xcalibur system.

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Syntaxin 6 (C34B2) Rabbit mAb (antibody)

RRID:AB_2196500

This monoclonal targets Syntaxin 6 (C34B2) Rabbit mAb

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ANTI-FLAG(R) M2 Affinity Gel (antibody)

RRID:AB_10063035

This unknown targets ANTI-FLAG(R) M2 Affinity Gel

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Raf-1 (C-20) (antibody)

RRID:AB_632303

This polyclonal targets RAF1

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Raf-B (C-19) (antibody)

RRID:AB_630938

This polyclonal targets Raf-B (C-19)

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A-Raf (C-20) (antibody)

RRID:AB_630882

This polyclonal targets A-Raf (C-20)

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K-Ras-2A (C-17) (antibody)

RRID:AB_2134128

This polyclonal targets KRAS

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Transferrin Receptor antibody (antibody)

RRID:AB_10673794

This polyclonal targets Transferrin Receptor antibody

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Anti-Sirt1, clone 3H10.2 (antibody)

RRID:AB_1163501

This monoclonal targets Human Sirt1, aa 508-616

View all literature mentions

Anti-RAS-Related protein Ral-A (antibody)

RRID:AB_11204894

This unknown targets RAS-Related protein Ral-A

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Rat Anti-v-H-Ras Monoclonal Antibody, Agarose Conjugated, Clone Y13-259 (antibody)

RRID:AB_10681741

This monoclonal targets Rat v-H-Ras Agarose Clone Y13-259

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Fiji (software resource)

RRID:SCR_002285

Software package as distribution of ImageJ and ImageJ2 together with Java, Java3D and plugins organized into coherent menu structure. Used to assist research in life sciences.

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NIH 3T3 (cell line)

RRID:CVCL_0594

Cell line NIH 3T3 is a Spontaneously immortalized cell line with a species of origin Mus musculus

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HCT 116 (cell line)

RRID:CVCL_0291

Cell line HCT 116 is a Cancer cell line with a species of origin Homo sapiens (Human)

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HEK293T (cell line)

RRID:CVCL_0063

Cell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)

View all literature mentions

Fiji (software resource)

RRID:SCR_002285

Software package as distribution of ImageJ and ImageJ2 together with Java, Java3D and plugins organized into coherent menu structure. Used to assist research in life sciences.

View all literature mentions

Syntaxin 6 (C34B2) Rabbit mAb (antibody)

RRID:AB_2196500

This monoclonal targets Syntaxin 6 (C34B2) Rabbit mAb

View all literature mentions

ANTI-FLAG(R) M2 Affinity Gel (antibody)

RRID:AB_10063035

This unknown targets ANTI-FLAG(R) M2 Affinity Gel

View all literature mentions

Raf-1 (C-20) (antibody)

RRID:AB_632303

This polyclonal targets RAF1

View all literature mentions

Raf-B (C-19) (antibody)

RRID:AB_630938

This polyclonal targets Raf-B (C-19)

View all literature mentions

A-Raf (C-20) (antibody)

RRID:AB_630882

This polyclonal targets A-Raf (C-20)

View all literature mentions

K-Ras-2A (C-17) (antibody)

RRID:AB_2134128

This polyclonal targets KRAS

View all literature mentions

Transferrin Receptor antibody (antibody)

RRID:AB_10673794

This polyclonal targets Transferrin Receptor antibody

View all literature mentions

Anti-Sirt1, clone 3H10.2 (antibody)

RRID:AB_1163501

This monoclonal targets Human Sirt1, aa 508-616

View all literature mentions

Anti-RAS-Related protein Ral-A (antibody)

RRID:AB_11204894

This unknown targets RAS-Related protein Ral-A

View all literature mentions

Rat Anti-v-H-Ras Monoclonal Antibody, Agarose Conjugated, Clone Y13-259 (antibody)

RRID:AB_10681741

This monoclonal targets Rat v-H-Ras Agarose Clone Y13-259

View all literature mentions

NIH 3T3 (cell line)

RRID:CVCL_0594

Cell line NIH 3T3 is a Spontaneously immortalized cell line with a species of origin Mus musculus

View all literature mentions

HCT 116 (cell line)

RRID:CVCL_0291

Cell line HCT 116 is a Cancer cell line with a species of origin Homo sapiens (Human)

View all literature mentions

HEK293T (cell line)

RRID:CVCL_0063

Cell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)

View all literature mentions