Site-specific processing of Ras and Rap1 Switch i by a MARTX toxin effector domain

Irena Antic; Marco Biancucci; Yueming Zhu; David R. Gius; Karla J.F. Satchell

doi:10.1038/ncomms8396

Site-specific processing of Ras and Rap1 Switch i by a MARTX toxin effector domain

Irena Antic, Marco Biancucci, Yueming Zhu, David R. Gius, Karla J.F. Satchell

Research output: Contribution to journal › Article › peer-review

55 Scopus citations

Abstract

Ras (Rat sarcoma) protein is a central regulator of cell growth and proliferation. Mutations in the RAS gene are known to occur in human cancers and have been shown to contribute to carcinogenesis. In this study, we show that the multifunctional-autoprocessing repeats-in-toxin (MARTX) toxin-effector domain DUF5_Vv from Vibrio vulnificus to be a site-specific endopeptidase that cleaves within the Switch 1 region of Ras and Rap1. DUF5_Vv processing of Ras, which occurs both biochemically and in mammalian cell culture, inactivates ERK1/2, thereby inhibiting cell proliferation. The ability to cleave Ras and Rap1 is shared by DUF5_Vv homologues found in other bacteria. In addition, DUF5_Vv can cleave all Ras isoforms and KRas with mutations commonly implicated in malignancies. Therefore, we speculate that this new family of Ras/Rap1-specific endopeptidases (RRSPs) has potential to inactivate both wild-type and mutant Ras proteins expressed in malignancies.

Original language	English (US)
Article number	7396
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms8396
State	Published - Jun 8 2015
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

Access to Document

10.1038/ncomms8396

Cite this

@article{6d5bdbd9bba141d2b4cfb8f8ebfa524b,

title = "Site-specific processing of Ras and Rap1 Switch i by a MARTX toxin effector domain",

abstract = "Ras (Rat sarcoma) protein is a central regulator of cell growth and proliferation. Mutations in the RAS gene are known to occur in human cancers and have been shown to contribute to carcinogenesis. In this study, we show that the multifunctional-autoprocessing repeats-in-toxin (MARTX) toxin-effector domain DUF5Vv from Vibrio vulnificus to be a site-specific endopeptidase that cleaves within the Switch 1 region of Ras and Rap1. DUF5Vv processing of Ras, which occurs both biochemically and in mammalian cell culture, inactivates ERK1/2, thereby inhibiting cell proliferation. The ability to cleave Ras and Rap1 is shared by DUF5Vv homologues found in other bacteria. In addition, DUF5Vv can cleave all Ras isoforms and KRas with mutations commonly implicated in malignancies. Therefore, we speculate that this new family of Ras/Rap1-specific endopeptidases (RRSPs) has potential to inactivate both wild-type and mutant Ras proteins expressed in malignancies.",

author = "Irena Antic and Marco Biancucci and Yueming Zhu and Gius, {David R.} and Satchell, {Karla J.F.}",

year = "2015",

month = jun,

day = "8",

doi = "10.1038/ncomms8396",

language = "English (US)",

volume = "6",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Site-specific processing of Ras and Rap1 Switch i by a MARTX toxin effector domain

AU - Antic, Irena

AU - Biancucci, Marco

AU - Zhu, Yueming

AU - Gius, David R.

AU - Satchell, Karla J.F.

PY - 2015/6/8

Y1 - 2015/6/8

N2 - Ras (Rat sarcoma) protein is a central regulator of cell growth and proliferation. Mutations in the RAS gene are known to occur in human cancers and have been shown to contribute to carcinogenesis. In this study, we show that the multifunctional-autoprocessing repeats-in-toxin (MARTX) toxin-effector domain DUF5Vv from Vibrio vulnificus to be a site-specific endopeptidase that cleaves within the Switch 1 region of Ras and Rap1. DUF5Vv processing of Ras, which occurs both biochemically and in mammalian cell culture, inactivates ERK1/2, thereby inhibiting cell proliferation. The ability to cleave Ras and Rap1 is shared by DUF5Vv homologues found in other bacteria. In addition, DUF5Vv can cleave all Ras isoforms and KRas with mutations commonly implicated in malignancies. Therefore, we speculate that this new family of Ras/Rap1-specific endopeptidases (RRSPs) has potential to inactivate both wild-type and mutant Ras proteins expressed in malignancies.

AB - Ras (Rat sarcoma) protein is a central regulator of cell growth and proliferation. Mutations in the RAS gene are known to occur in human cancers and have been shown to contribute to carcinogenesis. In this study, we show that the multifunctional-autoprocessing repeats-in-toxin (MARTX) toxin-effector domain DUF5Vv from Vibrio vulnificus to be a site-specific endopeptidase that cleaves within the Switch 1 region of Ras and Rap1. DUF5Vv processing of Ras, which occurs both biochemically and in mammalian cell culture, inactivates ERK1/2, thereby inhibiting cell proliferation. The ability to cleave Ras and Rap1 is shared by DUF5Vv homologues found in other bacteria. In addition, DUF5Vv can cleave all Ras isoforms and KRas with mutations commonly implicated in malignancies. Therefore, we speculate that this new family of Ras/Rap1-specific endopeptidases (RRSPs) has potential to inactivate both wild-type and mutant Ras proteins expressed in malignancies.

UR - http://www.scopus.com/inward/record.url?scp=84930959441&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84930959441&partnerID=8YFLogxK

U2 - 10.1038/ncomms8396

DO - 10.1038/ncomms8396

M3 - Article

C2 - 26051945

AN - SCOPUS:84930959441

SN - 2041-1723

VL - 6

JO - Nature communications

JF - Nature communications

M1 - 7396

ER -

Site-specific processing of Ras and Rap1 Switch i by a MARTX toxin effector domain

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this