Small GTPase RBJ mediates nuclear entrapment of MEK1/MEK2 in tumor progression

Taoyong Chen; Mingjin Yang; Zhou Yu; Songqing Tang; Chen Wang; Xuhui Zhu; Jun Guo; Nan Li; Weiping Zhang; Jin Hou; Haibo Liu; Chaofeng Han; Qiuyan Liu; Yan Gu; Cheng Qian; Tao Wan; Long Cui; Minghua Zhu; Weiqiang Zheng; Xuetao Cao

doi:10.1016/j.ccr.2014.03.009

Small GTPase RBJ mediates nuclear entrapment of MEK1/MEK2 in tumor progression

Cancer Cell. 2014 May 12;25(5):682-96. doi: 10.1016/j.ccr.2014.03.009. Epub 2014 Apr 17.

Authors

Taoyong Chen¹, Mingjin Yang¹, Zhou Yu², Songqing Tang², Chen Wang³, Xuhui Zhu³, Jun Guo³, Nan Li³, Weiping Zhang³, Jin Hou³, Haibo Liu³, Chaofeng Han³, Qiuyan Liu³, Yan Gu³, Cheng Qian³, Tao Wan³, Long Cui⁴, Minghua Zhu⁵, Weiqiang Zheng⁵, Xuetao Cao⁶

Affiliations

¹ National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China; National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China.
² Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
³ National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
⁴ Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China.
⁵ Department of Pathology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
⁶ National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China; National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China; Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: caoxt@immunol.org.

PMID: 24746703
DOI: 10.1016/j.ccr.2014.03.009

Abstract

Ras-related small GTPases play important roles in cancer. However, the roles of RBJ, a representative of the sixth subfamily of Ras-related small GTPases, in tumorigenesis and tumor progression remain unknown. Here, we report that RBJ is dysregulated in human gastrointestinal cancers and can promote carcinogenesis and tumor progression via nuclear entrapment of mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)1/MEK2 and activation of ERK1/ERK2. Nucleus-localized RBJ interacts with MEK/ERK and prolongs the duration of MEK/ERK activation. Rbj deficiency abrogates nuclear accumulation of MEK1/MEK2, attenuates ERK1/ERK2 activation, and impairs AOM/DSS-induced colonic carcinogenesis. Moreover, Rbj knockdown inhibits growth of established tumors. Our data suggest that RBJ may be an oncogenic Ras-related small GTPase mediating nuclear accumulation of active MEK1/MEK2 in tumor progression.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3T3 Cells
Animals
Cell Line, Tumor
Cell Transformation, Neoplastic / genetics
Extracellular Signal-Regulated MAP Kinases / metabolism*
GTP Phosphohydrolases / genetics
GTP Phosphohydrolases / metabolism*
Gastrointestinal Neoplasms / genetics
Gastrointestinal Neoplasms / pathology
Gene Expression
HSP40 Heat-Shock Proteins
Humans
MAP Kinase Kinase 1 / metabolism*
MAP Kinase Kinase 2 / metabolism*
MAP Kinase Signaling System / genetics
MAP Kinase Signaling System / physiology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Mice, Nude
Molecular Sequence Data
RNA Interference
RNA, Small Interfering
rab GTP-Binding Proteins / genetics
rab GTP-Binding Proteins / metabolism*

Substances

HSP40 Heat-Shock Proteins
RNA, Small Interfering
Extracellular Signal-Regulated MAP Kinases
MAP Kinase Kinase 1
MAP Kinase Kinase 2
DNAJC27 protein, human
GTP Phosphohydrolases
RBJ protein, mouse
rab GTP-Binding Proteins

Associated data

GENBANK/AF178983
GENBANK/NM153082