title: Erbin interacts with c-Cbl and promotes tumourigenesis and tumour growth in colorectal cancer by preventing c-Cbl-mediated ubiquitination and down-regulation of EGFR.
abstract: The epidermal growth factor receptor (EGFR) is implicated in many types of cancer, including colorectal cancer (CRC), and has become one of the most common candidates for targeted therapy. Here, we found that Erbin, a member of the leucine-rich repeat and PDZ domain (LAP) family, plays a key role in EGFR signalling. Erbin inhibited EGFR ubiquitination and stabilized the EGFR protein by interacting with c-Cbl. Moreover, the PDZ domain of Erbin was critical for the interaction between Erbin and c-Cbl and EGFR ubiquitination. Interestingly, Erbin expression was elevated in tumour samples from CRC patients, increased in advanced clinical stage disease and correlated with EGFR expression. In vivo studies using mouse xenograft models of CRC showed that Erbin promotes tumour growth, and that the effects of Erbin on tumour growth are mainly related to the regulatory effects of Erbin on EGFR. The azoxymethane (AOM)-induced colon carcinogenesis model in Erbin(ΔC) (/) (ΔC) mice, with the PDZ domain of Erbin deleted, demonstrated that the PDZ domain of Erbin and its regulation of EGFR signalling are necessary for the tumourigenesis and tumour growth of CRC. We found that Erbin promotes tumourigenesis and tumour growth in CRC by stabilizing EGFR. Our study sheds light on developing Erbin, especially its PDZ domain, as a potential target for CRC treatment.
authors.affiliation: Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.
authors.forename: Su
authors.initials: S
authors.lastname: Yao
authors.forename: Ping
authors.initials: P
authors.lastname: Zheng
authors.forename: Hua
authors.initials: H
authors.lastname: Wu
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Song
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Ying
authors.forename: Cheng
authors.initials: C
authors.lastname: Xing
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Zheng-Quan
authors.initials: ZQ
authors.lastname: Xiao
authors.forename: Xing-Ni
authors.initials: XN
authors.lastname: Zhou
authors.forename: Tong
authors.initials: T
authors.lastname: Shen
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.forename: Yu-Hong
authors.initials: YH
authors.lastname: Liu
authors.forename: Mao-De
authors.initials: MD
authors.lastname: Lai
authors.forename: Lin
authors.initials: L
authors.lastname: Mei
authors.forename: Tian-Ming
authors.initials: TM
authors.lastname: Gao
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D015536:Down-Regulation; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C413364:ERBIN protein, human; C498804:Erbb2ip protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D050721:Proto-Oncogene Proteins c-cbl; C512478:EGFR protein, human; C541485:EGFR protein, mouse; D066246:ErbB Receptors; C067419:CBL protein, human; C493849:Cbl protein, mouse
keywords: EGFR; Erbin; colorectal cancer; tumour growth; tumourigenesis; ubiquitination