skip to main content

DOE PAGESDOE PAGES

Title: Distinct Interactions of EBP1 Isoforms with FBXW7 Elicits Different Functions in Cancer

The ErbB3 receptor–binding protein EBP1 encodes two alternatively spliced isoforms P48 and P42. While there is evidence of differential roles for these isoforms in tumorigenesis, little is known about their underlying mechanisms. In this paper, we demonstrate that EBP1 isoforms interact with the SCF-type ubiquitin ligase FBXW7 in distinct ways to exert opposing roles in tumorigenesis. EBP1 P48 bound to the WD domain of FBXW7 as an oncogenic substrate of FBXW7. EBP1 P48 binding sequestered FBXW7α to the cytosol, modulating its role in protein degradation and attenuating its tumor suppressor function. In contrast, EBP1 P42 bound to both the F-box domain of FBXW7 as well as FBXW7 substrates. This adapter function of EBP1 P42 stabilized the interaction of FBXW7 with its substrates and promoted FBXW7-mediated degradation of oncogenic targets, enhancing its overall tumor-suppressing function. Finally and overall, our results establish distinct physical and functional interactions between FBXW7 and EBP1 isoforms, which yield their mechanistically unique isoform-specific functions of EBP1 in cancer.
Authors:
 [1] ;  [2] ;  [3] ;  [2] ;  [2] ;  [4] ;  [1]
  1. Shandong Univ. School of Medicine (China). Dept. of Human Anatomy. Key Lab. of Experimental Teratology. Ministry of Education
  2. Shandong Univ. School of Medicine (China). Dept. of Biochemistry and Molecular Biology
  3. Shandong Univ. School of Medicine (China). Dept. of Human Anatomy. Key Lab. of Experimental Teratology. Ministry of Education; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Biological Systems and Engineering Division
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Biological Systems and Engineering Division
Publication Date:
Grant/Contract Number:
AC02-05CH11231; R01 CA116481; 31271461; 81472583; 81528017; 81402193; 81470127; ZR2014HM032; 2011M501136; 2012T50616; 147751; 2015M570597
Type:
Accepted Manuscript
Journal Name:
Cancer Research
Additional Journal Information:
Journal Volume: 77; Journal Issue: 8; Journal ID: ISSN 0008-5472
Publisher:
American Association for Cancer Research
Research Org:
Shandong Univ. School of Medicine (China); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); National Inst. of Health (NIH) (United States); National Natural Science Foundation of China (NNSFC); Taishan Scholar Program of Shandong Province (China); Natural Science Foundation of Shandong Province (China); China Postdoctoral Science Foundation
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; colorectal cancer; FBXW7; protein isoform; EBP1 P48; EBP1 P42
OSTI Identifier:
1408428