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

Journal Article · · Cancer Research
 [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
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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.

Research Organization:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER); National Inst. of Health (NIH) (United States); National Natural Science Foundation of China (NSFC); Taishan Scholar Program of Shandong Province (China); Natural Science Foundation of Shandong Province (China); China Postdoctoral Science Foundation
Grant/Contract Number:
AC02-05CH11231; R01 CA116481; 31271461; 81472583; 81528017; 81402193; 81470127; ZR2014HM032; 2011M501136; 2012T50616; 147751; 2015M570597
OSTI ID:
1408428
Journal Information:
Cancer Research, Vol. 77, Issue 8; ISSN 0008-5472
Publisher:
American Association for Cancer ResearchCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 20 works
Citation information provided by
Web of Science

Cited By (3)

ErbB3-binding protein 1 (EBP1) represses HNF4α-mediated transcription and insulin secretion in pancreatic β-cells journal July 2019
FBXW7: a critical tumor suppressor of human cancers journal August 2018
YC-1 Antagonizes Wnt/β-Catenin Signaling Through the EBP1 p42 Isoform in Hepatocellular Carcinoma journal May 2019

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Related Subjects

60 APPLIED LIFE SCIENCES
59 BASIC BIOLOGICAL SCIENCES
colorectal cancer
FBXW7
protein isoform
EBP1 P48
EBP1 P42