In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 4437-4437
Abstract:
HPK1, a member of mammalian Ste20-like serine/threonine kinases, is lost in & gt;95% pancreatic cancer through proteasomemediated degradation. However, the mechanism of HPK1 loss has not been defined. The aims of this study are to identify the ubiquitin ligase and to examine the mechanisms that targets HPK1 degradation. We found that the CUL7 ubiquitin ligase targeted HPK1 for degradation via the 26S proteasome. The ubiquitination of HPK1 required its kinase activity and autophosphorylation. Wild-type protein phosphatase 4 (PP4), but not the phosphatase-dead PP4 mutant, PP4-RL, inhibits the interaction of Fbxw8 with HPK1 and Fbxw8-mediated ubiquitination of HPK1. In addition, we showed that Thr355 of HPK1 is a key PP4 dephosphorylation site, through which Fbxw8 and PP4 regulates HPK1 stability. Our study demonstrated that CUL7 ubiquitin ligase targets HPK1 for degradation which requires HPK1 kinase activity and autophosphorylation. Fbxw8-mediated HPK1 degradation revealed a direct link and novel role of CUL7 ubiquitin ligase in the MAPK pathway, which plays a critical role in cell proliferation and differentiation. Citation Format: Hua Wang, Yue Chen, Ping Lin, Lei Li, Guisheng Zhou, Guangchao Liu, Craig Logsdon, Jianping Jin, James L. Abbruzzese, Tse-Hua Tan, Huamin Wang. Fbxw8 targets hematopoietic progenitor kinase 1 for proteasomal degradation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4437. doi:10.1158/1538-7445.AM2014-4437
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2014-4437
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2014
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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