SCF β-TRCP suppresses angiogenesis and thyroid cancer cell migration by promoting ubiquitination and destruction of VEGF receptor 2

Shavali Shaik, Carmelo Nucera, Hiroyuki Inuzuka, Daming Gao, Maija Garnaas, Gregory Frechette, Lauren Harris, Lixin Wan, Hidefumi Fukushima, Amjad Husain, Vania Nose, Guido Fadda, Peter M. Sadow, Wolfram Goessling, Trista North, Jack Lawler, Wenyi Wei

Research output: Contribution to journalArticlepeer-review

55 Citations (Scopus)

Abstract

The incidence of human papillary thyroid cancer (PTC) is increasing and an aggressive subtype of this disease is resistant to treatment with vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor. VEGFR2 promotes angiogenesis by triggering endothelial cell proliferation and migration. However, the molecular mechanisms governing VEGFR2 stability in vivo remain unknown. Additionally, whether VEGFR2 influences PTC cell migration is not clear. We show that the ubiquitin E3 ligase SCF β-TRCP promotes ubiquitination and destruction of VEGFR2 in a casein kinase I (CKI)-dependent manner. β-TRCP knockdown or CKI inhibition causes accumulation of VEGFR2, resulting in increased activity of signaling pathways downstream of VEGFR2. β-TRCP-depleted endothelial cells exhibit enhanced migration and angiogenesis in vitro. Furthermore, β-TRCP knockdown increased angiogenesis and vessel branching in zebrafish. Importantly, we found an inverse correlation between β-TRCP protein levels and angiogenesis in PTC. We also show that β-TRCP inhibits cell migration and decreases sensitivity to the VEGFR2 inhibitor sorafenib in poorly differentiated PTC cells. These results provide a new biomarker that may aid a rational use of tyrosine kinase inhibitors to treat refractory PTC.

Original languageEnglish
Pages (from-to)1289-1307
Number of pages19
JournalJournal of Experimental Medicine
Volume209
Issue number7
DOIs
Publication statusPublished - 2012 Jul 2

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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