SCF(β-TRCP) suppresses angiogenesis and thyroid cancer cell migration by promoting ubiquitination and destruction of VEGF receptor 2.
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.
Division of Cancer Biology and Angiogenesis, Department of Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Shavali
S
Shaik
Carmelo
C
Nucera
Hiroyuki
H
Inuzuka
Daming
D
Gao
Maija
M
Garnaas
Gregory
G
Frechette
Lauren
L
Harris
Lixin
L
Wan
Hidefumi
H
Fukushima
Amjad
A
Husain
Vania
V
Nose
Guido
G
Fadda
Peter M
PM
Sadow
Wolfram
W
Goessling
Trista
T
North
Jack
J
Lawler
Wenyi
W
Wei
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D002478:Cells, Cultured; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D054875:Ubiquitination; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult; D015027:Zebrafish
D044843:SKP Cullin F-Box Protein Ligases; D040301:Vascular Endothelial Growth Factor Receptor-2