Negative regulation of EphA2 receptor by Cbl.
The c-Cbl proto-oncogene product Cbl has emerged as a negative regulator of receptor and non-receptor tyrosine kinases, a function dependent on its recently identified ubiquitin ligase activity. Here, we report that EphA2, a member of Eph receptor tyrosine kinases is negatively regulated by Cbl. The negative regulation of EphA2 mediated by Cbl is dependent on the activity of EphA2, as the kinase inactive mutant of EphA2 cannot be regulated by Cbl. Moreover, a point mutation (G306E-Cbl) in TKB region of Cbl that has been reported to abolish Cbl binding to RTKs and non-receptor tyrosine kinases impaired the binding to active EphA2. The dominant negative mutant 70Z-Cbl, which has a 17-amino acids deletion in the N-boundary of the RING finger domain, defuncted negative regulatory function of Cbl to EphA2. These results demonstrate that the TKB domain and RING finger domain of Cbl are essential for this negative regulation.
Wang
You jie
Yj
First Department of Pathology, Hamamatsu University School of Medicine, 1-20-1, Handayama, 431-3192, Hamamatsu, Japan.
Ota
Satoshi
S
Kataoka
Hideki
H
Kanamori
Masao
M
Li
Zhong you
Zy
Band
Hamid
H
Tanaka
Masamitsu
M
Sugimura
Haruhiko
H
D002460:Cell Line; D006801:Humans; D050722:Oncogene Protein v-cbl; D010766:Phosphorylation; D000090063:Proto-Oncogene Mas; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D036104:Receptor, EphA2; D015682:Retroviridae Proteins, Oncogenic / Q000502:physiology*
C000715470:MAS1 protein, human; D050722:Oncogene Protein v-cbl; D000090063:Proto-Oncogene Mas; D015682:Retroviridae Proteins, Oncogenic; D020794:Receptor Protein-Tyrosine Kinases; D036104:Receptor, EphA2