Ligand stimulation induces clathrin- and Rab5-dependent downregulation of the kinase-dead EphB6 receptor preceded by the disruption of EphB6-Hsp90 interaction

被引:8
|
作者
Allonby, Odette [1 ]
El Zawily, Amr M. [1 ]
Freywald, Tanya [1 ]
Mousseau, Darrell D. [2 ,3 ]
Chlan, Jennifer [2 ,4 ]
Anderson, Deborah [5 ,6 ]
Benmerah, Alexandre [7 ,8 ]
Sidhu, Vishaldeep [9 ]
Babu, Mohan [9 ]
DeCoteau, John [1 ]
Fretwald, Andrew [1 ,5 ]
机构
[1] Univ Saskatchewan, Coll Med, Dept Pathol, Saskatoon, SK S7N 5E5, Canada
[2] Univ Saskatchewan, Coll Med, Dept Psychiat, Saskatoon, SK S7N 5E5, Canada
[3] Univ Saskatchewan, Coll Med, Dept Physiol, Saskatoon, SK S7N 5E5, Canada
[4] Univ Saskatchewan, Coll Med, Dept Anat & Cell Biol, Saskatoon, SK S7N 5E5, Canada
[5] Univ Saskatchewan, Coll Med, Dept Biochem, Saskatoon, SK S7N 5E5, Canada
[6] Univ Saskatchewan, Saskatchewan Canc Agcy, Canc Res Unit, Saskatoon, SK S7N 5E5, Canada
[7] INSERM, U1163, Lab Inherited Kidney Dis, F-75015 Paris, France
[8] Univ Paris 05, Sorbonne Paris Cite, Inst Imagine, F-75015 Paris, France
[9] Univ Regina, Res & Innovat Ctr, Dept Biochem, Regina, SK S4S 0A2, Canada
基金
加拿大健康研究院;
关键词
EphB6; EphB4; Hsp90; Internalisation; Receptor tyrosine kinase; Downregulation; GROWTH-FACTOR RECEPTOR; TYROSINE KINASE; ONCOGENIC ACTIVATION; ERBB RECEPTORS; C-CBL; ENDOCYTOSIS; HSP90; INHIBITION; GELDANAMYCIN; DEGRADATION;
D O I
10.1016/j.cellsig.2014.08.007
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Ligand-induced internalisation and subsequent downregulation of receptor tyrosine kinases (RTKs) serve to determine biological outputs of their signalling. Intrinsically kinase-deficient RTKs control a variety of biological responses, however, the mechanism of their downregulation is not well understood and its analysis is focused exclusively on the ErbB3 receptor. The Eph group of RTKs is represented by the EphA and EphB subclasses. Each bears one kinase-inactive member, EphA10 and EphB6, respectively, suggesting an important role for these molecules in the Eph signalling network. While EphB6 effects on cell behaviour have been assessed, the mechanism of its downregulation remains elusive. Our work reveals that EphB6 and its kinase-active relative, and signalling partner, EphB4, are downregulated in a similar manner in response to their common ligand, ephrin-B2. Following stimulation, both receptors are internalised through clathrin-coated pits and are degraded in lysosomes. Their targeting for lysosomal degradation relies on the activity of an early endosome regulator, the Rab5 GTPase, as this process is inhibited in the presence of a Rab5 dominant-negative mutant. EphB6 also interacts with the Hsp90 chaperone and EphB6 downregulation is preceded by their rapid dissociation. Moreover, the inhibition of Hsp90 results in EphB6 degradation, mimicking its ligand-induced downregulation. These processes appear to rely on overlapping mechanisms, since Hsp90 inhibition does not significantly enhance ligand-induced EphB6 elimination. Taken together, our observations define a novel mechanism for intrinsically kinase-deficient RTK downregulation and support an intriguing model, where Hsp90 dissociation acts as a trigger for ligand-induced receptor removal. (C) 2014 Elsevier Inc All rights reserved.
引用
收藏
页码:2645 / 2657
页数:13
相关论文
empty
未找到相关数据