In:
Journal of Cell Science, The Company of Biologists
Abstract:
Growth factor signalling regulates multiple cellular functions and its misregulation has been linked to cancer development and progression. Ack1 (Activated Cdc42-associated kinase 1, TNK2), a non-receptor tyrosine kinase, has been implicated in trafficking and degradation of epidermal growth factor receptor (EGFR), yet the precise functions remain elusive. In this report we investigate the role of Ack1 in EGFR trafficking and show that Ack1 partially colocalises to Atg16L-positive structures upon EGF stimulation. These are proposed to be the isolation membranes during autophagosome formation. In addition we find that Ack1 colocalises and interacts with sequestosome 1 (p62/SQSTM1), a receptor for selective autophagy, via a ubiquitin associated domain and this interaction decreases upon EGF treatment, thus suggesting that Ack1 moves away from p62/SQSTM1 compartments. Furthermore, Ack1 interacts and colocalises with NBR1, another autophagic receptor, and this colocalisation is enhanced in the presence of ectopically expressed p62/SQSTM1. Finally, Ack1 knock-down results in accelerated lysosomal localisation of EGFR upon EGF treatment. Structure-function analyses of a panel of Ack1 deletion mutants have revealed key mechanistic aspects of these relationships. The Mig6-homology domain and clathrin binding domain both contribute to the colocalisation with EGFR, whereas the UBA domain is critical for the colocalisation with p62/SQSTM1, but not NBR1. Taken together, our studies demonstrate a novel role for Ack1 in diverting activated EGFR into a non-canonical degradative pathway, marked by association with p62/SQSTM1, NBR1 and Atg16L.
Type of Medium:
Online Resource
ISSN:
1477-9137
,
0021-9533
Language:
English
Publisher:
The Company of Biologists
Publication Date:
2014
detail.hit.zdb_id:
219171-4
detail.hit.zdb_id:
1483099-1
SSG:
12
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