Phosphorylation‐Regulated Degradation of the Tumor‐Suppressor Form of PED by Chaperone‐Mediated Autophagy in Lung Cancer Cells
Identifieur interne : 001057 ( Main/Exploration ); précédent : 001056; suivant : 001058Phosphorylation‐Regulated Degradation of the Tumor‐Suppressor Form of PED by Chaperone‐Mediated Autophagy in Lung Cancer Cells
Auteurs : Cristina Quintavalle [Italie] ; Stefania Di Costanzo [Italie] ; Ciro Zanca [Italie] ; Immaculada Tasset [États-Unis] ; Alessandro Fraldi [Italie] ; Mariarosaria Incoronato [Italie] ; Peppino Mirabelli [Italie] ; Maria Monti [Italie] ; Andrea Ballabio [Italie] ; Piero Pucci [Italie] ; Ana Maria Cuervo [États-Unis] ; Gerolama Condorelli [Italie]Source :
- Journal of Cellular Physiology [ 0021-9541 ] ; 2014-10.
Abstract
PED/PEA‐15 is a death effector domain (DED) family member with a variety of effects on cell growth and metabolism. To get further insight into the role of PED in cancer, we aimed to find new PED interactors. Using tandem affinity purification, we identified HSC70 (Heat Shock Cognate Protein of 70 kDa)—which, among other processes, is involved in chaperone‐mediated autophagy (CMA)—as a PED‐interacting protein. We found that PED has two CMA‐like motifs (i.e., KFERQ), one of which is located within a phosphorylation site, and demonstrate that PED is a bona fide CMA substrate and the first example in which phosphorylation modifies the ability of HSC70 to access KFERQ‐like motifs and target the protein for lysosomal degradation. Phosphorylation of PED switches its function from tumor suppression to tumor promotion, and we show that HSC70 preferentially targets the unphosphorylated form of PED to CMA. Therefore, we propose that the up‐regulated CMA activity characteristic of most types of cancer cell enhances oncogenesis by shifting the balance of PED function toward tumor promotion. This mechanism is consistent with the notion of a therapeutic potential for targeting CMA in cancer, as inhibition of this autophagic pathway may help restore a physiological ratio of PED forms. J. Cell. Physiol. 229: 1359–1368, 2014. © 2014 Wiley Periodicals, Inc.
Url:
DOI: 10.1002/jcp.24569
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To get further insight into the role of PED in cancer, we aimed to find new PED interactors. Using tandem affinity purification, we identified HSC70 (Heat Shock Cognate Protein of 70 kDa)—which, among other processes, is involved in chaperone‐mediated autophagy (CMA)—as a PED‐interacting protein. We found that PED has two CMA‐like motifs (i.e., KFERQ), one of which is located within a phosphorylation site, and demonstrate that PED is a bona fide CMA substrate and the first example in which phosphorylation modifies the ability of HSC70 to access KFERQ‐like motifs and target the protein for lysosomal degradation. Phosphorylation of PED switches its function from tumor suppression to tumor promotion, and we show that HSC70 preferentially targets the unphosphorylated form of PED to CMA. Therefore, we propose that the up‐regulated CMA activity characteristic of most types of cancer cell enhances oncogenesis by shifting the balance of PED function toward tumor promotion. This mechanism is consistent with the notion of a therapeutic potential for targeting CMA in cancer, as inhibition of this autophagic pathway may help restore a physiological ratio of PED forms. J. Cell. Physiol. 229: 1359–1368, 2014. © 2014 Wiley Periodicals, Inc.</div></front></TEI><affiliations><list><country><li>Italie</li><li>États-Unis</li></country><region><li>État de New York</li></region></list><tree><country name="Italie"><noRegion><name sortKey="Quintavalle, Cristina" sort="Quintavalle, Cristina" uniqKey="Quintavalle C" first="Cristina" last="Quintavalle">Cristina Quintavalle</name></noRegion><name sortKey="Ballabio, Andrea" sort="Ballabio, Andrea" uniqKey="Ballabio A" first="Andrea" last="Ballabio">Andrea Ballabio</name><name sortKey="Condorelli, Gerolama" sort="Condorelli, Gerolama" uniqKey="Condorelli G" first="Gerolama" last="Condorelli">Gerolama Condorelli</name><name sortKey="Condorelli, Gerolama" sort="Condorelli, Gerolama" uniqKey="Condorelli G" first="Gerolama" last="Condorelli">Gerolama Condorelli</name><name sortKey="Condorelli, Gerolama" sort="Condorelli, Gerolama" uniqKey="Condorelli G" first="Gerolama" last="Condorelli">Gerolama Condorelli</name><name sortKey="Di Costanzo, Stefania" sort="Di Costanzo, Stefania" uniqKey="Di Costanzo S" first="Stefania" last="Di Costanzo">Stefania Di Costanzo</name><name sortKey="Fraldi, Alessandro" sort="Fraldi, Alessandro" uniqKey="Fraldi A" first="Alessandro" last="Fraldi">Alessandro Fraldi</name><name sortKey="Incoronato, Mariarosaria" sort="Incoronato, Mariarosaria" uniqKey="Incoronato M" first="Mariarosaria" last="Incoronato">Mariarosaria Incoronato</name><name sortKey="Mirabelli, Peppino" sort="Mirabelli, Peppino" uniqKey="Mirabelli P" first="Peppino" last="Mirabelli">Peppino Mirabelli</name><name sortKey="Monti, Maria" sort="Monti, Maria" uniqKey="Monti M" first="Maria" last="Monti">Maria Monti</name><name sortKey="Pucci, Piero" sort="Pucci, Piero" uniqKey="Pucci P" first="Piero" last="Pucci">Piero Pucci</name><name sortKey="Quintavalle, Cristina" sort="Quintavalle, Cristina" uniqKey="Quintavalle C" first="Cristina" last="Quintavalle">Cristina Quintavalle</name><name sortKey="Zanca, Ciro" sort="Zanca, Ciro" uniqKey="Zanca C" first="Ciro" last="Zanca">Ciro Zanca</name></country><country name="États-Unis"><region name="État de New York"><name sortKey="Tasset, Immaculada" sort="Tasset, Immaculada" uniqKey="Tasset I" first="Immaculada" last="Tasset">Immaculada Tasset</name></region><name sortKey="Cuervo, Ana Maria" sort="Cuervo, Ana Maria" uniqKey="Cuervo A" first="Ana Maria" last="Cuervo">Ana Maria Cuervo</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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