Phosphorylation-regulated degradation of the tumor-suppressor form of PED by chaperone-mediated autophagy in lung cancer cells.
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.
Department of Molecular Medicine and Medical Biotechnology, "Federico II" University of Naples, Naples, Italy; Institute of Endocrinology and Experimental Oncology "G. Salvatore" (IEOS), Consiglio Nazionale delle Ricerche (CNR), Naples, Italy.
Cristina
C
Quintavalle
Stefania
S
Di Costanzo
Ciro
C
Zanca
Immaculada
I
Tasset
Alessandro
A
Fraldi
Mariarosaria
M
Incoronato
Peppino
P
Mirabelli
Maria
M
Monti
Andrea
A
Ballabio
Piero
P
Pucci
Ana Maria
AM
Cuervo
Gerolama
G
Condorelli
D020816:Amino Acid Motifs; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D050883:HSC70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D059748:Proteolysis; D034622:RNA Interference; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D050883:HSC70 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; C092039:PEA15 protein, human; D010750:Phosphoproteins; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins