Promoting the degradation of Hsp90 client proteins by inhibiting Hsp90, an 
important protein chaperone, has been shown to be a promising new anticancer 
strategy. In this study, we show that an oxazoline analogue of apratoxin A 
(oz-apraA), a cyclodepsipeptide isolated from a marine cyanobacterium, promotes 
the degradation of Hsp90 clients through chaperone-mediated autophagy (CMA). We 
identify a KFERQ-like motif as a conserved pentapeptide sequence in the kinase 
domain of epidermal growth factor receptor (EGFR) necessary for recognition as a 
CMA substrate. Mutation of this motif prevents EGFR degradation by CMA and 
promotes the degradation of EGFR through the proteasomal pathway in 
oz-apraA-treated cells. Oz-apraA binds to Hsc70/Hsp70. We propose that apratoxin 
A inhibits Hsp90 function by stabilizing the interaction of Hsp90 client 
proteins with Hsc70/Hsp70 and thus prevents their interactions with Hsp90. Our 
study provides the first examples for the ability of CMA to mediate degradation 
of membrane receptors and cross talks of CMA and proteasomal degradation 
mechanisms.