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Apratoxin chaperones EGFR to its destruction

A small toxin from a cyanobacterium pushes growth-promoting proteins such as the EGF receptor (EGFR) along an unusual path to destruction, report Shen et al.

Several oncogenic proteins, including EGFR, p53, and cyclindependent kinases are collectively known as Hsp90 client proteins due to their reliance on the Hsp90 chaperone for maintaining their conformation and stability. Hsp90 inhibitors are undergoing cancer therapy trials, since disrupting the chaperone's function results in its clients targeting to the proteasome for degradation.

The cyanobacterium compound Apratoxin A can also kill cancer cells—at least in vitro—but its mode of action was unknown. Shen et al. found that treating cells with Apratoxin A reduced the levels of several Hsp90 client proteins and prevented their interaction with Hsp90. But the toxin works in a different way to Hsp90 inhibitors like geldanamycin. Apratoxin A directly bound to chaperones of the Hsp70/Hsc70 family, stabilizing their association with Hsp90 client proteins such as EGFR. The client proteins could no longer bind Hsp90 and were instead delivered by Hsc70 to the lysosomes for degradation—a process called chaperone-mediated autophagy (CMA).

Blocking the CMA pathway prevented EGFR's degradation in response to Apratoxin A. EGFR is the first membrane protein known to undergo CMA—a process previously thought to be reserved for cytosolic proteins. But Shen et al. identified a short sequence within EGFR that allows Hsc70 to recognize it as a CMA substrate. Apratoxin A's ability to bind Hsp70/Hsc70 chaperones and induce the degradation of EGFR and other Hsp90 client proteins makes it an interesting candidate for cancer treatments, although author Shensi Shen warns that the drug is extremely toxic and will need to be further modified.

References

Shen, S., et al. 2009. J. Cell Biol. doi:10.1083/jcb.200810183.[Abstract/Free Full Text]

bshort{at}rockefeller.edu

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This Article Full Text (PDF, 489K) Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Short, B. Search for Related Content PubMed Articles by Short, B. Related Collections Related Article Social Bookmarking                            What's this?