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Originally published as MBoC in Press, 10.1091/mbc.E08-04-0346 on January 21, 2009

Vol. 20, Issue 6, 1855-1864, March 15, 2009

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The Chaperone Activity of GRP94 Toward Insulin-like Growth Factor II Is Necessary for the Stress Response to Serum Deprivation

Olga Ostrovsky, Noreen T. Ahmed*, and Yair Argon

Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, PA 19104

Submitted April 3, 2008; Revised January 13, 2009; Accepted January 14, 2009
Monitoring Editor: Jeffrey L. Brodsky

Insulin-like growth factor (IGF)-II is a hormone with mitogenic activity for many cell types and tissues. We demonstrate that its intracellular processing and secretion strictly depend on the endoplasmic reticulum chaperone glucose-regulated protein (GRP) 94. GRP94 interacts physically and transiently with pro-IGF-II intermediates, and its activity is essential for secretion of active IGF-II, thus establishing IGF-II as a client of GRP94. Embryonic stem (ES) cells that lack GRP94 are hypersensitive to stress conditions such as serum deprivation and die by apoptosis because they cannot respond to the stress by producing active IGF-II. This chaperone–client interaction may explain the previously documented antiapoptotic activity of GRP94 in a number of stress responses.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E08-04-0346) on January 21, 2009.

*Present address: Department of Biochemistry and Molecular Biology, Thomas Jefferson Medical School, Philadelphia, PA 19107.

Address correspondence to: Yair Argon (yargon{at}mail.med.upenn.edu)

Abbreviations used: ES, embryonic stem; GRP, glucose-regulated protein; IGF, insulin-like growth factor; 17-AAG, 17-allylamino-17-demethoxygeldanamycin.




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