The chaperone activity of GRP94 toward insulin-like growth factor II is necessary for the stress response to serum deprivation.
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.
Ostrovsky
Olga
O
Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, PA 19104, USA.
Ahmed
Noreen T
NT
Argon
Yair
Y
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D004789:Enzyme Activation; D005260:Female; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D013312:Stress, Physiological
D016895:Culture Media, Serum-Free; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; C053387:endoplasmin; D007335:Insulin-Like Growth Factor II; D053148:Caspase 3