The endoplasmic reticulum (ER) consists of an interconnected, membranous network 
that is the major site for the synthesis and folding of integral membrane and 
secretory proteins. Within the ER lumen, protein folding is facilitated by 
molecular chaperones and a variety of enzymes that ensure that polypeptides 
obtain their appropriate, tertiary conformation (Dobson, C. M. (2004). 
Principles of protein folding, misfolding and aggregation. Semin. Cell Dev. 
Biol. 15, 3-16; Ni, M., and Lee, A. S. (2007). ER chaperones in mammalian 
development and human diseases. FEBS Lett. 581, 3641-3651.). Physiological 
conditions that increase protein synthesis or stimuli that disturb the processes 
by which proteins obtain their native conformation, create an imbalance between 
the protein-folding demand and capacity of the ER. This results in the 
accumulation of unfolded or improperly folded proteins in the ER lumen and a 
state of ER stress. The cellular response, referred to as the unfolded protein 
response (UPR), results in activation of three linked signal transduction 
pathways: PKR-like kinase (PERK), inositol requiring 1 α (IRE1α), and activating 
transcription factor 6α (ATF6α) (Ron, D., and Walter, P. (2007). Signal 
integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. 
Mol. Cell. Biol. 8, 519-529; Schroder, M., and Kaufman, R. (2005). ER stress and 
the unfolded protein response. Mutat. Res./Fundam. Mol. Mech. Mutagen. 569, 
29-63.). Collectively, the combined actions of these signaling cascades serve to 
reduce ER stress through attenuation of translation to reduce protein synthesis 
and through activation of transcriptional programs that ultimately serve to 
increase ER protein-folding capacity. Recently, we and Park et al. have 
characterized a novel function for the p85α and p85β subunits as modulators of 
the UPR by virtue of their ability to facilitate the nuclear entry of XBP-1s 
following induction of ER stress (Park, S. W., Zhou, Y., Lee, J., Lu, A., Sun, 
C., Chung, J., Ueki, K., and Ozcan, U. (2010). Regulatory subunits of PI3K, 
p85alpha and p85 beta, interact with XBP1 and increase its nuclear 
translocation. Nat. Med. 16, 429-437; Winnay, J. N., Boucher, J., Mori, M. A., 
Ueki, K., and Kahn, C. R. (2010). A regulatory subunit of phosphoinositide 
3-kinase increases the nuclear accumulation of X-box-binding protein-1 to 
modulate the unfolded protein response. Nat. Med. 16, 438-445.). This chapter 
describes the recently elucidated role for the regulatory subunits of PI 
3-kinase as modulators of the UPR and provides methods to measure UPR pathway 
activation.