The presence of misfolded proteins in the endoplasmic reticulum (ER) is sensed by cells and initiates a stress response. In yeast, the transmembrane protein IRE1p senses misfolded proteins and produces signals that lead to appropriate changes in gene expression. Mammalian cells have related transmembrane proteins known as IRE1α and IRE1β that also appear to act as receptors for improperly folded proteins. Urano et al . report that IRE1 appears to activate the c-Jun NH2-terminal kinase (Jnk) in much the same way as do tumor necrosis factor α receptors on the cell surface--that is, IRE1 appears to bind to a TRAF (TNF receptor-associated factors) protein. Such interaction with TRAF2 appears to initiate a cascade of activation of protein kinases that leads to activation of Jnk. Cells can apparently use similar signaling mechanisms to sense and transmit both intracellular and extracellular signals. Urano, F., Wang, X.Z., Bertolotti, A., Zhang, Y., Chung, P., Harding, H.P., and Ron, D. (2000) Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287: 664-666. [Abstract] [Full Text]