New tricks for KDEL receptors

The function of KDEL receptors (KDELR) is to capture endoplasmic reticulum (ER)-resident chaperones in the acidic environment of the Golgi apparatus, by recognizing their C-terminal motif, and retrieve them back to the ER [1]. Certain structural features of KDELR, for example a similar topology to that of G-protein-coupled receptors (GPCR), a large family of proteins involved in virtually all pathways of cellular signaling, hinted to a more sophisticated activity. Specifically, binding of chaperones to KDELR recruits additional G proteins and trigger signaling pathways that result in the activation of both retrograde and anterograde transport, effectively dispatching the incoming membraane load at the Golgi during activated secretion [2, 3]. These findings place KDLER at the center of a complex system of signals, which originate at the Golgi but exert their effects at multiple levels. Two recent papers have shed new light on the role of KDELR by implicating them in as diverse functions as cell invasion [4] and virus infection [5]. The traffic sensor hypothesis posits that, in the Golgi, chaperones bind to KDELR and trigger a G q-dependent activation of Src, accelerating anterograde transport [2]. Ruggiero et al. zoomed in on the role of this molecular device in invadopodia formation, a Src-dependent process that requires activation of the exocytic machinery for extracellular matrix (ECM) degradation and invasive growth [4]. They found that persistent stimulation of KDELR increased ECM degradation, and that inhibition produced the expected opposite effect. These observations correlated with the presence of phosphorylated Src in the regions overlapping ECM degradation patches. KDLER stimulation led to tyrosine phosphorylation of ASAP1, a known Src effector, and experimental manipulations leading to either activation or inhibition of ASAP1 resulted in the predicted effect on ECM degradation. If Src regulates the signaling pathway leading to ECM degradation, however, any change in its activity will impact this process. The authors speculate that a KDELR-dependent mechanism may be operational under specific circumstances, because the microenvironment of solid tumors is characterized by low oxygen, which, in turn, triggers the unfolded protein response and chaperone overexpression. This would be equivalent to a chronic stimulation of KDELR by an overabundance of ligands, activating a signaling circuit that links KDELR to Src phosphorylation, invadopodia formation and ECM degradation, facilitating tumor dissemination. This possibility will no doubt be tested in more relevant cellular and animal models. KDELR travel without cargo to the Golgi because binding to the KDEL motif is …