The 78 kDa
glucose-regulated
protein (
GRP78) is an endoplasmic reticulum chaperone, whose function is generally thought to be restricted to controlling the structural maturation of nascent
glycoproteins. However,
GRP78 also is expressed on the cell surface where it functions as a receptor for a wide variety of
ligands, behaving as an
autoantigen for several classes of
autoantibodies.
GRP78 is a signaling receptor for activated
alpha2-macroglobulin,
plasminogen kringle 5, and microplasminogen, and it plays a critical role in viral entry of coxsackie B, and
dengue fever viruses.
GRP78 is also implicated in the regulation of
tissue factor procoagulant activity and functions as a receptor for
angiogenic peptides via a mechanism independent of the
VEGF receptor. Cell surface
GRP78 is found associated with such diverse
proteins as the
voltage-dependent anion channel (VDAC), the major histocompatibility complex class I (MHC-I), the
teratocarcinoma-derived
growth factor I (Cripto), and the DnaJ-like
protein MTJ-1. These associations suggest a unique
GRP78 cell surface topography, which appears to be compartmentalized to respond differently to agonists that bind to its N- or C-terminal domains. Here, we discuss the significance of these associations, and the possible mechanisms involved in the transportation of
GRP78 from the cytosol to the cell surface.