Figure 3.

csGRP78 functions as a signaling receptor that mediates cell proliferation or apoptosis. At the cell surface, GRP78 associates with GPI-anchored proteins. Activated α₂M binds to csGRP78 and activates the PI3K/AKT pathway, which stimulates the PDK1/PLK1 pathway to upregulate c-MYC expression and cell proliferation (red arrows). Similarly, T-cadherin interacts with GRP78 to activate the PI3K/AKT pathway and stimulates GSK3β to increase cell proliferation (green arrows). Furthermore, Cripto binds to csGRP78 and inhibits TGF-β-mediated Smad2/3 activation and results in cell proliferation (yellow arrows). Cell surface GRP78 can also induce apoptosis through isthmin-1 interacting with csGRP78 to allow for GRP78 internalization. This leads to the inhibition of mitochondrial ATP transport and apoptosis (blue arrows). Furthermore, Kringle 5 interacts with csGRP78, which enhances caspase 7 activity (purple arrows). Moreover, Par-4 binds to GRP78 and activates the FADD-induced caspase 8/caspase 3 pathway to lead to apoptosis (maroon arrows). Image generated with BioRender.