Calreticulin mediates nerve growth factor-induced neuronal differentiation.

The nerve growth factor (NGF)/TrkA-signaling is necessary for neural development, and its abnormality has been tightly associated with the tumorigenesis of various cancers originated from the nervous system. The characterization of key molecules involved in the NGF/TrkA-mediated neuronal differentiation could pave the way for the development of novel therapeutic strategies against neural malignancy. We have previously demonstrated that calreticulin (CRT) is a favorable prognostic factor highly expressed in primary neuroblastomas (NBs) with a more differentiated histology. In the present study, we found that the level of CRT was enhanced in NGF-stimulated differentiation of PC-12 cells through the extracellular signal-regulated kinase (ERK)-dependent mitogen-activated protein kinase (MAPK) pathway. A deficiency of CRT significantly decreased NGF-elicited neuronal differentiation. Furthermore, overexpression of CRT enhanced neuronal differentiation via simultaneously activating the ERK-dependent MAPK pathway. The Ca(2+)-regulating capacity of CRT was demonstrated to be indispensable for NGF-elicited neuronal differentiation. Intriguingly, the expression levels of CRT and NGF receptor TrkA were highly correlated in NBs with differentiated histology, and the coexistence of CRT and TrkA in NB tumors synergistically predicted a better 5-year survival rate. Together, our present findings delineate a CRT-dependent regulation of NGF-induced neuronal differentiation.