Calnexin Controls the STAT3-Mediated Transcriptional Response to EGF

Abstract

Calnexin is a well-characterized transmembrane chaperone involved in the folding of newly synthesized glycoproteins in the lumen of the endoplasmic reticulum (ER). Here, we reveal a previously unrecognized function of calnexin in regulating the transcriptional response downstream of epidermal growth factor receptor (EGF), the product of a well-known human oncogene. We find that cell stimulation with EGF leads to the caspase-8-dependent cleavage of the calnexin cytoplasmic domain, preferentially at ER-mitochondria interaction sites. The released fragment translocates into the nucleus, binds to PIAS3--a natural inhibitor of activated STAT3--and, thus, acts as an enhancer of the STAT3-mediated transcriptional response to EGF. Also, we reveal the unsuspected capacity of calnexin to sense ER stress and, in response, prevent the EGF-induced processing of its cytosolic domain. Thus, cells integrate the health status of the ER to determine the amplitude of their response to EGF.

Alantolactone selectively suppresses STAT3 activation and exhibits potent anticancer activity in MDA-MB-231 cells

“…In addition, this pretreatment decreased STAT3 activation to levels below that in unstimulated cells. EGF activates STAT3 via gp130-independent EGFR [19]. We examined whether alantolactone inhibits EGF-stimulated STAT3 phosphorylation.…”

UBC9-dependent Association between Calnexin and Protein Tyrosine Phosphatase 1B (PTP1B) at the Endoplasmic Reticulum

“…7C). Indeed, the C-tail of calnexin has been proposed to play an important role in the regulation of protein-protein interactions via post-translational modification: the C-tail has been shown to be phosphorylated and palmitoylated, both of which promote calnexin interaction with the ribosome-translocon complex (6,9,11,12,(42)(43)(44)(45).…”

“…Calnexin spans the ER membrane with a large portion of the C-terminal domain (C-tail) residing in the cytoplasm where it may play a role in substrate folding (5,6). The C-tail undergoes distinct posttranslational modifications including phosphorylation and palmitoylation (7)(8)(9)(10)(11)(12). The C-tail also affects FGF-dependent STAT3 signaling (13).…”

The many functions of the endoplasmic reticulum chaperones and folding enzymes

“…For example, calreticulin impacts WNT3a secretion affecting downstream signaling , whereas GRP94 is involved in cell surface expression of LRP6 (lipoprotein receptor‐related protein 6) and activation Wnt signaling . Another example of functional specialization of the ER chaperones is STAT3 signaling pathway affected by calnexin and ERp57 independently. ERp57 indirectly inhibits STAT3 activity whereas calnexin enhances STAT3‐mediated transcriptional activity through binding STAT3 inhibitor upon EGF activation .…”

“…Another example of functional specialization of the ER chaperones is STAT3 signaling pathway affected by calnexin and ERp57 independently. ERp57 indirectly inhibits STAT3 activity whereas calnexin enhances STAT3‐mediated transcriptional activity through binding STAT3 inhibitor upon EGF activation .…”