CREB3L2 Modulates Nerve Growth Factor-Induced Cell Differentiation

Abstract

Nerve growth factor (NGF) stimulates numerous cellular physiological processes, including growth, differentiation, and survival, and maintains the phenotype of several neuronal types. Most of these NGF-induced processes require adaptation of the secretory pathway since they involve extensive remodeling of membranes and protein redistribution along newly formed neuritic processes. CREB3 transcription factors have emerged as signaling hubs for the regulation of numerous genes involved in the secretory pathway and Golgi homeostasis, integrating stimuli from multiple sources to control secretion, posttranslational modifications and trafficking of proteins. Although recent studies have focused on their role in the central nervous system, little is known about their participation in cell differentiation. Therefore, we aimed to analyze the expression and signaling mechanism of CREB3 transcription factor family members, using the NGF-induced PC12 cell differentiation model. Results show that NGF treatment causes Golgi enlargement and a parallel increased expression of proteins and mRNAs encoding for proteins required for membrane transport (transport factors). Additionally, a significant increase in CREB3L2 protein and mRNA levels is detected in response to NGF. Both MAPK and cAMP signaling pathways are required for this response. Interestingly, CREB3L2 overexpression hampers the NGF-induced neurite outgrowth while its inhibition enhances the morphological changes driven by NGF. In agreement, CREB3L2 overexpressing cells display higher immunofluorescence intensity of Rab5 GTPase (a negative regulator of PC12 differentiation) than control cells. Also, Rab5 immunofluorescence levels decrease in CREB3L2-depleted cells. Taken together, our findings imply that CREB3L2 is an important downstream effector of NGF-activated pathways, leading to neuronal differentiation.

MIWE: detecting the critical states of complex biological systems by the mutual information weighted entropy

“…CREB1 plays a role in cell proliferation, myogenic differentiation and other related pathways [ 20 ]. CREB3 is involved in embryonic development and the differentiation of other tissues and organs, such as osteoblast differentiation [ 21 ]. In order to visualize the downstream signaling genes regulated by these two TFs, we present the regulatory network centered on TFs (Fig.…”

CREB3L2 Regulates Hemidesmosome Formation during Epithelial Sealing

“…In this study, however, we found that the expression of N-terminal domains of CREB3L2 was reduced in GECs and PIE after GMSC sheet treatment both in vitro and in vivo. In a previous study, as a crucial downstream effector of the NGF activation pathway, the CREB3L2 protein negatively regulates neurite outgrowth (Sampieri et al 2021). The modulatory effects are similar to our results for overexpressing and knocking down CREB3L2, indicating that CREB3L2 may act as negative feedback on the formation of HDs.…”

Non-canonical Endoplasmic Reticulum Stress Transducers CREB3 family in cancer and other diseases

“…From a mechanical perspective, the C-terminal CREB3L2 binds to Patched-1 receptors on developing axons with Shh ligands, facilitating axon growth 58 . Additional findings suggest that CREB3L2 plays a significant regulatory role in modulating neuron differentiation induced by nerve growth factor, as well as oligodendrocyte maturation and apoptosis [59][60][61] . In addition to the well-studied N-terminal and C-terminal fragments, another fraction of CREB3L2, the so-called BBF2H7-derived small peptide (BSP), which was a short peptide located between the S1P and S2P splice sites and a product upon RIP during ER stress, was found in many neural tissues.…”