Mitogen-activated protein kinase (MAPK/ERK) regulates adenomatous polyposis coli during growth-factor-induced cell extension

Abstract

SummaryRegulation of the microtubule-and actin-binding protein adenomatous polyposis coli (APC) is crucial for the formation of cell extensions in many cell types. This process requires inhibition of glycogen synthase kinase-3b (GSK-3b), which otherwise phosphorylates APC and decreases APC-mediated microtubule bundling. Although it is assumed, therefore, that APC phosphorylation is decreased during initiation of cell extensions, the phosphorylation state of APC has never been analyzed directly. We show here that NGF-and EGF-induced initial cell extensions result in APC phosphorylation by the MAPK/ERK pathway, which, in parallel with inhibition of GSK-3b, promotes localization of APC to the tip of cell extensions. Whereas GSK-3b inhibition promotes APC binding and stabilization of microtubules, we show that phosphorylation by ERK inhibits the interaction of APC with F-actin, and APCmediated F-actin bundling, but not APC-mediated microtubule bundling, in vitro. These results identify a previously unknown APC regulatory pathway during growth-factor-induced cell extension, and indicate that the GSK-3b and ERK pathways act in parallel to regulate interactions between APC and the cytoskeleton during the formation of cell extensions.

Biological Mechanisms Underlying Structural Changes Induced by Colorectal Field Carcinogenesis Measured with Low-Coherence Enhanced Backscattering (LEBS) Spectroscopy

“…For instance, mutation of the adenomatous polyposis coli (APC) gene is the initiating event in greater than three-quarters of all CRCs, and the APC protein is a key regulator of microtubules [29]. Moreover, there have been striking changes seen in the cytoskeleton of microscopically normal cells from patients with familial adenomatous polyposis – patients who have a germline APC mutation [30].…”

Widespread changes in transcriptome profile of human mesenchymal stem cells induced by two-dimensional nanosilicates

“…Following nanosilicates treatment, activation of the membrane can lead to differentiation and extracellular matrix deposition, following an ERK-based cascade. The kinase signaling follows similar progressions in hMSCs after growth factor stimulation to promote osteochondral differentiation ( 52 – 56 ). Evidence of hMSC inclination toward bone and cartilage lineages following nanosilicate treatment was observed with GO term enrichment ( Fig.…”

IQGAPs choreograph cellular signaling from the membrane to the nucleus

“…IQGAP1 [87] and IQGAP3 [3] both regulate the formation of membrane extensions during neurite outgrowth. Moreover, depletion of IQGAP1 [86] or IQGAP3 [98] attenuated the accumulation of adenomatous polyposis coli (APC) at the leading edge of migrating Vero cells or PC12 extensions, respectively. Additional studies are needed to elucidate the binding partners and biological roles of IQGAP3.…”