Metastasis Associated in Colon Cancer 1 (MACC1) is a novel prognostic, predictive and causal biomarker for tumor progression and metastasis in many cancer types, including colorectal cancer. Besides its clinical value, little is known about its molecular function. Its similarity to SH3BP4, involved in regulating uptake and recycling of transmembrane receptors, suggests a role of MACC1 in endocytosis. By exploring the MACC1 interactome, we identified the clathrin-mediated endocytosis (CME)-associated proteins CLTC, DNM2 and AP-2 as MACC1 binding partners. We unveiled a MACC1-dependent routing of internalized transferrin receptor towards recycling. Elevated MACC1 expression caused also the activation and internalization of EGFR, a higher rate of receptor recycling, as well as earlier and stronger receptor activation and downstream signaling. These effects are limited by deletion of CME-related protein interaction sites in MACC1. Thus, MACC1 regulates CME and receptor recycling, causing increased growth factor-mediated downstream signaling and cell proliferation. This novel mechanism unveils potential therapeutic intervention points restricting MACC1-driven metastasis.
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http://dx.doi.org/10.1007/s00018-020-03734-1 | DOI Listing |
ADMET DMPK
October 2024
Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USA.
Background And Purpose: The main features of the dynamics of the glucocorticoid receptor (GR) have been known for 50 years: 1) in the absence of glucocorticoid (G), the receptor is localized entirely in the cytoplasm; 2) upon G binding, GR is converted into a tightly bound G form and is rapidly imported into the nucleus where it can bind DNA and modulate transcription; 3) nuclear export of GR is very slow; and 4) the nuclear form of GR can recycle through an unbound form, back to the bound transcription modulating form without leaving the nucleus.
Experimental Approach: A kinetic model that captures these features is presented, a set of model parameters for dexamethasone is derived, and the clinical implication for the commonly used glucocorticoids is discussed.
Key Results: At the high concentrations normally used to describe G pharmacodynamics, the model reduces to the standard Michaelis-Menten equation with a that is a function of 4 model parameters.
J Environ Manage
December 2024
Institute of Environmental Research at the Greater Bay Area, Key Laboratory for Water Quality and Conservation of the Pearl River Delta, Ministry of Education, Guangzhou University, Guangzhou, 510006, China. Electronic address:
Anaerobic digestion of food waste is increasingly utilized for bioenergy generation, producing a byproduct known as food waste digestate (FWD), which has potential applications as a fertilizer within the circular economy. However, accumulating numerous pollutants in FWD poses significant challenges to environmental management and human health. The complex nature of these pollutants complicates both targeted and non-targeted chemical analyses, making safety evaluations difficult.
View Article and Find Full Text PDFJ Biol Chem
December 2024
School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen. Electronic address:
The formyl-peptide receptor 2 (FPR2) is a G-protein-coupled receptor (GPCR) that responds to pathogen-derived peptides and regulates both pro-inflammatory and pro-resolution cellular processes. While ligand selectivity and G-protein-signalling of FPR2 have been well characterized, molecular mechanisms controlling subsequent events such as endocytosis and recycling to the plasma membrane are less understood. Here we show the key role of the GPCR kinase 5 (GRK5) in facilitating FPR2 endocytosis and post-endocytic trafficking.
View Article and Find Full Text PDFBasic Clin Pharmacol Toxicol
January 2025
Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Raloxifene has low bioavailability due to extensive glucuronidation in the intestine and the liver, and its pharmacokinetics is associated with high intra- and interindividual variability. Some of this variability could be explained by the enterohepatic recycling of raloxifene, which is driven by transporter-mediated uptake and efflux and gut microbial deglucuronidation of raloxifene glucuronides. These individual processes involved in raloxifene disposition, however, have not been characterized in full detail.
View Article and Find Full Text PDFPLoS One
December 2024
Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Okhla, New Delhi, India.
Background: Multiple sclerosis (MS) is a complex neurological disorder marked by neuroinflammation and demyelination. Understanding its molecular basis is vital for developing effective treatments. This study aims to elucidate the molecular progression of MS using multiomics and network-based approach.
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