Extracellular Matrix Remodeling Regulates Glucose Metabolism through TXNIP Destabilization

William J Sullivan; Peter J Mullen; Ernst W Schmid; Aimee Flores; Milica Momcilovic; Mark S Sharpley; David Jelinek; Andrew E Whiteley; Matthew B Maxwell; Blake R Wilde; Utpal Banerjee; Hilary A Coller; David B Shackelford; Daniel Braas; Donald E Ayer; Thomas Q de Aguiar Vallim; William E Lowry; Heather R Christofk

doi:10.1016/j.cell.2018.08.017

Extracellular Matrix Remodeling Regulates Glucose Metabolism through TXNIP Destabilization

Cell. 2018 Sep 20;175(1):117-132.e21. doi: 10.1016/j.cell.2018.08.017. Epub 2018 Sep 6.

Authors

William J Sullivan¹, Peter J Mullen², Ernst W Schmid², Aimee Flores³, Milica Momcilovic⁴, Mark S Sharpley⁵, David Jelinek⁵, Andrew E Whiteley², Matthew B Maxwell², Blake R Wilde⁶, Utpal Banerjee⁷, Hilary A Coller⁸, David B Shackelford⁹, Daniel Braas¹⁰, Donald E Ayer⁶, Thomas Q de Aguiar Vallim¹¹, William E Lowry¹², Heather R Christofk¹³

Affiliations

¹ Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
² Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
³ Department of Molecular, Cell, and Developmental Biology, UCLA, Los Angeles, CA 90095, USA; Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA.
⁴ Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
⁵ Department of Molecular, Cell, and Developmental Biology, UCLA, Los Angeles, CA 90095, USA.
⁶ Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
⁷ Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Molecular, Cell, and Developmental Biology, UCLA, Los Angeles, CA 90095, USA; Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA 90095, USA.
⁸ Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Molecular, Cell, and Developmental Biology, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA.
⁹ Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA.
¹⁰ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA; UCLA Metabolomics Center, Los Angeles, CA 90095, USA.
¹¹ Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
¹² Department of Molecular, Cell, and Developmental Biology, UCLA, Los Angeles, CA 90095, USA; Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA.
¹³ Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA. Electronic address: hchristofk@mednet.ucla.edu.

Abstract

The metabolic state of a cell is influenced by cell-extrinsic factors, including nutrient availability and growth factor signaling. Here, we present extracellular matrix (ECM) remodeling as another fundamental node of cell-extrinsic metabolic regulation. Unbiased analysis of glycolytic drivers identified the hyaluronan-mediated motility receptor as being among the most highly correlated with glycolysis in cancer. Confirming a mechanistic link between the ECM component hyaluronan and metabolism, treatment of cells and xenografts with hyaluronidase triggers a robust increase in glycolysis. This is largely achieved through rapid receptor tyrosine kinase-mediated induction of the mRNA decay factor ZFP36, which targets TXNIP transcripts for degradation. Because TXNIP promotes internalization of the glucose transporter GLUT1, its acute decline enriches GLUT1 at the plasma membrane. Functionally, induction of glycolysis by hyaluronidase is required for concomitant acceleration of cell migration. This interconnection between ECM remodeling and metabolism is exhibited in dynamic tissue states, including tumorigenesis and embryogenesis.

Keywords: GLUT1 trafficking; TXNIP; ZFP36; cell biology; cell migration; extracellular matrix; glucose metabolism; hyaluronidase; mRNA degradation; receptor tyrosine kinase signaling.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Carbohydrate Metabolism / physiology
Carrier Proteins / metabolism
Carrier Proteins / physiology*
Cell Line, Tumor
Extracellular Matrix / metabolism*
Extracellular Matrix / physiology*
Glucose / metabolism
Glucose Transporter Type 1
Glycolysis / physiology
Humans
Hyaluronic Acid / physiology
Hyaluronoglucosaminidase / pharmacology
Intercellular Signaling Peptides and Proteins / metabolism
Signal Transduction
Tristetraprolin / metabolism
Tristetraprolin / physiology

Substances

Carrier Proteins
Glucose Transporter Type 1
Intercellular Signaling Peptides and Proteins
SLC2A1 protein, human
TXNIP protein, human
Tristetraprolin
ZFP36 protein, human
Hyaluronic Acid
Hyaluronoglucosaminidase
Glucose

Abstract

Publication types

MeSH terms

Substances

Grants and funding