Abstract

The cell-surface proteome controls numerous cellular functions and is dynamically controlled by endocytosis and recycling under different cellular conditions. Energy stress is a state in which a cell must engage adaptive responses to ensure survival, including remodelling of the cell-surface proteome. AMP-activated protein kinase (AMPK) is an important metabolic regulator in the cell. Recent studies suggest AMPK activation may alter the endocytosis of a few specific proteins. How increased AMPK activity globally regulates the cell surface proteome is not known. I have developed a method to isolate the cell surface proteome from cultured cells. Coupling this method to quantitative mass spectrometry has allowed systematic identification of changes in the cell-surface proteome upon metabolic regulation. I found that activation of AMPK results in robust changes in the cell surface proteome, including cell adhesion and migration proteins. I confirmed that AMPK activation elicits a decrease in the cell surface abundance of the adhesion and migration protein β1-integrin, and that this is correlated with altered function of the endocytosis protein Dab2. Thus, my research furthers our understanding of how AMPK regulates the cell surface proteome and the specific mechanism by which AMPK regulates cellular adhesion and migration.

Highlights

  • Proteins on the surface of cells control numerous aspects of cellular function including signaling, nutrient uptake, and adhesion

  • The proteins identified by this method were subjected to Gene Ontology (GO) clustering to identify cellular processes involving cell surface proteins that are regulated by AMPK activation

  • Mass spectrometry experiments and functional clustering analysis revealed a connection between AMPK activation and changes in cellular adhesion and migration. β1-integrin is the major binding partner for integrins α4 and α11 and for other alpha integrins not identified in the screen but known binding partners. β1-integrin is, a candidate target protein to be regulated by AMPK upon energetic stress

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Summary

Introduction

Proteins on the surface of cells control numerous aspects of cellular function including signaling, nutrient uptake, and adhesion. The profile of all the proteins on the cell surface is termed the “cell surface proteome”. These proteins exact their function by necessarily gaining access to the extracellular milieu – extracellular matrix proteins, hormones, nutrients, and so on. Glucose Transporter type 1 (GLUT-1) is an important sugar transporter responsible for the uptake of glucose into the cell. Adhesion molecules are responsible for forming contact sites with the extracellular matrix (ECM) or with other cells. Integrins are adhesion proteins that facilitate coupling of the ECM to the cytoskeleton and regulate cellular adhesion and migration

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