Merlin/ERM proteins regulate growth factor-induced macropinocytosis and receptor recycling by organizing the plasma membrane:cytoskeleton interface

Genes Dev. 2018 Sep 1;32(17-18):1201-1214. doi: 10.1101/gad.317354.118. Epub 2018 Aug 24.

Abstract

The architectural and biochemical features of the plasma membrane are governed by its intimate association with the underlying cortical cytoskeleton. The neurofibromatosis type 2 (NF2) tumor suppressor merlin and closely related membrane:cytoskeleton-linking protein ezrin organize the membrane:cytoskeleton interface, a critical cellular compartment that both regulates and is regulated by growth factor receptors. An example of this poorly understood interrelationship is macropinocytosis, an ancient process of nutrient uptake and membrane remodeling that can both be triggered by growth factors and manage receptor availability. We show that merlin deficiency primes the membrane:cytoskeleton interface for epidermal growth factor (EGF)-induced macropinocytosis via a mechanism involving increased cortical ezrin, altered actomyosin, and stabilized cholesterol-rich membranes. These changes profoundly alter EGF receptor (EGFR) trafficking in merlin-deficient cells, favoring increased membrane levels of its heterodimerization partner, ErbB2; clathrin-independent internalization; and recycling. Our work suggests that, unlike Ras transformed cells, merlin-deficient cells do not depend on macropinocytic protein scavenging and instead exploit macropinocytosis for receptor recycling. Finally, we provide evidence that the macropinocytic proficiency of NF2-deficient cells can be used for therapeutic uptake. This work provides new insight into fundamental mechanisms of macropinocytic uptake and processing and suggests new ways to interfere with or exploit macropinocytosis in NF2 mutant and other tumors.

Keywords: EGFR/ErbB2; Merlin/ERMs; cholesterol-rich domains; macropinocytosis; membrane:cytoskeleton interface.

Publication types

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

MeSH terms

  • Actomyosin / metabolism
  • Animals
  • Cell Membrane / metabolism*
  • Cells, Cultured
  • Cytoskeletal Proteins / metabolism
  • Cytoskeleton / metabolism
  • Epidermal Growth Factor / physiology*
  • ErbB Receptors / metabolism*
  • Humans
  • Mice
  • Neurofibromin 2 / genetics
  • Neurofibromin 2 / physiology*
  • Pinocytosis*
  • Protein Biosynthesis

Substances

  • Cytoskeletal Proteins
  • Neurofibromin 2
  • ezrin
  • Epidermal Growth Factor
  • Actomyosin
  • ErbB Receptors