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

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 mutant and other tumors.

Akt and SGK protein kinases are required for efficient feeding by macropinocytosis

“…The present work suggests that activating mutations of Akt, and possibly SGK, could drive macropinocytic feeding in mammalian cells, increasing the size of macropinosomes and hence nutrient acquisition. Consistent with this hypothesis, recent studies have shown Akt to be activated at sites of macropinocytosis, while inhibition of macropinocytosis inhibits Akt activation (Chiasson-MacKenzie et al, 2018; Erami et al, 2017; Yoshida et al, 2018). Akt inhibition does not depress macropinosome formation in macrophages, although these studies did not rule out smaller macropinosomes and reduced fluid uptake (Pacitto et al, 2017; Yoshida et al, 2015).…”

Tailoring Iron Oxide Nanoparticles for Efficient Cellular Internalization and Endosomal Escape

“…The resulting vacuolar structure is called the macropinosome, which exhibits no apparent coating structure and is usually larger than 200 nm in diameter [ 90 ]. In turn, macropinocytosis readily provides an efficient, non-specific sampling of the extracellular environment that may contribute to the regulation of cellular dynamics [ 91 , 92 ].…”

Key Role of Microtubule and Its Acetylation in a Zinc Oxide Nanoparticle–Mediated Lysosome–Autophagy System

“…We found some colocalization between fluorescein isothiocyanate (FITC)‐labeled ZNPs and caveolin staining patterns, suggesting that FITC‐ZNPs may undergo caveolin‐mediated endocytosis (Figure C). In addition, as the primary endocytosis pathway for aggregated particles, macropinocytosis was also examined using rhodamine‐labeled dextran (Rhod‐dextran, 70 kD), which enters cells exclusively via macropinocytosis . FITC‐ZNPs were observed in Rhod‐dextran‐containing vacuoles, suggesting that macropinocytosis may be another endocytosis pathway for FITC‐ZNPs (Figure C).…”

“…In addition, as the primary endocytosis pathway for aggregated particles, macropinocytosis was also examined using rhodamine-labeled dextran (Rhod-dextran, 70 kD), which enters cells exclusively via macropinocytosis. [24,25] FITC-ZNPs were observed in Rhod-dextrancontaining vacuoles, suggesting that macropinocytosis may be another endocytosis pathway for FITC-ZNPs ( Figure 1C).…”