Plasma membrane localization of the GFL receptor components: a nexus for receptor crosstalk

Christopher R Donnelly,Brian A Pierchala

doi:10.1007/s00441-020-03235-4

Abstract

The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) comprise a group of four homologous and potent growth factors that includes GDNF, neurturin (NRTN), artemin (ARTN), and persephin (PSPN). The survival, growth, and mitotic activities of the GFLs are conveyed by a single receptor tyrosine kinase, Ret. The GFLs do not bind directly to Ret in order to activate it, and instead bind with high affinity to glycerophosphatidylinositol (GPI)-anchored coreceptors called the GDNF family receptor-αs (GFRαs). Several mechanisms have recently been identified that influence the trafficking of Ret and GFRαs in and out of the plasma membrane, thereby affecting their availability for ligand binding, as well as their levels by targeting to degradative pathways. This review describes these mechanisms and their powerful effects on GFL signaling and function. We also describe the recent discovery that p75 and Ret form a signaling complex, also regulated by plasma membrane shuttling, that either enhances GFL survival signals or p75 pro-apoptotic signals, dependent on the cellular context.

Highlights

In the past, illustrations detailing neurotrophic factor signaling pathways often indicated relatively simplistic interactions between well-established ligand-receptor pairs, with each complex separately leading to the activation of downstream signaling cascades controlling a variety of cell fates
For example, nerve growth factor (NGF) binds to TrkA, brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4) bind to TrkB, and neurotrophin-3 binds to TrkC, and all four ligands can bind with reduced affinity to p75 (Reichardt 2006)
We provide a brief overview of neurotrophic factor receptor crosstalk with an emphasis on Ret, the receptor tyrosine kinase for the glial cell line-derived neurotrophic factor (GDNF) family of ligands (GFLs), for which all three of these mechanisms has recently come to light

Summary

Introduction

Illustrations detailing neurotrophic factor signaling pathways often indicated relatively simplistic interactions between well-established ligand-receptor pairs, with each complex separately leading to the activation of downstream signaling cascades controlling a variety of cell fates. Phosphorylation of Ret increases with age in sympathetic neurons, both in vitro and in vivo, and in a manner which is both GFLand GFRα-independent (Tsui-Pierchala et al 2002) Instead, this effect was found to be dependent on NGF/TrkA signaling and required several hours to induce maximal Ret activation. The apoptotic function of Ret in developing sympathetic neurons raises the question of whether Ret acts as a dependence receptor, in which the binding of ligand (GFLs) induces kinase activity and downstream signaling cascades leading to survival, but in the absence of ligand Ret actively signals apoptosis (Bordeaux et al 2000) While this is an alluring mechanism, in this context, Ret appears to act in concert with p75 to enhance p75-dependent apoptotic signaling. It has recently been reported that the tyrosine kinase activity of TrkA is critical for apoptosis triggered by NGF withdrawal from sympathetic neurons (Feinberg et al 2017), and whether Ret kinase activity is required its apoptotic function is an important unanswered question

Summary

Findings

Compliance with ethical standards