Plasma membrane localization of the GFL receptor components: a nexus for receptor crosstalk
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AT-A-GLANCE ARTICLE
Plasma membrane localization of the GFL receptor components: a nexus for receptor crosstalk Christopher R. Donnelly 1 & Brian A. Pierchala 2 Received: 19 March 2020 / Accepted: 4 June 2020 # The Author(s) 2020
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. Keywords Ret . GFRα . Plasma membrane . Intracellular trafficking . GDNF . GFLs . TGF-β regulation
Introduction 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. Within the neurotrophin family, 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). However, as our understanding of neurotrophic factor signaling has evolved over the last several decades, we have come to appreciate that a highly complex set of interactions exists between neurotrophic factor
* Brian A. Pierchala [email protected] 1
Department of Anesthesiology Center for Translational Pain Medicine, Duke University Medical Center, Durham, NC 27710, USA
2
Department of Anatomy, Cell Biology & Physiology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA
receptors, as well as other classes of receptors, and the cellular context of these interactions ultimately determines the fate of neurons during neural development (e.g., survival, death, differentiation, axon growth). Interactions between neurotrophic factor receptor signaling pathways have been demonstrated in a variety of cellular contexts, including (1) indirectly, via integration of shared downstream signaling pathways; (2) directly, through ligand-dependent or ligand-independent in
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