Abstract
Neurotrophins are a family of proteins that are important for neuronal development, neuronal survival and neuronal functions. Neurotrophins exert their role by binding to their receptors, the Trk family of receptor tyrosine kinases (TrkA, TrkB, and TrkC) and p75NTR, a member of the tumor necrosis factor (TNF) receptor superfamily. Binding of neurotrophins to receptors triggers a complex series of signal transduction events, which are able to induce neuronal differentiation but are also responsible for neuronal maintenance and neuronal functions. Rab proteins are small GTPases localized to the cytosolic surface of specific intracellular compartments and are involved in controlling vesicular transport. Rab proteins, acting as master regulators of the membrane trafficking network, play a central role in both trafficking and signaling pathways of neurotrophin receptors. Axonal transport represents the Achilles' heel of neurons, due to the long-range distance that molecules, organelles and, in particular, neurotrophin-receptor complexes have to cover. Indeed, alterations of axonal transport and, specifically, of axonal trafficking of neurotrophin receptors are responsible for several human neurodegenerative diseases, such as Huntington’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis and some forms of Charcot-Marie-Tooth disease. In this review, we will discuss the link between Rab proteins and neurotrophin receptor trafficking and their influence on downstream signaling pathways.
Highlights
Neurotrophins constitute a small family of growth factors that play a key role in several different aspects of the development and maintenance of the nervous system
When neurotrophins bind to tropomyosin-receptor kinases (Trks) receptors, they lead to Trk dimerization and phosphorylation of specific tyrosine residues in the cytoplasmic domain, initiating signaling cascades
The anterograde transport of plasmalemmal precursor vesicles, which are found in growing neurites and involved in plasma membrane expansion, is mediated by a complex formed of three elements, c-Jun N-terminal kinase-interacting protein 1 (JIP1), kinesin-1 light chain (KLC) and GTP-bound Rab10 [111,112,113]
Summary
Neurotrophins constitute a small family of growth factors that play a key role in several different aspects of the development and maintenance of the nervous system. Secreted neurotrophins bind to their receptors and initiate signaling cascades that serve to communicate with the nucleus in order to regulate neuronal growth, differentiation, survival and maintenance [8]. Rab proteins are a large family small GTPases that direct intracellular vesicular trafficking. In the active state, which is induced by GEFs (guanine nucleotide exchange factors), Rab proteins are able to bind to a number of effector proteins that regulate a wide range of membrane transport processes and cell signaling transduction pathways [12]. Rab GTPases determine compartment identity and function by ordering membrane trafficking events [13,14]. We will focus on the role of Rab proteins in the regulation of neurotrophin receptors trafficking, highlighting their role in modulating neurotrophin signaling and functions. We will consider neuropathological conditions caused by defective neurotrophin signaling, possibly due to alterations of neurotrophin axonal transport
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