Abstract
The classic neurotrophins Nerve Growth Factor (NGF), Brain Derived Neurotrophic Factor (BDNF) and Neurotrophins NT-3 and NT-4 are well known to regulate various aspects of neuronal differentiation, survival and growth. They do this by binding to their cognate receptors, members of the Tropomyosin-related kinase (Trk) receptor tyrosine kinase family, namely TrkA, TrkB, and TrkC. These receptors are then internalized and localized to different cellular compartments, where signal transduction occurs. Conversely, members of the suppressor of cytokine signaling (SOCS) family are best known as negative regulators of signaling via the JAK/STAT pathway. Some members of the family, and in particular SOCS2, have roles in the nervous system that at least partially overlap with that of neurotrophins, namely neuronal differentiation and neurite outgrowth. Recent evidence suggests that SOCS2 is a novel regulator of NGF signaling, altering TrkA cellular localization and downstream signaling to affect neurite growth but not neuronal survival. This review first discusses regulation of Trk receptor signaling, followed by the role of SOCS2 in the nervous system and finishes with a discussion of possible mechanisms by which SOCS2 may regulate TrkA function.
Highlights
A great deal of interest has focused on the therapeutic potential of neurotrophins to prevent neurodegeneration and promote neural regeneration in a range of neurological diseases and neurotrauma (Allen et al, 2011; Colafrancesco and Villoslada, 2011; Ossipov, 2011; Duman and Voleti, 2012)
Mice lacking both STAT5b and SOCS2 and were found to grow normally (Greenhalgh et al, 2002b) which suggested that the SOCS2 modulation of Janus kinases (JAKs)/STAT signaling downstream of the growth hormone (GH) receptor depends on the activity of STAT5b
Depletion of NHE5 [a Na(+)/H(+) exchanger that acidifies recycling endosomes to promote cell surface expression] resulted in decreased levels of TrkA at the cell surface in PC12 cells, with concomitant decreased phosphorylation of AKT and ERK1/2 and decreased neurite outgrowth in response to Nerve Growth Factor (NGF) treatment (Diering et al, 2013). Neurotrophins and their receptors are expressed in specific areas throughout the nervous system. Their expression levels, signal transduction pathways and localization are tightly regulated by a range of different mechanisms, including dephosphorylation and degradation
Summary
Regulation of neurotrophin receptor (Trk) signaling: suppressor of cytokine signaling 2 (SOCS2) is a new player. The classic neurotrophins Nerve Growth Factor (NGF), Brain Derived Neurotrophic Factor (BDNF) and Neurotrophins NT-3 and NT-4 are well known to regulate various aspects of neuronal differentiation, survival and growth. They do this by binding to their cognate receptors, members of the Tropomyosin-related kinase (Trk) receptor tyrosine kinase family, namely TrkA, TrkB, and TrkC. These receptors are internalized and localized to different cellular compartments, where signal transduction occurs.
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