Regulation of neurotrophin receptor (Trk) signaling: suppressor of cytokine signaling 2 (SOCS2) is a new player

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.

Keywords: DRG neurons; NGF; PC12 cells; SOCS-2; Trk receptors; neurite outgrowth; signal transduction; ubiquitin.

Figure 1

Domain organization of the Trk neurotrophin receptors. This figure highlights the key structural elements of the Trk neurotrophin receptors; the extracellular ligand-binding domain comprising leucine-rich motifs (LRR1-3), two cysteine clusters (C1 and C2) and two immunoglobulin-like domains (Ig1 and Ig2), the transmembrane domain, and the intracellular tyrosine kinase domain. Critical tyrosine residues of the human TrkA intracellular domain are highlighted. Tyrosine residues at positions 670, 674, and 675 are located in the activation loop of the human TrkA tyrosine kinase domain. Tyrosine 490 forms a PTB binding motif (NPXpY) known to bind SHC and FRS2 (Obermeier et al., ; Ong et al., 2000) and tyrosine 785 binds to PLCγ (Obermeier et al., 1993a). The juxtamembrane KFG motif is an ubiquitination site involved in receptor localization.

Figure 2

Trk receptor signaling pathways. Upon neurotrophin binding, the activated Trk receptors engage various intracellular signaling pathways such as those mediated by extracellular signal-regulated kinases (ERKs), phosphatidylinositol 3-kinase (PI3K) and phospholipase Cγ (PLC-γ) to promote cellular differentiation, growth, survival, synaptic plasticity and changes to cell motility (adapted from Huang and Reichardt, 2003). Critical tyrosine (Y) residues of the human TrkA intracellular domain are shown. Direct, indirect and inhibitory pathways are denoted by solid arrows, dashed arrows and blunt arrows respectively.

Figure 3

Inhibition of JAK-STAT cytokine signaling by the SOCS proteins. The different SOCS proteins can inhibit JAK-STAT signaling via different mechanisms including competition for STAT binding sites on activated receptors, direct inhibition of JAK kinase activity or targeting of associated signaling molecules for proteasomal degradation. Adapted from Palmer and Restifo (2009).

Figure 4

Domain organization of the SOCS proteins. Each of the 8 SOCS proteins (SOCS1-7 and CIS) comprise a variable N-terminal region, a central Src Homology 2 (SH2) domain to recognize motifs containing phosphorylated tyrosine residues and a highly conserved C-terminal SOCS box to facilitate association with components of the ubiquitin ligase machinery such as elongin BC and cullin5. The kinase inhibitory region (KIR) (Sasaki et al., ; Yasukawa et al., ; Kershaw et al., 2013) within the extended SH2 subdomain (ESS) of SOCS1 and SOCS3 are denoted by an asterisk. The most closely related pairs of SOCS proteins according to amino acid sequence similarity are denoted on the right.