LNX1/LNX2 proteins: functions in neuronal signalling and beyond.

Paul W Young

doi:10.1042/ns20170191

Abstract

Ligand of NUMB Protein X1 and X2 (LNX1 and LNX2) are E3 ubiquitin ligases, named for their ability to interact with and promote the degradation of the cell fate determinant protein NUMB. On this basis they are thought to play a role in modulating NUMB/NOTCH signalling during processes such as cortical neurogenesis. However, LNX1/2 proteins can bind, via their four PDZ (PSD95, DLGA, ZO-1) domains, to an extraordinarily large number of other proteins besides NUMB. Many of these interactions suggest additional roles for LNX1/2 proteins in the nervous system in areas such as synapse formation, neurotransmission and regulating neuroglial function. Twenty years on from their initial discovery, I discuss here the putative neuronal functions of LNX1/2 proteins in light of the anxiety-related phenotype of double knockout mice lacking LNX1 and LNX2 in the central nervous system (CNS). I also review what is known about non-neuronal roles of LNX1/2 proteins, including their roles in embryonic patterning and pancreas development in zebrafish and their possible involvement in colorectal cancer (CRC), osteoclast differentiation and immune function in mammals. The emerging picture places LNX1/2 proteins as potential regulators of multiple cellular signalling processes, but in many cases the physiological significance of such roles remains only partly validated and needs to be considered in the context of the tight control of LNX1/2 protein levels in vivo.

Highlights

The ligand of NUMB protein X (LNX) (Ligand of NUMB Protein-X) protein family evolved from a common ancestral protein that contained a really interesting new gene (RING) (Really Interesting New Gene) domain and four PDZ (PSD95, DLGA, ZO-1) domains [1]
NOTCH signalling is known to play multiple roles in maintaining bone homoeostasis and controlling osteoclast differentiation [47,48]. These findings suggest that the effects of LNX2 on osteoclast formation could be mediated by modulation of NOTCH2 signalling through NUMB
Two decades of research have highlighted a multitude of potential functions for LNX1/2 proteins have either an NPAY (LNX1)/2 proteins, based largely on their ability to interact with many binding partners (Figure 2 and Table 1)

Summary

Introduction

The LNX (Ligand of NUMB Protein-X) protein family evolved from a common ancestral protein that contained a RING (Really Interesting New Gene) domain and four PDZ (PSD95, DLGA, ZO-1) domains [1]. A number of studies have examined the general binding specificities and potential intra- and intermolecular interactions of LNX1/2 proteins via their PDZ domains.

Results

Conclusion