Versatile Roles of LKB1 Kinase Signaling in Neural Development and Homeostasis

Ken-Ichiro Kuwako,Hideyuki Okano

doi:10.3389/fnmol.2018.00354

Abstract

Kinase signaling pathways orchestrate a majority of cellular structures and functions across species. Liver kinase B1 (LKB1, also known as STK11 or Par-4) is a ubiquitously expressed master serine/threonine kinase that plays crucial roles in numerous cellular events, such as polarity control, proliferation, differentiation and energy homeostasis, in many types of cells by activating downstream kinases of the AMP-activated protein kinase (AMPK) subfamily members. In contrast to the accumulating evidence for LKB1 functions in nonneuronal tissues, its functions in the nervous system have been relatively less understood until recently. In the brain, LKB1 initially emerged as a principal regulator of axon/dendrite polarity in forebrain neurons. Thereafter, recent investigations have rapidly uncovered diverse and essential functions of LKB1 in the developing and mature nervous system, such as migration, neurite morphogenesis, myelination and the maintenance of neural integrity, demonstrating that LKB1 is also a multifunctional master kinase in the nervous system. In this review article, we summarize the expanding knowledge about the functional aspects of LKB1 signaling in neural development and homeostasis.

Highlights

Liver kinase B1 (LKB1; Par-4 in Caenorhabditis elegans (C. elegans)) was originally identified by screening for genes that regulate the anterior-posterior axis in the C. elegans zygote (Kemphues et al, 1998)
In light of the combined evidence, LKB1 may sequentially function in a variety of steps in axon and dendrite development through adopting different downstream effector kinases, such as SAD-A/B, NUAK1 and SIK1/2, in the regulatory pathway of each event, highlighting the central roles of LKB1 signaling in the developmental program that constructs neurite architecture (Figure 1)
LKB1-mediated microtubule stabilization in the tip of the leading process, via local inactivation of glycogen synthase kinase 3β (GSK3β) followed by adenomatous polyposis coli (APC) binding to microtubules, is a key mechanism for the migration of developing cortical neurons (Asada et al, 2007; Asada and Sanada, 2010)

Summary

INTRODUCTION

Liver kinase B1 (LKB1; Par-4 in Caenorhabditis elegans (C. elegans)) was originally identified by screening for genes that regulate the anterior-posterior axis in the C. elegans zygote (Kemphues et al, 1998). LKB1 possesses many conserved phosphorylation sites that are mainly enriched in the C-terminal regulatory domain and are highly conserved in Drosophila, Xenopus and mammalian LKB1 (Alessi et al, 2006). These phosphorylation sites are targeted by autophosphorylation (Thr185, Thr189, Thr336 and Ser404) or by upstream kinases (Ser, Ser325, Thr366 and Ser431), such as cyclic AMP-dependent protein kinase A (PKA) and p90 ribosomal S6 protein kinase (p90RSK; Collins et al, 2000; Sapkota et al, 2002). We will introduce recent advances in elucidating the neural functions of LKB1

Neurite Development

Neuronal Migration

Cell Polarity

CONCLUDING REMARKS