Suppression of Tubulin Polymerization by the LKB1-Microtubule-associated Protein/Microtubule Affinity-regulating Kinase Signaling

Yasushi Kojima,Hiroyuki Miyoshi,Hans C Clevers,Masanobu Oshima,Masahiro Aoki,Makoto M Taketo

doi:10.1074/jbc.m700590200

Abstract

LKB1, a tumor suppressor gene mutated in the Peutz-Jeghers syndrome, encodes a serine/threonine protein kinase. Recent biochemical studies have shown that LKB1 activates 14 AMP-activated protein kinase-related kinases including MARKs (microtubule-associated protein/microtubule affinity-regulating kinases) that regulate microtubule dynamics. Here we show in vitro that LKB1 phosphorylates and activates MARK2, which in turn phosphorylates microtubule-associated protein Tau at the KXGS motif and suppresses tubulin polymerization. In cells, forced expression of LKB1 suppresses microtubule regrowth, whereas LKB1 knockdown accelerates it. We further show that the phosphorylation of Tau by the LKB1-MARK signaling triggers proteasome-mediated degradation of Tau. These results indicate that LKB1 is involved in the regulation of microtubule dynamics through the activation of MARKs.

Highlights

Regarding the normal functions of LKB1, several lines of evidence indicate that LKB1 plays an important role in cell polarity
Suppression of Tubulin Polymerization by LKB1 in Vitro—To examine the potential role of LKB1 in MT dynamics, we first tested whether LKB1 would affect Tau phosphorylation in vitro
We examined whether LKB1 activity could modulate the activity of MARK2 in phosphorylating microtubule-associated protein Tau at serine 262 of the KXGS motif [39]

Summary

Introduction

Regarding the normal functions of LKB1, several lines of evidence indicate that LKB1 plays an important role in cell polarity. We examined the roles of LKB1 on the in vitro tubulin polymerization reaction in the presence of 0.3 ␮M Tau protein (Fig. 1C).

Results

Conclusion