Suppression of tubulin polymerization by the LKB1-microtubule-associated protein/microtubule affinity-regulating kinase signaling.
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.
Kojima
Yasushi
Y
Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Miyoshi
Hiroyuki
H
Clevers
Hans C
HC
Oshima
Masanobu
M
Aoki
Masahiro
M
Taketo
Makoto M
MM
D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D006801:Humans; D008094:Lithium / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D008870:Microtubules / Q000378:metabolism*; D010766:Phosphorylation; D011108:Polymers / Q000737:chemistry; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D014404:Tubulin / Q000737:chemistry*
D011108:Polymers; D034741:RNA, Small Interfering; D014404:Tubulin; D008094:Lithium; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D046988:Proteasome Endopeptidase Complex