The PI3K-Akt pathway promotes microtubule stabilization in migrating fibroblasts.
Directed cell migration is controlled by extracellular cues such as growth factors/chemokines and extracellular matrix. In a migrating cell, a subset of microtubules becomes stabilized, and this stabilization is implicated in the establishment and maintenance of cell polarity. It is still not fully understood, however, how extracellular cues regulate the dynamics of microtubules. Here we show that the PI3K-Akt signaling pathway plays a pivotal role in growth factor regulation of microtubule stability. Treatment of NIH 3T3 fibroblasts with platelet-derived growth factor (PDGF) increases the amount of stabilized microtubules, and this increase is abrogated by the addition of a PI3K inhibitor or by expression of a dominant-negative form of Akt (DN-Akt), but not by the addition of a MEK inhibitor. Expression of an active form of Akt slightly increases the bulk amount of stabilized microtubules. Stabilization of microtubules induced in edge cells in the wounded monolayer culture is also attenuated by the PI3K inhibitor treatment or by expression of DN-Akt. Given that Akt is activated at the leading edge of a migrating cell and plays an essential role in directed cell migration, these results reveal a novel mechanism linking extracellular cues to directed cell migration, namely Akt regulation of microtubule stability.
Onishi
Keisuke
K
Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Higuchi
Maiko
M
Asakura
Tomoko
T
Masuyama
Norihisa
N
Gotoh
Yukiko
Y
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism; D002070:Butadienes / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D002867:Chromones / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D008870:Microtubules / Q000378:metabolism*; D009025:Morpholines / Q000378:metabolism; D041681:NIH 3T3 Cells; D009570:Nitriles / Q000378:metabolism; D015739:Nocodazole / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D000970:Antineoplastic Agents; D002070:Butadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D009570:Nitriles; D010982:Platelet-Derived Growth Factor; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020930:MAP Kinase Kinase Kinases; D015739:Nocodazole