ErbB2-Dependent Chemotaxis Requires Microtubule Capture and Stabilization Coordinated by Distinct Signaling Pathways

被引:19
作者
Benseddik, Khedidja [1 ,2 ,3 ,4 ]
Sen Nkwe, Nadine [1 ,2 ,3 ,4 ]
Daou, Pascale [1 ,2 ,3 ,4 ]
Verdier-Pinard, Pascal [1 ,2 ,3 ,4 ]
Badache, Ali [1 ,2 ,3 ,4 ]
机构
[1] INSERM, Ctr Rech Cancerol Marseille, U1068, F-13258 Marseille, France
[2] Inst J Paoli I Calmettes, F-13009 Marseille, France
[3] Aix Marseille Univ, Marseille, France
[4] CNRS, UMR7258, Marseille, France
关键词
CELL-MIGRATION; BREAST-CANCER; KINASE; PHOSPHORYLATION; POLARITY; NETWORK; PROTEIN; CDC42; ERBB2; ACTIVATION;
D O I
10.1371/journal.pone.0055211
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Activation of the ErbB2 receptor tyrosine kinase stimulates breast cancer cell migration. Cell migration is a complex process that requires the synchronized reorganization of numerous subcellular structures including cell-to-matrix adhesions, the actin cytoskeleton and microtubules. How the multiple signaling pathways triggered by ErbB2 coordinate, in time and space, the various processes involved in cell motility, is poorly defined. We investigated the mechanism whereby ErbB2 controls microtubules and chemotaxis. We report that activation of ErbB2 increased both cell velocity and directed migration. Impairment of the Cdc42 and RhoA GTPases, but not of Rac1, prevented the chemotactic response. RhoA is a key component of the Memo/ACF7 pathway whereby ErbB2 controls microtubule capture at the leading edge. Upon Memo or ACF7 depletion, microtubules failed to reach the leading edge and cells lost their ability to follow the chemotactic gradient. Constitutive ACF7 targeting to the membrane in Memo-depleted cells reestablished directed migration. ErbB2-mediated activation of phospholipase C gamma (PLC gamma) also contributed to cell guidance. We further showed that PLC gamma signaling, via classical protein kinases C, and Memo signaling converged towards a single pathway controlling the microtubule capture complex. Finally, inhibiting the PI3K/Akt pathway did not affect microtubule capture, but disturbed microtubule stability, which also resulted in defective chemotaxis. PI3K/Akt-dependent stabilization of microtubules involved repression of GSK3 activity on the one hand and inhibition of the microtubule destabilizing protein, Stathmin, on the other hand. Thus, ErbB2 triggers distinct and complementary pathways that tightly coordinate microtubule capture and microtubule stability to control chemotaxis.
引用
收藏
页数:12
相关论文
共 40 条
[1]   Heregulin regulates cytoskeletal reorganization and cell migration through the p21-activated kinase-1 via phosphatidylinositol-3 kinase [J].
Adam, L ;
Vadlamudi, R ;
Kondapaka, SB ;
Chernoff, J ;
Mendelsohn, J ;
Kumar, R .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (43) :28238-28246
[2]   A role for Cdc42 in macrophage chemotaxis [J].
Allen, WE ;
Zicha, D ;
Ridley, AJ ;
Jones, GE .
JOURNAL OF CELL BIOLOGY, 1998, 141 (05) :1147-1157
[3]   The ErbB2 signaling network as a target for breast cancer therapy [J].
Badache, Ali ;
Goncalves, Anthony .
JOURNAL OF MAMMARY GLAND BIOLOGY AND NEOPLASIA, 2006, 11 (01) :13-25
[4]   Centrosome positioning in interphase cells [J].
Burakov, A ;
Nadezhdina, E ;
Slepchenko, B ;
Rodionov, V .
JOURNAL OF CELL BIOLOGY, 2003, 162 (06) :963-969
[6]   Diacylglycerol kinase α mediates HGF-induced Rac activation and membrane ruffling by regulating atypical PKC and RhoGDI [J].
Chianale, Federica ;
Rainero, Elena ;
Cianflone, Cristina ;
Bettio, Valentina ;
Pighini, Andrea ;
Porporato, Paolo E. ;
Filigheddu, Nicoletta ;
Serini, Guido ;
Sinigaglia, Fabiola ;
Baldanzi, Gianluca ;
Graziani, Andrea .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (09) :4182-4187
[7]   The stathmin/tubulin interaction in vitro [J].
Curmi, PA ;
Andersen, SSL ;
Lachkar, S ;
Gavet, O ;
Karsenti, E ;
Knossow, M ;
Sobel, A .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (40) :25029-25036
[8]   Rac/Cdc42 and p65PAK regulate the microtubule-destabilizing protein stathmin through phosphorylation at serine 16 [J].
Daub, H ;
Gevaert, K ;
Vandekerckhove, J ;
Sobel, A ;
Hall, A .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (03) :1677-1680
[9]   The formin mDia regulates GSK3β through novel PKCs to promote microtubule stabilization but not MTOC reorientation in migrating fibroblasts [J].
Eng, Christina H. ;
Huckaba, Thomas M. ;
Gundersen, Gregg G. .
MOLECULAR BIOLOGY OF THE CELL, 2006, 17 (12) :5004-5016
[10]   Cdc42 regulates GSK-3β and adenomatous polyposis coli to control cell polarity [J].
Etienne-Manneville, S ;
Hall, A .
NATURE, 2003, 421 (6924) :753-756