title: ErbB2-dependent chemotaxis requires microtubule capture and stabilization coordinated by distinct signaling pathways.
abstract: 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 (PLCγ) also contributed to cell guidance. We further showed that PLCγ 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.
authors: Centre de Recherche en Cancérologie de Marseille, Inserm U1068, Marseille, France.
authors: Khedidja
authors: K
authors: Benseddik
authors: Nadine
authors: N
authors: Sen Nkwe
authors: Pascale
authors: P
authors: Daou
authors: Pascal
authors: P
authors: Verdier-Pinard
authors: Ali
authors: A
authors: Badache
mesh_terms: D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002633:Chemotaxis / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D008870:Microtubules / Q000502:physiology*; D008954:Models, Biological; D020890:Neuregulin-1 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D020890:Neuregulin-1; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; C087230:heregulin beta1; C508053:ERBB2 protein, human
references: J Biol Chem. 2001 Jan 19;276(3):1677-80
references: 11058583
references: J Mammary Gland Biol Neoplasia. 2006 Jan;11(1):13-25
references: 16947083
references: J Biol Chem. 1998 Oct 23;273(43):28238-46
references: 9774445
references: Nat Rev Mol Cell Biol. 2001 Feb;2(2):127-37
references: 11252954
references: J Cell Biol. 2003 Sep 15;162(6):963-9
references: 12975343
references: Nat Cell Biol. 2004 Jun;6(6):515-22
references: 15156151
references: J Cell Biol. 1998 Jun 1;141(5):1147-57
references: 9606207
references: Science. 2003 Dec 5;302(5651):1704-9
references: 14657486
references: Science. 2004 Apr 30;304(5671):743-6
references: 15118165
references: EMBO J. 1996 Jan 15;15(2):254-64
references: 8617201
references: Cell. 2012 Feb 3;148(3):502-14
references: 22304918
references: EMBO J. 2000 Jul 3;19(13):3159-67
references: 10880430
references: Exp Cell Res. 1995 Dec;221(2):526-9
references: 7493653
references: Science. 1987 Jan 9;235(4785):177-82
references: 3798106
references: J Cell Sci. 2009 Mar 15;122(Pt 6):787-97
references: 19223396
references: Cell. 2008 Oct 3;135(1):137-48
references: 18854161
references: J Cell Biol. 2008 Nov 3;183(3):401-8
references: 18955552
references: Curr Opin Cell Biol. 2002 Feb;14(1):18-24
references: 11792540
references: J Cell Sci. 2001 Nov;114(Pt 21):3795-803
references: 11719546
references: Mol Cell Biol. 2003 Nov;23(22):8058-69
references: 14585966
references: Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18517-22
references: 20937854
references: Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4182-7
references: 20160093
references: J Biol Chem. 1997 Oct 3;272(40):25029-36
references: 9312110
references: Cell Mol Life Sci. 2009 Oct;66(20):3263-76
references: 19585080
references: Front Mol Neurosci. 2011 Nov 23;4:48
references: 22131966
references: Cell. 2001 Aug 24;106(4):489-98
references: 11525734
references: Cell. 2005 Jan 14;120(1):137-49
references: 15652488
references: Cancer Res. 2006 Oct 1;66(19):9591-600
references: 17018616
references: J Cell Sci. 1999 Oct;112 ( Pt 19):3373-84
references: 10504342
references: Nature. 2003 Feb 13;421(6924):753-6
references: 12610628
references: Semin Cell Dev Biol. 2011 Dec;22(9):968-74
references: 22001384
references: J Cell Biol. 2000 Jan 24;148(2):385-97
references: 10648571
references: Curr Biol. 2006 Nov 21;16(22):2193-205
references: 17113383
references: Mol Biol Cell. 2006 Dec;17(12):5004-16
references: 16987962
references: J Biol Chem. 2003 Aug 15;278(33):31020-3
references: 12754216
references: EMBO J. 1997 Apr 1;16(7):1647-55
references: 9130710
references: Dev Cell. 2011 Dec 13;21(6):1038-50
references: 22172670
references: J Biol Chem. 2000 Dec 29;275(52):41201-9
references: 10995762
references: Biochem J. 1998 Jun 1;332 ( Pt 2):281-92
references: 9601053
references: J Cell Biol. 2010 Nov 1;191(3):585-98
references: 21041448