title: Endosomal-sorting complexes required for transport (ESCRT) pathway-dependent endosomal traffic regulates the localization of active Src at focal adhesions.
abstract: Active Src localization at focal adhesions (FAs) is essential for cell migration. How this pool is linked mechanistically to the large pool of Src at late endosomes (LEs)/lysosomes (LY) is not well understood. Here, we used inducible Tsg101 gene deletion, TSG101 knockdown, and dominant-negative VPS4 expression to demonstrate that the localization of activated cellular Src and viral Src at FAs requires the endosomal-sorting complexes required for transport (ESCRT) pathway. Tsg101 deletion also led to impaired Src-dependent activation of STAT3 and focal adhesion kinase and reduced cell migration. Impairment of the ESCRT pathway or Rab7 function led to the accumulation of active Src at aberrant LE/LY compartments followed by its loss. Analyses using fluorescence recovery after photo-bleaching show that dynamic mobility of Src in endosomes is ESCRT pathway-dependent. These results reveal a critical role for an ESCRT pathway-dependent LE/LY trafficking step in Src function by promoting localization of active Src to FAs.
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases and University of Nebraska Medical Center-Eppley Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Tu
authors.forename: Cesar F
authors.initials: CF
authors.lastname: Ortega-Cava
authors.forename: Paul
authors.initials: P
authors.lastname: Winograd
authors.forename: Marissa Jo
authors.initials: MJ
authors.lastname: Stanton
authors.forename: Alagarsamy Lakku
authors.initials: AL
authors.lastname: Reddi
authors.forename: Ingrid
authors.initials: I
authors.lastname: Dodge
authors.forename: Ranjana
authors.initials: R
authors.lastname: Arya
authors.forename: Manjari
authors.initials: M
authors.lastname: Dimri
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Clubb
authors.forename: Mayumi
authors.initials: M
authors.lastname: Naramura
authors.forename: Kay-Uwe
authors.initials: KU
authors.lastname: Wagner
authors.forename: Vimla
authors.initials: V
authors.lastname: Band
authors.forename: Hamid
authors.initials: H
authors.lastname: Band
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D021381:Protein Transport; D014157:Transcription Factors / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*; D000099177:Tsg101 Protein
chemical_list: D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D014157:Transcription Factors; D019061:src-Family Kinases; D000099177:Tsg101 Protein
references.citation: Arch Biochem Biophys. 2007 Jan 15;457(2):142-9
references.pmid: 17174262
references.citation: Cell. 2001 Oct 5;107(1):55-65
references.pmid: 11595185
references.citation: Mol Cell Biol. 2009 Dec;29(24):6462-72
references.pmid: 19822664
references.citation: EMBO J. 2007 Oct 3;26(19):4215-27
references.pmid: 17853893
references.citation: EMBO J. 1999 May 4;18(9):2459-71
references.pmid: 10228160
references.citation: J Biol Chem. 2005 Feb 4;280(5):3414-25
references.pmid: 15557335
references.citation: Methods. 2005 Oct;37(2):154-64
references.pmid: 16288889
references.citation: Traffic. 2000 Mar;1(3):248-58
references.pmid: 11208108
references.citation: Growth Factors. 2005 Jun;23(2):161-7
references.pmid: 16019438
references.citation: J Cell Sci. 2009 Apr 1;122(Pt 7):965-75
references.pmid: 19258394
references.citation: Mol Cell Biol. 1998 May;18(5):2545-52
references.pmid: 9566874
references.citation: EMBO J. 1998 Jun 1;17(11):2982-93
references.pmid: 9606181
references.citation: J Cell Sci. 2003 Jan 15;116(Pt 2):401-14
references.pmid: 12482925
references.citation: Cell Signal. 2008 Jul;20(7):1359-67
references.pmid: 18448311
references.citation: Biochem J. 2005 Apr 1;387(Pt 1):17-26
references.pmid: 15511219
references.citation: J Biol Chem. 2002 Aug 2;277(31):28238-46
references.pmid: 12029088
references.citation: Mol Biol Cell. 2000 Feb;11(2):747-63
references.pmid: 10679028
references.citation: Exp Cell Res. 2007 Jul 15;313(12):2651-66
references.pmid: 17537435
references.citation: Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1859-64
references.pmid: 11172041
references.citation: Int J Biochem Cell Biol. 2009 Mar;41(3):687-93
references.pmid: 18762272
references.citation: J Biol Chem. 2005 Feb 18;280(7):6036-46
references.pmid: 15579470
references.citation: J Cell Sci. 2005 Jul 15;118(Pt 14):3003-17
references.pmid: 16014378
references.citation: Biochemistry. 2009 Oct 13;48(40):9321-3
references.pmid: 19673488
references.citation: Immunity. 2010 Apr 23;32(4):531-40
references.pmid: 20399684
references.citation: Biochem J. 2005 Nov 1;391(Pt 3):677-85
references.pmid: 16004603
references.citation: J Biol Chem. 2005 Mar 11;280(10):9258-64
references.pmid: 15611048
references.citation: Mol Cell. 1999 May;3(5):629-38
references.pmid: 10360179
references.citation: J Cell Sci. 2007 Aug 1;120(Pt 15):2555-64
references.pmid: 17623777
references.citation: Trends Cell Biol. 2008 Jul;18(7):322-9
references.pmid: 18515107
references.citation: Mol Cell Biol. 1996 Oct;16(10):5623-33
references.pmid: 8816475
references.citation: Biochem J. 2002 Jul 15;365(Pt 2):349-53
references.pmid: 11931639
references.citation: J Biol Chem. 2001 Apr 13;276(15):11735-42
references.pmid: 11134028
references.citation: Trends Cell Biol. 2006 Jun;16(6):317-26
references.pmid: 16716591
references.citation: Cancer Cell. 2004 Sep;6(3):209-14
references.pmid: 15380511
references.citation: Mol Biol Cell. 2000 Jan;11(1):227-39
references.pmid: 10637304
references.citation: Mol Cell Biol. 2003 Jan;23(1):150-62
references.pmid: 12482969
references.citation: J Cell Biol. 1996 Dec;135(6 Pt 1):1551-64
references.pmid: 8978822
references.citation: Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7626-31
references.pmid: 12802020
references.citation: Oncogene. 2004 Oct 18;23(48):7906-9
references.pmid: 15489908
references.citation: Mol Cell. 2008 May 23;30(4):426-36
references.pmid: 18498747
references.citation: Nature. 2007 Oct 11;449(7163):740-4
references.pmid: 17928862
references.citation: J Cell Biol. 1998 Mar 9;140(5):1075-89
references.pmid: 9490721
references.citation: Science. 2007 Jun 29;316(5833):1908-12
references.pmid: 17556548
references.citation: Mol Cell Biol. 2006 Mar;26(5):1932-47
references.pmid: 16479011
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 29;105(17):6308-13
references.pmid: 18434552
references.citation: Dev Cell. 2004 Dec;7(6):855-69
references.pmid: 15572128
references.citation: J Cell Biol. 2009 Apr 20;185(2):357-70
references.pmid: 19364917
references.citation: Cell. 1987 Apr 10;49(1):65-73
references.pmid: 3103925
references.citation: EMBO J. 1998 Jan 2;17(1):81-92
references.pmid: 9427743
references.citation: J Biol Chem. 2002 Nov 8;277(45):43216-23
references.pmid: 12205095
references.citation: J Virol. 1986 Dec;60(3):840-8
references.pmid: 3023673