title: Rab40b regulates trafficking of MMP2 and MMP9 during invadopodia formation and invasion of breast cancer cells.
abstract: Invadopodia-dependent degradation of the basement membrane plays a major role during metastasis of breast cancer cells. Basement membrane degradation is mediated by targeted secretion of various matrix metalloproteinases (MMPs). Specifically, MMP2 and MMP9 (MMP2/9) possess the ability to hydrolyze components of the basement membrane and regulate various aspects of tumor growth and metastasis. However, the membrane transport machinery that mediates targeting of MMP2/9 to the invadopodia during cancer cell invasion remains to be defined. Because Rab GTPases are key regulators of membrane transport, we screened a human Rab siRNA library and identified Rab40b GTPase as a protein required for secretion of MMP2/9. We also have shown that Rab40b functions during at least two distinct steps of MMP2/9 transport. Here, we demonstrate that Rab40b is required for MMP2/9 sorting into VAMP4-containing secretory vesicles. We also show that Rab40b regulates transport of MMP2/9 secretory vesicles during invadopodia formation and is required for invadopodia-dependent extracellular matrix degradation. Finally, we demonstrate that Rab40b is also required for breast cancer cell invasion in vitro. On the basis of these findings, we propose that Rab40b mediates trafficking of MMP2/9 during invadopodia formation and metastasis of breast cancer cells.
authors.affiliation: Department of Cell and Developmental Biology, School of Medicine, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Abitha
authors.initials: A
authors.lastname: Jacob
authors.forename: Jian
authors.initials: J
authors.lastname: Jing
authors.forename: James
authors.initials: J
authors.lastname: Lee
authors.forename: Pepper
authors.initials: P
authors.lastname: Schedin
authors.forename: Simon M
authors.initials: SM
authors.lastname: Gilbert
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Peden
authors.forename: Jagath R
authors.initials: JR
authors.lastname: Junutula
authors.forename: Rytis
authors.initials: R
authors.lastname: Prekeris
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D011554:Pseudopodia / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D020691:rab GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D020691:rab GTP-Binding Proteins
keywords: Invadopodia; Invasion; MMP2; MMP9; Rab40b; Secretion
references.citation: Nat Rev Mol Cell Biol. 2011 Jun 23;12(7):413-26
references.pmid: 21697900
references.citation: Clin Cancer Res. 2001 Aug;7(8):2396-404
references.pmid: 11489818
references.citation: J Biol Chem. 1995 Mar 10;270(10):5331-8
references.pmid: 7890645
references.citation: Dev Cell. 2012 Jan 17;22(1):131-45
references.pmid: 22197222
references.citation: J Cell Biol. 2008 Jun 16;181(6):985-98
references.pmid: 18541705
references.citation: Cancer Cell. 2005 Feb;7(2):155-65
references.pmid: 15710328
references.citation: Trends Cell Biol. 2001 Dec;11(12):487-91
references.pmid: 11719054
references.citation: J Cell Sci. 2009 Sep 1;122(Pt 17):3015-24
references.pmid: 19692588
references.citation: Cancer Res. 2006 Mar 15;66(6):3034-43
references.pmid: 16540652
references.citation: Cytokine Growth Factor Rev. 2008 Oct-Dec;19(5-6):371-81
references.pmid: 18948053
references.citation: Nat Rev Cancer. 2002 Mar;2(3):161-74
references.pmid: 11990853
references.citation: Eur J Cell Biol. 2008 Sep;87(8-9):581-90
references.pmid: 18342393
references.citation: PLoS One. 2012;7(4):e34870
references.pmid: 22523562
references.citation: Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):7959-64
references.pmid: 9223295
references.citation: J Cell Biol. 2010 Apr 5;189(1):13-22
references.pmid: 20351064
references.citation: Curr Opin Cell Biol. 1995 Oct;7(5):736-47
references.pmid: 8573350
references.citation: Eur J Cell Biol. 2008 Sep;87(8-9):555-67
references.pmid: 18417249
references.citation: EMBO J. 2006 Apr 19;25(8):1590-602
references.pmid: 16601685
references.citation: Indian J Cancer. 2009 Jul-Sep;46(3):194-202
references.pmid: 19574670
references.citation: Cancer Res. 1998 Mar 1;58(5):1048-51
references.pmid: 9500469
references.citation: Br J Cancer. 2006 Apr 10;94(7):941-6
references.pmid: 16538215
references.citation: Dev Cell. 2007 Oct;13(4):496-510
references.pmid: 17925226
references.citation: Traffic. 2010 Sep;11(9):1191-204
references.pmid: 20545907
references.citation: EMBO J. 2007 Mar 21;26(6):1499-510
references.pmid: 17332756
references.citation: J Biol Chem. 2005 Oct 7;280(40):33992-4002
references.pmid: 16046398
references.citation: Oncogene. 2009 Jan 22;28(3):431-44
references.pmid: 18931703
references.citation: Biochem Cell Biol. 1995 Jul-Aug;73(7-8):391-7
references.pmid: 8703411
references.citation: Clin Exp Metastasis. 1999 Mar;17(2):177-81
references.pmid: 10411111
references.citation: Genes Dev. 2006 Oct 1;20(19):2673-86
references.pmid: 16983145
references.citation: Cold Spring Harb Symp Quant Biol. 2005;70:167-71
references.pmid: 16869750
references.citation: J Natl Cancer Inst. 1997 Sep 3;89(17):1260-70
references.pmid: 9293916
references.citation: Circ Res. 2003 May 2;92(8):827-39
references.pmid: 12730128
references.citation: Cancer Res. 1993 Jul 1;53(13):3159-64
references.pmid: 8391388
references.citation: J Clin Neurosci. 2008 Jul;15(7):725-37
references.pmid: 18468901
references.citation: J Cell Physiol. 1998 Jul;176(1):206-15
references.pmid: 9618160
references.citation: Curr Opin Cell Biol. 1999 Oct;11(5):614-21
references.pmid: 10508651
references.citation: Mol Biol Cell. 2004 Aug;15(8):3530-41
references.pmid: 15181150
references.citation: Eur J Immunol. 2011 Nov;41(11):3323-9
references.pmid: 21805468
references.citation: PLoS One. 2011;6(7):e22499
references.pmid: 21799874
references.citation: Cancer Lett. 2008 Jul 8;265(2):157-66
references.pmid: 18406052
references.citation: Mol Biol Cell. 1999 Jun;10(6):1957-72
references.pmid: 10359608
references.citation: Cancer Res. 2007 May 1;67(9):4227-35
references.pmid: 17483334
references.citation: J Cell Sci. 2003 Oct 1;116(Pt 19):3905-16
references.pmid: 12915589
references.citation: Crit Rev Oncol Hematol. 2004 Mar;49(3):179-86
references.pmid: 15036258