Faciogenital dysplasia protein Fgd1 regulates invadopodia biogenesis and extracellular matrix degradation and is up-regulated in prostate and breast cancer.
[en] Invadopodia are proteolytically active membrane protrusions that extend from the ventral surface of invasive tumoral cells grown on an extracellular matrix (ECM). The core machinery controlling invadopodia biogenesis is regulated by the Rho GTPase Cdc42. To understand the upstream events regulating invadopodia biogenesis, we investigated the role of Fgd1, a Cdc42-specific guanine nucleotide exchange factor. Loss of Fgd1 causes the rare inherited human developmental disease faciogenital dysplasia. Here, we show that Fgd1 is required for invadopodia biogenesis and ECM degradation in an invasive cell model and functions by modulation of Cdc42 activation. We also find that Fgd1 is expressed in human prostate and breast cancer as opposed to normal tissue and that expression levels matched tumor aggressiveness. Our findings suggest a central role for Fgd1 in the focal degradation of the ECM in vitro and, for the first time, show a connection between Fgd1 and cancer progression, proposing that it might function during tumorigenesis.
Castronovo, Vincenzo ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie générale et cellulaire - GIGA-R : Labo de recherche sur les métastases
Buccione, Roberto
Language :
English
Title :
Faciogenital dysplasia protein Fgd1 regulates invadopodia biogenesis and extracellular matrix degradation and is up-regulated in prostate and breast cancer.
Publication date :
2009
Journal title :
Cancer Research
ISSN :
0008-5472
eISSN :
1538-7445
Publisher :
American Association for Cancer Research, Inc. (AACR), Baltimore, United States - Maryland
Volume :
69
Issue :
3
Pages :
747-52
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
AIRC - Associazione Italiana per la Ricerca sul Cancro [IT] EC - European Commission [BE] Fondazione Cassa di Resparmio della Provincia di Teramo [IT] Ministero della Salute [IT] F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE] Calogero Musarra Foundation
Weaver AM. Invadopodia: specialized cell structures for cancer invasion. Clin Exp Metastasis 2006;23:97-105.
Yamaguchi H, Lorenz M, Kempiak S, et al. Molecular mechanisms of invadopodium formation: the role of the N-WASP-Arp2/3 complex pathway and cofilin. J Cell Biol 2005;168:441-52.
Bishop AL, Hall A. Rho GTPases and their effector proteins. Biochem J 2000;348 Pt 2:241-55.
Schmidt A, Hall A. Guanine nucleotide exchange factors for Rho GTPases: turning on the switch. Genes Dev 2002;16:1587-609.
Zheng Y, Fischer DJ, Santos MF, et al. The faciogenital dysplasia gene product FGD1 functions as a Cdc42Hs-specific guanine-nucleotide exchange factor. J Biol Chem 1996;271:33169-72.
Gorski JL, Estrada L, Hu C, Liu Z. Skeletal-specific expression of Fgd1 during bone formation and skeletal defects in faciogenital dysplasia (FGDY; Aarskog syndrome). Dev Dyn 2000;218:573-86.
Hou P, Estrada L, Kinley AW, Parsons JT, Vojtek AB, Gorski JL. Fgd1, the Cdc42 GEF responsible for Faciogenital Dysplasia, directly interacts with cortactin and mAbp1 to modulate cell shape. Hum Mol Genet 2003;12:1981-93.
Kim K, Hou P, Gorski JL, Cooper JA. Effect of Fgd1 on cortactin in Arp2/3 complex-mediated actin assembly. Biochemistry 2004;43:2422-7.
Ayala I, Baldassarre M, Giacchetti G, et al. Multiple regulatory inputs converge on cortactin to control invadopodia biogenesis and extracellular matrix degradation. J Cell Sci 2008;121:369-78.
Baldassarre M, Pompeo A, Beznoussenko G, et al. Dynamin participates in focal extracellular matrix degradation by invasive cells. Mol Biol Cell 2003;14:1074-84.
Usui I, Imamura T, Huang J, Satoh H, Olefsky JM. Cdc42 is a Rho GTPase family member that can mediate insulin signaling to glucose transport in 3T3-1 adipocytes. J Biol Chem 2003;278:13765-74.
Bowden ET, Coopman PJ, Mueller SC. Invadopodia: unique methods for measurement of extracellular matrix degradation in vitro. Methods Cell Biol 2001;63:613-27.
Nagata K, Driessens M, Lamarche N, Gorski JL, Hall A. Activation of G1 progression, JNK mitogen-activated protein kinase, and actin filament assembly by the exchange factor FGD1. J Biol Chem 1998;273:15453-7.
Estrada L, Caron E, Gorski JL. Fgd1, the Cdc42 guanine nucleotide exchange factor responsible for faciogenital dysplasia, is localized to the subcortical actin cytoskeleton and Golgi membrane. Hum Mol Genet 2001;10:485-95.
Brown PD. Matrix metalloproteinase inhibitors: a novel class of anticancer agents. Adv Enzyme Regul 1995;35:293-301.
Artym VV, Zhang Y, Seillier-Moiseiwitsch F, Yamada KM, Mueller SC. Dynamic interactions of cortactin and membrane type 1 matrix metalloproteinase at invadopodia: defining the stages of invadopodia formation and function. Cancer Res 2006;66:3034-43.
Pasteris NG, Buckler J, Cadle AB, Gorski JL. Genomic organization of the faciogenital dysplasia (FGD1; Aarskog syndrome) gene. Genomics 1997;43:390-4.
Pelish HE, Peterson JR, Salvarezza SB, et al. Secramine inhibits Cdc42-dependent functions in cells and Cdc42 activation in vitro. Nat Chem Biol 2006;2:39-46.
Olson MF. Guanine nucleotide exchange factors for the Rho GTPases: a role in human disease? J Mol Med 1996;74:563-71.