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Faciogenital Dysplasia 1
Identifiers
SymbolFGD1, FGDY, ZFYVE3
NCBI gene3641690
HGNCHGNC:3663
OMIM300546
UniProtQ5A4P0
Other data
LocusChr. X p11.22
Search for
StructuresSwiss-model
DomainsInterPro

Human FGD1 (Faciogenital Dysplasia 1 protein, officially called: FYVE, RhoGEF and PH domain containing 1 protein, also know as AAS; FGDY; ZFYVE3) is a guanine-nucleotide exchange factor (GEF), that can activate the GTPase Cdc42. It localizes preferentially to the trans-Golgi network (TGN) of mammalian cells and regulates the secretory transport of e.g. bone-specific proteins from the Golgi complex. Thus Cdc42 and FGD1 regulate secretory membrane trafficking that occurs especially during bone growth and mineralization in humans[1]. Human FGD1 is encoded by the human FGD1 gene that lies on the X chromosome and is conserved in dog, cow, mouse, rat, and zebrafish, and also studied in budding yeast and C. elegans[2]. Mutations in the FGD1 gene that cause the production of non-functional proteins are responsible for the severe phenotype of the X-linked disorder faciogential dysplasia (FGDY), also called Aarskog-Scott syndrome.

Introduction

Multiple signal transduction pathways are co-ordinated to ensure proper cell division. FGD1 plays an important role in this co-ordination, because it promotes the nucleotide exchange on the GTPase Cdc42, a key player in the establishment of cell polarity in all eukaryotic cells. By activating Cdc42 via its DH domain, FGD1 also activates c-Jun N-terminal kinase (JNK) signaling cascade, important in cell differentiation and cell apoptosis [3]. The FGD1 gene is located on the short arm of the X-chromosome and is essential for normal mammalian embryonic development. The GEF activity is harbored in the DH domain and can result in actin organization and filopodia formation. Mice embryos that carried experimentally introduced mutations in the FGD1 gene had skeletal abnormalities affecting bone size, cartilage growth, vertebrae formation and distal extremities [4]. These severe phenotypes are consistent with a lack of Cdc42 activity, as it results in alterations of membrane traffic as well as improper coordination of the actin cytoskeleton. [5]


Structure

The mature human protein contains several characteristic motifs and domains that are involved in the protein´s function. The 951 amino acid long protein has an approximate size of 106kDa. A proline-rich SH3-binding motif stretches from amino acid 7 – 330, a DH domain (DBL homology domain), which harbors the GEF enzymatic activity, lies between the residue 373 – 561, a first PH domain between residues 590 – 689, a zinc finger domain (FYVE, Fab1p, YOTB, Vac1p, and EEA1) between residues 730 – 790 and a second PH domain between residues 821 – 921 (Orrico, 2009). The DH domain is required for the activation of Cdc42, while the PH domains confer membrane binding of the protein and catalyzes the exchange of GDP to GTP on Cdc42. The SH3 binding domain interacts with cortactin and actin-binding protein 1. [6] [7]


Function

Role of wild type protein FGD1

FGD1 activates Cdc42 by exchanging GDP bound to Cdc42 for GTP and regulates the recruitment of Cdc42 to Golgi membranes. Levels of both FGD1 and Cdc42 are enriched on the Golgi complex itself and their interdependence regulates the transport of cargo proteins from the Golgi. In vivo studies have shown the colocalization of FGD1 and Cdc42 in the trans-Golgi network. FGD1 inhibition has a general affect on post-Golgi transport.[8].

Another interaction partner of FGD1 is cortactin, which is directly bound by the SH3 binding domain. Thereby actin polymerization is promoted by the actin related protein (Arp)2/3 complex. Thus, cortactin ligated by FGD1 is fully active, indicating that the cell can use FGD1 additionally to target actin assembly.[9]. FGD1 is expressed mainly in areas of bone formation and postnatally in skeletal tissue, the perichondrium, joint capsule fibroblasts and resting chondrocytes.[10][11] FGD1 is also transiently associated with and required for the formation of membrane protrusions on invasive tumoral cells.

Disease

Nucleotide insertions cause a framshift and yield a protein mutated in the DH (Dbl homology domain) or PH (pleckstrin homology domain) domain of FGD1[12]. These mutations are known to cause the phenotypes associated with the X-linked recessively transmitted faciogential dysplasia (FGDY) also know as Aarskog-Scott syndrome, a human developmental disorder that can be associated with neurologial problems. The disease phenotypes are due to improper bone formation and is more often seen in males though the severity depends on age. Most of the identified mutations of FGD1 are within the DH or PH domain, responsible for activation of Cdc42 or membrane binding respectively. Increased expression of FGD1 correlates with tumor aggressiveness in prostate and breast cancer, linking the protein to cancer progression.[13]

See also

References

  1. ^ Faciogenital Dysplasia Protein (FGD1) Regulates Export of Cargo Proteins from the Golgi Complex via Cdc42 Activation Mikhail V. Egorov,* Mariagrazia Capestrano,* Olesya A. Vorontsova,† Alessio Di Pentima,* Anastasia V. Egorova,* Stefania Mariggio` ,* M. Inmaculada Ayala,* Stefano Tete` ,‡ Jerome L. Gorski,§ Alberto Luini,* Roberto Buccione,* and Roman S.Polishchuk*. Molecular Biology of the Cell Vol. 20, 2413–2427, May 1, 2009
  2. ^ The Caenorhabditis elegans homolog of FGD1, the human Cdc42 GEF gene responsible for faciogenital dysplasia, is critical for excretory cell morphogenesis Jingtong Gao1, Lourdes Estrada1,2, Soochin Cho3, Ronald E. Ellis3 and Jerome L. Gorski1,2,+. Human Molecular Genetics, 2001, Vol. 10, No. 26 3049-3062 © 2001 Oxford University Press
  3. ^ Faciogenital dysplasia protein (FGD1) and Vav, two related proteins required for normal embryonic development, are upstream regulators of Rho GTPases Michael F. Olson*†, N. German Pasteris‡, Jerome L. Gorski‡and Alan Hall*. Current Biology1996, Vol 6 No 12:1628–1633.
  4. ^ Faciogenital dysplasia protein (FGD1) and Vav, two related proteins required for normal embryonic development, are upstream regulators of Rho GTPases Michael F. Olson*†, N. German Pasteris‡, Jerome L. Gorski‡and Alan Hall*. Current Biology1996, Vol 6 No 12:1628–1633.
  5. ^ Cdc42 – the centre of polarity. Sandrine Etienne-Manneville, Journal of Cell Science, 2004 vol. 117 (Pt 8) pp. 1291-300
  6. ^ Faciogenital Dysplasia Protein (FGD1) Regulates Export of Cargo Proteins from the Golgi Complex via Cdc42 Activation Mikhail V. Egorov*, Mariagrazia Capestrano*, Olesya A. Vorontsova{dagger}, Alessio Di Pentima*, Anastasia V. Egorova*, Stefania Mariggiò*, M. Inmaculada Ayala*, Stefano Tetè{ddagger}, Jerome L. Gorski§, Alberto Luini*, Roberto Buccione*, and Roman S. Polishchuk* , MBoC in Press, 10.1091/mbc.E08-11-1136 Vol. 20, Issue 9, 2413-2427, May 1, 2009
  7. ^ Faciogenital Dysplasia Protein Fgd1 Regulates Invadopodia Biogenesis and Extracellular Matrix Degradation and Is Up-regulated in Prostate and Breast Cancer Inmaculada Ayala, Giada Giacchetti, Giusi Caldieri, Francesca Attanasio, Stefania Mariggiò, Stefano Tetè, Roman Polishchuk, Vincent Castronovo, and Roberto Buccione, Cancer Res February 1, 2009 69:747-752; doi:10.1158/0008-5472.CAN-08-1980
  8. ^ Faciogenital Dysplasia Protein (FGD1) Regulates Export of Cargo Proteins from the Golgi Complex via Cdc42 Activation Mikhail V. Egorov*, Mariagrazia Capestrano*, Olesya A. Vorontsova{dagger}, Alessio Di Pentima*, Anastasia V. Egorova*, Stefania Mariggiò*, M. Inmaculada Ayala*, Stefano Tetè{ddagger}, Jerome L. Gorski§, Alberto Luini*, Roberto Buccione*, and Roman S. Polishchuk* , MBoC in Press, 10.1091/mbc.E08-11-1136 Vol. 20, Issue 9, 2413-2427, May 1, 2009
  9. ^ Effect of Fgd1 on cortactin in Arp2/3 complex-mediated actin assembly Kim K, Hou P, Gorski JL, Cooper JA Biochemistry. 2004 Mar 9;43(9):2422-7
  10. ^ Faciogenital Dysplasia Protein (FGD1) Regulates Export of Cargo Proteins from the Golgi Complex via Cdc42 Activation Mikhail V. Egorov*, Mariagrazia Capestrano*, Olesya A. Vorontsova{dagger}, Alessio Di Pentima*, Anastasia V. Egorova*, Stefania Mariggiò*, M. Inmaculada Ayala*, Stefano Tetè{ddagger}, Jerome L. Gorski§, Alberto Luini*, Roberto Buccione*, and Roman S. Polishchuk* , MBoC in Press, 10.1091/mbc.E08-11-1136 Vol. 20, Issue 9, 2413-2427, May 1, 2009
  11. ^ Isolation and Characterization of the Faciogenital. Dysplasia (Aarskog-Scott Syndrome) Gene: A Putative Rho/Rat Guanine Nucleotide Exchange Factor. N. German Pasteris, Amy Cadle, Lindsay J. Logie,t Mary E. M. Potteous,t Charles E. Schwartz,* Roger E. Stevenson,*Thomas W. Glover,‘§ R. Ski Wilroy,II and Jerome L. Gorski’l plasia. Cell, Vol. 79, 669-678, November 18, 1994, Copyright 0 1994 by Cell Press
  12. ^ Isolation and Characterization of the Faciogenital. Dysplasia (Aarskog-Scott Syndrome) Gene: A Putative Rho/Rat Guanine Nucleotide Exchange Factor. N. German Pasteris, Amy Cadle, Lindsay J. Logie,t Mary E. M. Potteous,t Charles E. Schwartz,* Roger E. Stevenson,*Thomas W. Glover,‘§ R. Ski Wilroy,II and Jerome L. Gorski’l plasia. Cell, Vol. 79, 669-678, November 18, 1994, Copyright 0 1994 by Cell Press
  13. ^ Faciogenital Dysplasia Protein Fgd1 Regulates Invadopodia Biogenesis and Extracellular Matrix Degradation and Is Up-regulated in Prostate and Breast Cancer Inmaculada Ayala1, Giada Giacchetti1, Giusi Caldieri1, Francesca Attanasio1, Stefania Mariggiò2, Stefano Tetè4, Roman Polishchuk3, Vincent Castronovo5 and Roberto Buccione1 , Cancer Research 69, 747, February 1, 2009

[http://www.genenames.org/data/hgnc_data.php?match=FGD1 Page of FGD1]

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