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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 known as AAS; FGDY; ZFYVE3) is a guanine-nucleotide exchange factor (GEF), that can activate the Rho 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

FGD1 promotes the nucleotide exchange on the GTPase Cdc42, a key player in the establishment of cell polarity in all eukaryotic cells. The GEF activity of FGD1, causing the activation of Cdc42, is harbored in its DH domainand causes the formation of filopodia, the cells to migrate. FGD1 activates also c-Jun N-terminal kinase (JNK) signaling cascade, important in cell differentiation and apoptosis [3]. It also promotes the transitition through G1 during the cell cycle and causes tumorgenic transformation of NIH/3T3 fibroblasts [4] [5].

The FGD1 gene is located on the short arm of the X-chromosome and is essential for normal mammalian embryonic development. Mice embryos that carried experimentally introduced mutations in the FGD1 gene had skeletal abnormalities affecting bone size, cartilage growth, vertebrae formation and distal extremities [3]. These severe phenotypes are consistent with a lack of Cdc42 activity, as it controls membrane traffic as well as the organization of the actin cytoskeleton [6].

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 stretch, predicted to encode two partially overlapping src homology 3 (SH3)-binding domains, 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 (proper referencing is needed: Orrico, 2009). The DH domain is required for the activation of Cdc42, namely the catalysis of the exchange of GDP to GTP on Cdc42, while the PH domains confer membrane binding of the protein. The prolin-rich domain interacts with cortactin and actin-binding protein 1 [1] [7]. FYVE-finger domains are conserved through evolution and often involved in membrane trafficking (e.g. Vac1p, Vps27p, Fab1, Hrs-2). The domain was shown to bind selectively to phosphatidylinositol-3-phosphates. PH domains are known to specifically bind to polyphosphoinositides and phosphotyrosine residues [8].

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. [1].

Another interaction partner of FGD1 is cortactin, which is directly bound by the prolin-rich domain of FGD1. As cortactin is known to promote actin polymerization by the Arp2/3 complex, this interaction seems to promote actin assembly [6].

Human FGD1 is expressed predominantly in fetal tissues of brain and kidney, but also present in the heart and lung. It is hardly detectable in the corresponding adult tissues. FGD1 is expressed in areas of bone formation and postnatally in skeletal tissue, the perichondrium, joint capsule fibroblasts and resting chondrocytes (cite also : N G Pasteris Cell 1994 vol. 79 (4) pp. 669-78 'sorry don't get it... This article is cited or do you mean another one?? Stefan'[1] [9] FGD1 is also transiently associated with and required for the formation of membrane protrusions on invasive tumor cells (give ref).

Disease

Mutations in the FGD-1 gene cause phenotypes associated with the X-linked recessively transmitted faciogential dysplasia (FGDY) also know as Aarskog-Scott syndrome, a human developmental disorder that can occur with neurologial problems [9]. The disease phenotypes are due to improper bone formation and is more often seen in males though the severity depends on age. Mutations in the FGD-1 gene are randomly distributed in all the domains of the protein product, modifying the intracellular localization and/or the GEF catalytic activity of Fgd1 [10] [11] [12] [13]. To date, 20 distinct mutations have been reported, including three missense mutations (p.R402Q; p.S558W; p.K748E), four truncating mutations (p.Y530X; p.R656X; c.806delC; c.1620delC), one in-frame deletion (c.2020_2022delGAG) and the first reported splice site mutation (c.1935þ3A>C) [14].

Also, increased expression of FGD1 correlates with tumor aggressiveness in prostate and breast cancer, linking the protein to cancer progression [15].

See also

References

  1. ^ a b c d Egorov M., Capestrano M, Vorontsova O.A., Di Pentima A., Egorova A.V., Mariggio S., Ayala M.I., Tete S. ,Gorski J.L., Luini A., Buccione R., and Polishchuk R.S. (2009). "Faciogenital Dysplasia Protein (FGD1) Regulates Export of Cargo Proteins from the Golgi Complex via Cdc42 Activation". Molecular Biology of the Cell. 20: 2413–2427. PMID 19261807.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ Gao J., Estrada L., Cho S., Ellis R.E., and Gorski J.L. (2001). "The Caenorhabditis elegans homolog of FGD1, the human Cdc42 GEF gene responsible for faciogenital dysplasia, is critical for excretory cell morphogenesis". Human Molecular Genetics. 10: 3049–3062. PMID 19261807.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ a b Michael F., Olson F., Pasteris N.G., Gorski J.L., and Hall A. (1996). "Faciogenital dysplasia protein (FGD1) and Vav, two related proteins required for normal embryonic development, are upstream regulators of Rho GTPases". Current Biology. 6: 1628–1633. PMID 8994827.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ Whitehead IP, Abe K, Gorski JL, Der CJ. (1998). "DC42 and FGD1 cause distinct signaling and transforming activities". Mol Cell Biol. 18: 4689–97. PMID 9671479.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ Nagata K, Driessens M, Lamarche N, Gorski JL, Hall A. (1998). "Activation of G1 progression, JNK mitogen-activated protein kinase, and actin filament assembly by the exchange factor FGD1". J Biol Chem. 273: 15453–7. PMID 9624130.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ a b Etienne-Manneville S. (2004). "Cdc42 – the centre of polarity". Journal of Cell Science. 117: 1291–1300. PMID 15020669. Cite error: The named reference "Cdc42" was defined multiple times with different content (see the help page).
  7. ^ Giacchetti G., Caldieri G., Attanasio F., Mariggiò S., Tetè S., Polishchuk R., Castronovo V., and Buccione R. (2009). "Faciogenital Dysplasia Protein Fgd1 Regulates Invadopodia Biogenesis and Extracellular Matrix Degradation and Is Up-regulated in Prostate and Breast Cancer Inmaculada Ayala". Cancer Research. 69: 747–752. PMID 19141649.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ Estrada L., Caron E., Gorski JL. (2001). "Fgd1, the Cdc42 guanine nucleotide exchange factor responsible for faciogenital dysplasia, is localized to the subcortical actin cytoskeleton and Golgi membrane". Hum Mol Genet. 10: 485–95. PMID 11181572.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ a b Pasteris NG, Cadle A, Logie LJ, Porteous ME, Schwartz CE, Stevenson RE, Glover TW, Wilroy RS, Gorski JL. (1994). "Isolation and Characterization of the Faciogenital. Dysplasia (Aarskog-Scott Syndrome) Gene: A Putative Rho/Rat Guanine Nucleotide Exchange Factor". Cell. 20: 669–678. PMID 7954831.{{cite journal}}: CS1 maint: multiple names: authors list (link) Cite error: The named reference "Pasteris" was defined multiple times with different content (see the help page).
  10. ^ Orrico A, Galli L, Falciani M, Bracci M, Cavaliere ML, Rinaldi MM, Musacchio A, Sorrentino V. (2000). "A mutation in the pleckstrin homology (PH) domain of the FGD1 gene in an Italian family with faciogenital dysplasia (Aarskog-Scott syndrome)". FEBS Letters. 478: 216–20. PMID 10930571.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ Bedoyan JK, Friez MJ, DuPont B, Ahmad A. (2009). "A mutation in the pleckstrin homology (PH) domain of the FGD1 gene in an Italian family with faciogenital dysplasia (Aarskog-Scott syndrome)". Eur J Med Genet. 52: 262–4. PMID 19110080.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ Orrico A, Galli L, Cavaliere ML, Garavelli L, Fryns JP, Crushell E, Rinaldi MM, Medeira A, Sorrentino V. (2004). "Phenotypic and molecular characterisation of the Aarskog-Scott syndrome: a survey of the clinical variability in light of FGD1 mutation analysis in 46 patients". Eur J Hum Genet. 12: 16–23. PMID 14560308.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ Schwartz CE, Gillessen-Kaesbach G, May M, Cappa M, Gorski J, Steindl K, Neri G. (2000). "Two novel mutations confirm FGD1 is responsible for the Aarskog syndrome". Eur J Hum Genet. 8: 869–74. PMID 11093277.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ Orrico A, Galli L, Faivre L, Clayton-Smith J, Azzarello-Burri SM, Hertz JM, Jacquemont S, Taurisano R, Arroyo Carrera I, Tarantino E, Devriendt K, Melis D, Thelle T, Meinhardt U, Sorrentino V. (2000). "Aarskog-Scott syndrome: clinical update and report of nine novel mutations of the FGD1 gene". Eur J Hum Genet. 152A: 313–8. PMID 20082460.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ Ayala I, Giacchetti G, Caldieri G, Attanasio F, Mariggiò S, Tetè S, Polishchuk R, Castronovo V, Buccione R. (2009). "Faciogenital Dysplasia Protein Fgd1 Regulates Invadopodia Biogenesis and Extracellular Matrix Degradation and Is Up-regulated in Prostate and Breast Cancer". Cancer Research. 69: 747–52. PMID 19141649.{{cite journal}}: CS1 maint: multiple names: authors list (link)

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

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