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User:Cellular Biochemistry II/Course 2010/FGD1

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FDG1
Identifiers
Symbol?
NCBI gene3641690
HGNCHGNC:3663
OMIMItalic text 300546Italic text
UniProtQ5A4P0
Other data
LocusChr. X p11.22
Search for
StructuresSwiss-model
DomainsInterPro

Human FGD1 (Faciogenital Dysplasia 1 protien, officially called: FYVE, RhoGEF and PH domain containing 1 protein, also know as AAS; FGDY; ZFYVE3) is a guanine-nucleotide exchange factor, that can activate the GTPase Cdc42. It localizes preferentially to the trans-Golgi network (TGN)of mammalian cells and regulates the secretory trasport 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 cause the production of non-functional proteins that are responsible for the severe phenotype of the X-linked disorder faciogential dysplasia (FGDY), also called Aarskog-Scott syndrome, a human developmental disorder that can be associated with neurologial problems...mention this in the disease part?.

Introduction

In both mammals and budding yeast (why is yeast here mentioned and not E.coli?- drop? why mammals?) multiple signal transduction pathways are co-ordinated to ensure proper cell division. FDG1 proteins 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, FDG1 also activates c-Jun N-terminal kinase (JNK) signaling cascade, important in cell differentiation and cell apoptosis (which role does this play in the disease? and which domain in FGD1 is responsible for this? give more facts [3]. The FDG1 gene is located on the short arm of the X-chromosome and is essential for normal mammalian embryonic development. The protein harbors the following domains ... The GEF activity is harbored in the ...domain. and can result in .... actin organization and filopodia formation. Mice embryos that carried spontaneously occuring or experimentally introduced? mutations where are in genearl the "naturally muations occuring in patiens with FGDY?- all clustered? in which domain? the FDG1 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 cite here Sandrine Etienne-Manneville, Journal of Cell Science, 2004 vol. 117 (Pt 8) pp. 1291-300 .

Function

Role of wild type protein FDG1

FDG1 activates Cdc42 by exchanging GDP bound on Cdc42 for GTP. One consequence of this activation is that: FDG1 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 interdependence of FGD1 and Cdc42 using FDG1 knockout cells that results in higher Cdc42 levels around the Golgi... but how does this fit with the above- true at all??. [5]. Specifically in osteoblasts, FDG1 regulates is vague- how does it regualte? what is ti doing with PC-1? proteins such as the [PC-1 protein], that are important for the mineralization of the extracellular matrix vital during bone development, especially during embryogenesis. [6]

?? is there an other consequcne described? on actin?

File:Cell94-fig 2(2).jpg
Fig. 1 The diagram shows FDG1 mRNA expression in human

NOT SURE HOW TO LINK THE PICTURE OF THE FIGURE YOU ATTACHED TO BE INCLUDED. NORTHERN BLOT FIGURE COMPARING FETAL VS ADULT FGD1 mRNA expression. Read the guidelines for Wikipedia - such figures should not be shown anyway! The content of this image is also not at all realted to the here displayed text. Anyway the statement of th efigure could and should be easily expressed in words. and before you describe the functin of FGD1 in cells you need to say in which cells it is expressed. Thus start with this with in the section "function". 

1. Structure...then 2. Function

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. What are the other domains good for? [7]

Disease

Mutations What kind of AA substitutions deletions? stop codons? in the DH (Dbl homology domain) and both??? PH (pleckstrin homology domain)domains of the FGD1 gene are known to cause the phenotypes associated with the X-linked recessively transmitted faciogential dysplasia (FGDY) also know as Aarskog-Scott syndrome. The disease phenotypes are due to improper bone formation and is more often seen in males though the severity depends on age. FGD1 is transiently associated with and required for the formation of membrane protrusions on invasive tumoral cells in a model system (so what? why do you wrte this here? make links to sentences before and after or move the location of this sentence and give a ref). Correlation between expression of FGD1 in prostate and breast cancer and tumor aggressiveness in vivo suggests a link between the protein and the cancer progression of better write the facts...the level of FGD1 exresssion is increased in...give the real facts...this stentence is vague. [8]

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. ^ 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
  6. ^ 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
  7. ^ 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
  8. ^ 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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