FGD1
Encyclopedia
FYVE, RhoGEF and PH domain-containing protein 1 (FGD1) also known as faciogenital dysplasia 1 protein (FGDY), zinc finger FYVE domain-containing protein 3 (ZFYVE3), or Rho/Rac guanine nucleotide exchange factor FGD1 (Rho/Rac GEF) is a protein
that in humans is encoded by the FGD1 gene
that lies on the X chromosome. Orthologs of the FGD1 gene are found in dog, cow, mouse, rat, and zebrafish, and also budding yeast and C. elegans
. It is a member of the FYVE, RhoGEF and PH domain containing
family.
FGD1 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, for example, the secretory transport of 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. FGD1 promotes nucleotide exchange on the GTPase Cdc42, a key player in the establishment of cell polarity in all eukaryotic
cells. The GEF activity of FGD1, which activates Cdc42, is harbored in its DH domain
and causes the formation of filopodia
, enabling the cells to migrate. FGD1 also activates the c-Jun N-terminal kinase (JNK) signaling cascade, important in cell differentiation and apoptosis. It also promotes the transition through G1 during the cell cycle and causes tumorgenic transformation of NIH/3T3
fibroblasts.
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. 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. 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
.
(DBL homology domain), which harbors the GEF enzymatic activity, and lies between the residue 373 – 561, then a first PH domain between residues 590 – 689, a FYVE zinc finger
domain (named after the four proteins it was found in Fab1
, YOTB, Vac1, and EEA1
) between residues 730 – 790, and a second PH domain between residues 821 – 921.
The DH domain is required for the activation of Cdc42, through the catalytic exchange of GDP with GTP on Cdc42, while the PH domains confer membrane binding. The prolin-rich domain interacts with cortactin and actin-binding protein 1. FYVE-finger domains are conserved through evolution and often involved in membrane trafficking (e.g. Vac1p, Vps27p, Fab1, Hrs-2). One class of these domains was shown to bind selectively to phosphatidylinositol 3-phosphate
. PH domains are known to specifically bind to polyphosphoinositides and influence the enzymatic activity of the GEF they are located in.
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. FGD1 and Cdc42 colocalize in the trans-Golgi network. FGD1 inhibition has an inhibitory effect on post-Golgi transport. Another interaction partner of FGD1 is cortactin
, which is directly bound by the proline-rich domain of FGD1. As cortactin is known to promote actin polymerization by the Arp2/3 complex
, this interaction seems to promote actin assembly.
FGD1 is also transiently associated with and required for the formation of membrane protrusions on invasive tumor cells.
, a human developmental disorder that can occur 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. Mutations in the FGD1 gene are randomly distributed in all the domains of the protein product, modifying the intracellular localization and/or the GEF catalytic activity of FGD1. Up to 2010 twenty distinct mutations have been reported, including three missense mutations (R402Q; S558W; K748E), four truncating mutations (Y530X; R656X; 806delC; 1620delC), one in-frame deletion (2020_2022delGAG) and the first reported splice site mutation (1935þ3A→C).
Increased expression of FGD1 correlates with tumor aggressiveness in prostate and breast cancer, linking the protein to cancer progression.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the FGD1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
that lies on the X chromosome. Orthologs of the FGD1 gene are found in dog, cow, mouse, rat, and zebrafish, and also budding yeast and C. elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
. It is a member of the FYVE, RhoGEF and PH domain containing
FYVE, RhoGEF and PH domain containing
FYVE, RhoGEF and PH domain containing is a gene family consisting of:* FGD1* FGD2* FGD3* FGD4Type 1 is associated with Aarskog-Scott syndrome....
family.
FGD1 is a guanine-nucleotide exchange factor (GEF) that can activate the Rho GTPase Cdc42
CDC42
Cell division control protein 42 homolog also known as CDC42 is a protein involved in regulation of the cell cycle. In humans, CDC42 is encoded by the CDC42 gene.- Function :...
. It localizes preferentially to the trans-Golgi network
Golgi apparatus
The Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....
(TGN) of mammalian cells and regulates, for example, the secretory transport of 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. FGD1 promotes nucleotide exchange on the GTPase Cdc42, a key player in the establishment of cell polarity in all eukaryotic
Eukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...
cells. The GEF activity of FGD1, which activates Cdc42, is harbored in its DH domain
RhoGEF domain
RhoGEF domain is a structural domain of guanine nucleotide exchange factors for Rho/Rac/Cdc42-like GTPases. It is also called "Dbl-homologous" domain.-Human proteins containing this domain :...
and causes the formation of filopodia
Filopodia
Filopodia are slender cytoplasmic projections that extend beyond the leading edge of lamellipodia in migrating cells. They contain actin filaments cross-linked into bundles by actin-binding proteins, e.g. fascin and fimbrin. Filopodia form focal adhesions with the substratum, linking it to the...
, enabling the cells to migrate. FGD1 also activates the c-Jun N-terminal kinase (JNK) signaling cascade, important in cell differentiation and apoptosis. It also promotes the transition through G1 during the cell cycle and causes tumorgenic transformation of NIH/3T3
3T3 cells
3T3 cells come from a cell line established in 1962 by two scientists then at the Department of Pathology in the New York University School of Medicine, George Todaro and Howard Green. The 3T3 cell line has become the standard fibroblast cell line...
fibroblasts.
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. 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. 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
Aarskog-Scott syndrome
Aarskog–Scott syndrome is an inherited disease characterized by short stature, facial abnormalities, skeletal and genital anomalies.The Aarskog–Scott syndrome is also known as the Aarskog syndrome, faciodigitogenital syndrome, shawl scrotum syndrome and faciogenital dysplasia.-Signs and...
(FGDY), also called Aarskog-Scott syndrome
Aarskog-Scott syndrome
Aarskog–Scott syndrome is an inherited disease characterized by short stature, facial abnormalities, skeletal and genital anomalies.The Aarskog–Scott syndrome is also known as the Aarskog syndrome, faciodigitogenital syndrome, shawl scrotum syndrome and faciogenital dysplasia.-Signs and...
.
Structure
The mature human protein contains several characteristic motifs and domains that are involved in the protein's function. The 961 amino acid long protein has an approximate size of 106kDa. The N-terminal is a proline-rich stretch, predicted to encode two partially overlapping src homology 3 (SH3)-binding domains, stretches from amino acid 7 – 330, followed by a DH domainRhoGEF domain
RhoGEF domain is a structural domain of guanine nucleotide exchange factors for Rho/Rac/Cdc42-like GTPases. It is also called "Dbl-homologous" domain.-Human proteins containing this domain :...
(DBL homology domain), which harbors the GEF enzymatic activity, and lies between the residue 373 – 561, then a first PH domain between residues 590 – 689, a FYVE zinc finger
FYVE domain
FYVE zinc finger domain is named after the four cysteine-rich proteins: Fab 1 , YOTB, Vac 1 , and EEA1, in which it has been found....
domain (named after the four proteins it was found in Fab1
FAB1
FAB1 is the name given to the pink six-wheeled car in the Thunderbirds franchise.-The original series and films:In the original Supermarionation TV series Thunderbirds , as well as the films Thunderbirds Are GO and Thunderbird 6 , FAB1 is a modified Rolls-Royce...
, YOTB, Vac1, and EEA1
EEA1
EEA1 is Early Endosome Antigen 1 protein that binds phospholipid vesicles containing phosphatidylinositol 3-phosphate, which is necessary for endosomal trafficking. It binds lipids through its FYVE domain and forms a homodimer through a coiled coil domain....
) between residues 730 – 790, and a second PH domain between residues 821 – 921.
The DH domain is required for the activation of Cdc42, through the catalytic exchange of GDP with GTP on Cdc42, while the PH domains confer membrane binding. The prolin-rich domain interacts with cortactin and actin-binding protein 1. FYVE-finger domains are conserved through evolution and often involved in membrane trafficking (e.g. Vac1p, Vps27p, Fab1, Hrs-2). One class of these domains was shown to bind selectively to phosphatidylinositol 3-phosphate
Phosphatidylinositol 3-phosphate
Phosphatidylinositol 3-phosphate is a phospholipid found in cell membranes that helps to recruit a range of proteins, many of which are involved in protein trafficking, to the membranes...
. PH domains are known to specifically bind to polyphosphoinositides and influence the enzymatic activity of the GEF they are located in.
Function
FGD1 activates Cdc42 by exchanging GDP bound to Cdc42 for GTP and regulates the recruitment of Cdc42 to GolgiGolgi
Golgi may refer to:*Camillo Golgi , Italian physician and scientist after which the following terms are named:**Golgi apparatus , an organelle in the eukaryotic cell...
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. FGD1 and Cdc42 colocalize in the trans-Golgi network. FGD1 inhibition has an inhibitory effect on post-Golgi transport. Another interaction partner of FGD1 is cortactin
Cortactin
Cortactin is a monomeric protein located in the cytoplasm of cells that can be activated by external stimuli to promote polymerization and rearrangement of the actin cytoskeleton, especially the actin cortex around the cellular periphery. It is present in all cell types...
, which is directly bound by the proline-rich domain of FGD1. As cortactin is known to promote actin polymerization by the Arp2/3 complex
Arp2/3 complex
Arp2/3 complex is a seven-subunit protein that plays a major role in the regulation of the actin cytoskeleton. It is a major component of the actin cytoskeleton and is found in most in actin cytoskeleton-containing eukaryotic cells....
, this interaction seems to promote actin assembly.
FGD1 is also transiently associated with and required for the formation of membrane protrusions on invasive tumor cells.
Tissue distribution
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 post-natally in skeletal tissue, the perichondrium, joint capsule fibroblasts and resting chondrocytes.Clinical significance
Mutations in the FGD1 gene cause phenotypes associated with the X-linked recessively transmitted faciogential dysplasia (FGDY) also known as Aarskog-Scott syndromeAarskog-Scott syndrome
Aarskog–Scott syndrome is an inherited disease characterized by short stature, facial abnormalities, skeletal and genital anomalies.The Aarskog–Scott syndrome is also known as the Aarskog syndrome, faciodigitogenital syndrome, shawl scrotum syndrome and faciogenital dysplasia.-Signs and...
, a human developmental disorder that can occur 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. Mutations in the FGD1 gene are randomly distributed in all the domains of the protein product, modifying the intracellular localization and/or the GEF catalytic activity of FGD1. Up to 2010 twenty distinct mutations have been reported, including three missense mutations (R402Q; S558W; K748E), four truncating mutations (Y530X; R656X; 806delC; 1620delC), one in-frame deletion (2020_2022delGAG) and the first reported splice site mutation (1935þ3A→C).
Increased expression of FGD1 correlates with tumor aggressiveness in prostate and breast cancer, linking the protein to cancer progression.