Genomic Organization of the Faciogenital Dysplasia (FGD1; Aarskog Syndrome) Gene

Ng, Pasteris; Buckler, Joshua M; Ab, Cadle; Jl, Gorski

doi:10.1006/geno.1997.4837

Cited by 33 publications

(23 citation statements)

References 13 publications

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“…14,15) Genetic analyses revealed that different types of point mutations occurred in FGD1 are also responsible for AAS. 16,17) In one of such mutations, we focused on the mutation in proline-rich domain of FGD1 (S one of the patients with typical AAS phenotype.…”

Section: Resultsmentioning

confidence: 99%

Proline-Rich Domain Plays a Crucial Role in Extracellular Stimuli-Responsive Translocation of a Cdc42 Guanine Nucleotide Exchange Factor, FGD1

Oshima

Fujino

Ando

et al. 2010

Biological & Pharmaceutical Bulletin

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The Rho family small guanosine 5Ј-triphosphate (GTP)-binding proteins (G-proteins), consisting mainly of the Rho, Rac, and Cdc42 subfamilies, regulates various actin cytoskeleton-dependent cell functions, including cell shape change, cell migration, cell adhesion, and cytokinesis. [1][2][3] Like all G-proteins, Rho family proteins act as binary switches by cycling between an inactive (GDP-bound) and an active (GTP-bound) conformation state.Guanine nucleotide exchange factors (GEFs) stimulate the exchange of GDP for GTP to generate active forms of Rho proteins. A family of candidate GEFs for Rho proteins has been identified based on the homology with CDC24, a protein genetically as an upstream activator of CDC42 in yeast. 4)Dbl, isolated as an oncogene in a focus formation assay using NIH 3T3 cells transfected with DNA from a human diffuse B-cell lymphoma, was identified as the first mammalian Rho GEF showing significant sequence similarity to CDC24. 5)The domain conserved in both Dbl and CDC24 is now recognized as the Dbl homology (DH) domain and almost 60 DHdomain-containing proteins have been found.6) The activities of GEFs must be tightly regulated and each member of the GEF family is likely to have a unique mechanism for activation and inactivation.In our previous reports, we revealed that FGD1, a GEF for Cdc42 and known as the faciogenital dysplasia (or AarskogScott syndrome; AAS) gene product, and FGD3, a homologue of FGD1, underwent proteasomal degradation through the polyubiquitination by the ubiquitin ligase SCF FWD1 . 7,8) FGD3 contains adjacent DH and pleckstrin homology (PH) domains, both of which are highly homologous to those of FGD1. Pasteris et al. reported that DHϩPH domains of FGD3 induced long finger-like protrusions, filopodia, as DHϩPH domains of FGD1 did, suggesting that both FGD1 and FGD3 share the similar GEF activity to induce Cdc42 activation.9) However, we demonstrated that the inducible expression of the full-length FGD1 led to the formation of striking filopodia structures whereas that of full-length FGD3 induced broad sheet-like protrusions, i.e., remarkable lamellipodia structures.8) These results indicate that FGD1 and FGD3 play different roles in cells but undergo the same destruction pathway.Although higher sequence similarity between FGD1 and FGD3 is observed in their DH and adjacent PH domains (i.e., amino acid residue identity is 70.0% and 60.6%, respectively), 9) there exist striking differences in their sequence in other regions; for example, most prominently, FGD3 lacks the N-terminal proline-rich domain conserved in FGD1.Proline-rich sequences are known to bind to specific protein interaction modules such as Src homology 3 (SH3), WW, and Ena/VASP homology 1 (EVH1) domains. [10][11][12] These different modules recognize different types of prolinerich sequences and play important roles in various signal transduction pathways. Phenotypic and molecular analyses revealed that a patient with missense mutation occurred in the proline-rich domain in FGD1 showed typical clinical f...

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Section: Resultsmentioning

confidence: 99%

Proline-Rich Domain Plays a Crucial Role in Extracellular Stimuli-Responsive Translocation of a Cdc42 Guanine Nucleotide Exchange Factor, FGD1

Oshima

Fujino

Ando

et al. 2010

Biological & Pharmaceutical Bulletin

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“…pRK5-myc-FGD1 (36) encodes the tandem DH and PH domains of the FGD1 protein (residues 375 to 710) fused at the NH 2 terminus to a Myc epitope tag. pRK5-myc-FGD1⌬ (36) encodes a naturally occurring splice variant of FGD1 that contains a deletion within the DH domain; it encodes a derivative with the same NH 2 and COOH termini as pRK5-myc-FGD1 but is missing residues 398 to 433 (37). pAX142-myc-FGD1 and pAX142-myc-FGD1⌬ were made by isolating the ScaI/EcoRI inserts from pRK5-myc-FGD1 and pRK5-myc-FGD1⌬, respectively, filling in the ends of the fragments with T4 DNA polymerase, and ligating into pAX142 (58) (40).…”

Section: Methodsmentioning

confidence: 99%

CDC42 and FGD1 Cause Distinct Signaling and Transforming Activities

Whitehead

Abe

Gorski

et al. 1998

Molecular and Cellular Biology

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Activated forms of different Rho family members (CDC42, Rac1, RhoA, RhoB, and RhoG) have been shown to transform NIH 3T3 cells as well as contribute to Ras transformation. Rho family guanine nucleotide exchange factors (GEFs) (also known as Dbl family proteins) that activate CDC42, Rac1, and RhoA also demonstrate oncogenic potential. The faciogenital dysplasia gene product, FGD1, is a Dbl family member that has recently been shown to function as a CDC42-specific GEF. Mutations within the FGD1 locus cosegregate with faciogenital dysplasia, a multisystemic disorder resulting in extensive growth impairments throughout the skeletal and urogenital systems. Here we demonstrate that FGD1 expression is sufficient to cause tumorigenic transformation of NIH 3T3 fibroblasts. Although both FGD1 and constitutively activated CDC42 cooperated with Raf and showed synergistic focus-forming activity, both quantitative and qualitative differences in their functions were seen. FGD1 and CDC42 also activated common nuclear signaling pathways. However, whereas both showed comparable activation of c-Jun, CDC42 showed stronger activation of serum response factor and FGD1 was consistently a better activator of Elk-1. Although coexpression of FGD1 with specific inhibitors of CDC42 function demonstrated the dependence of FGD1 signaling activity on CDC42 function, FGD1 signaling activities were not always consistent with the direct or exclusive stimulation of CDC42 function. In summary, FGD1 and CDC42 signaling and transformation are distinct, thus suggesting that FGD1 may be mediating some of its biological activities through non-CDC42 targets.The Rho subfamily of Ras-related GTPases (14 mammalian members) controls multiple aspects of cell behavior, including cytoskeletal rearrangement, nuclear signaling, and cell growth (reviewed in reference 67). For example, CDC42 mediates the induction of actin microspikes and filopodia by bradykinin (26, 33), whereas Rac1 is required for growth factor-induced membrane ruffling and lamellipodia formation (47). In contrast, RhoA regulates the formation of actin stress fibers (46). In Swiss 3T3 cells, the assembly of these structures involves a cascade in which CDC42 activates Rac1, which in turn activates RhoA (33). Rho family proteins also have demonstrated roles in the regulation of gene expression as measured by (i) the transcriptional activation of the serum response factor (SRF) (19), (ii) activation of c-Jun NH 2 -terminal kinase (JNK) and its downstream target c-Jun (10, 32, 35), (iii) activation of the ternary complex factor protein Elk-1 (62), (iv) activation of p38/Mpk2 (63), and (v) regulation of expression from the cyclin D1 promoter (55). Finally, there is growing evidence that the deregulated expression of Rho family members has profound effects on the proliferative potential of cells. Activated derivatives of RhoA, RhoB, Rac1, and CDC42 cause oncogenic transformation when expressed in rodent fibroblast cell lines and may contribute to Ras-mediated malignant transformation (23,39,41,42,53,...

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“…Similar deficits may be responsible for learning deficits in tuberous sclerosis 2, resulting from mutations in tuberin, another GAP protein (51), and for X-linked mental retardation with seizures and ataxia resulting from mutations in oligophrenin-1, a rho GAP protein (52). The Aarskog or faciogenital dysplasia syndrome and nonsyndromic mental retardation resulting from mutations in p21-activated kinase 3 (PAK3) are also due to disorders in pathways related to Ras activation (53). A similar mechanism may contribute to cognitive impairment in children exposed to environmental lead, inasmuch as this toxin can activate PKC, which in turn can enhance Ras activity (54,55).…”

Section: Cognitive Disorders Caused By Defects In Upstream Signaling mentioning

confidence: 99%

Learning, Memory, and Transcription Factors

2003

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The following article is the second in this series. It reviews genes and metabolic pathways involved in learning and memory in lower animals and in humans. These new, exciting studies will contribute to greater understanding of the molecular abnormalities responsible for cognitive disorders in children. Cognitive disorders in children have traditionally been described in terms of clinical phenotypes or syndromes, chromosomal lesions, metabolic disorders, or neuropathology. Relatively little is known about how these disorders affect the chemical reactions involved in learning and memory. Experiments in fruit flies, snails, and mice have revealed some highly conserved pathways that are involved in learning, memory, and synaptic plasticity, which is the primary substrate for memory storage. These can be divided into short-term memory storage through local changes in synapses, and long-term storage mediated by activation of transcription to translate new proteins that modify synaptic function. This review summarizes evidence that disruptions in these pathways are involved in human cognitive disorders, including neurofibromatosis type I, Coffin-Lowry syndrome, Rubinstein-Taybi syndrome, Rett syndrome, tuberous sclerosis-2, Down syndrome, X-linked ␣-thalassemia/ mental retardation, cretinism, Huntington disease, and lead poisoning. More than a thousand types of mental retardation are listed currently in Online Mendelian Inheritance in Man (OMIM, 2002) and many milder learning disorders are seen in clinical practice. Many of these disorders are associated with syndromes, chromosomal disorders, or metabolic diseases, but it is unclear how most of them disrupt the brain's chemical machinery for learning and memory. Experimental work over several decades makes it clear that long-term memory storage, which is essential for cognition, involves activity-dependent synaptic plasticity and transcription of genes to synthesize synaptic proteins (1, 2). Recently, several genetic forms of mental retardation have been linked to mutations in intracellular pathways that mediate synaptic plasticity, learning, and memory in lower animals (3). These discoveries suggest that a Alvin Zipursky Editor-in-Chief

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Genomic Organization of the Faciogenital Dysplasia (FGD1; Aarskog Syndrome) Gene

Cited by 33 publications

References 13 publications

Proline-Rich Domain Plays a Crucial Role in Extracellular Stimuli-Responsive Translocation of a Cdc42 Guanine Nucleotide Exchange Factor, FGD1

Proline-Rich Domain Plays a Crucial Role in Extracellular Stimuli-Responsive Translocation of a Cdc42 Guanine Nucleotide Exchange Factor, FGD1

CDC42 and FGD1 Cause Distinct Signaling and Transforming Activities

Learning, Memory, and Transcription Factors

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