The gene for a new brain specific RhoA exchange factor maps to the highly unstable chromosomal region 1p36.2–1p36.3.

Toledo, Marion de; Coulon, Vincent; Schmidt, Susanne; Fort, Philippe; Blangy, Anne

doi:10.1038/sj.onc.1204921

Cited by 59 publications

(52 citation statements)

References 63 publications

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“…Furthermore, our analyses in the present study found that the isolated DH/PH domains of Ect2 acted as a RhoA-specific exchange factor in vitro and in vivo. The DH domain of Ect2 exhibits strongest sequence identity with the DH domain of GEF720/KIAA0720 (2), a RhoA-specific GEF (38). However, when we characterized Rho GEF activity in vivo for the DH/PH/C fragment, we showed that this mutant caused increased levels of RhoA-GTP, Rac1-GTP and Cdc42-GTP in vivo.…”

Section: Discussionmentioning

confidence: 99%

Requirement For C-terminal Sequences in Regulation of Ect2 Guanine Nucleotide Exchange Specificity and Transformation

Solski

Wilder

Rossman

et al. 2004

Journal of Biological Chemistry

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Ect2 was identified originally as a transforming protein and a member of the Dbl family of Rho guanine nucleotide exchange factors (GEFs). Like all Dbl family proteins, Ect2 contains a tandem Dbl homology (DH) and pleckstrin homology (PH) domain structure. Previous studies demonstrated that N-terminal deletion of sequences upstream of the DH domain created a constitutively activated, transforming variant of Ect2 (designated ⌬N-Ect2 DH/PH/C), indicating that the N terminus served as a negative regulator of DH domain function in vivo. The role of sequences C-terminal to the DH domain has not been established. Therefore, we assessed the consequences of mutation of C-terminal sequences on Ect2-transforming activity. Surprisingly, in contrast to observations with other Dbl family proteins, we found that mutation of the invariant tryptophan residue in the PH domain did not impair ⌬N-Ect2 DH/PH/C transforming activity. Furthermore, although the sequences Cterminal to the PH domain lack any known functional domains or motifs, deletion of these sequences (⌬N-Ect2 DH/PH) resulted in a dramatic reduction in transforming activity. Whereas ⌬N-Ect2 caused formation of lamellipodia, ⌬N-Ect2 DH/PH enhanced actin stress fiber formation, suggesting that C-terminal sequences influenced Ect2 Rho GTPase specificity. Consistent with this possibility, we determined that ⌬N-Ect2 DH/PH activated RhoA, but not Rac1 or Cdc42, whereas ⌬N-Ect2 DH/PH/C activated all three Rho GTPases in vivo. Taken together, these observations suggest that regions of Ect2 C-terminal to the DH domain alter the profile of Rho GTPases activated in vivo and consequently may contribute to the enhanced transforming activity of ⌬N-Ect2 DH/PH/C.

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Section: Discussionmentioning

confidence: 99%

Requirement For C-terminal Sequences in Regulation of Ect2 Guanine Nucleotide Exchange Specificity and Transformation

Solski

Wilder

Rossman

et al. 2004

Journal of Biological Chemistry

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“…A similarity search with the Syx cDNA sequence revealed that the human (chromosome 1, as previously reported; De Toledo et al, 2001), rat (chromosome 5), and cow genomes also contain a Syx gene with the same structure as in the mouse.…”

Section: Syx Is Transcribed As Two Nearly Identical Splice Variantsmentioning

confidence: 91%

“…Similarly, conflicting results were reported regarding the dependence of the transforming activity of Net1 on its PDZ-binding motif (Qin et al, 2005), where a mutant lacking the PDZ-binding motif was less efficient in transforming 3T3 fibroblasts, but a splice variant with a PDZ-binding motif was similarly inefficient. A previous study where expression of a Syx1 human orthologue was shown to transform 3T3 fibroblasts used a partial clone (GEF720) lacking 160 Nterminus residues (De Toledo et al, 2001) but containing the PDZ-binding motif. This truncated version of Syx1 may have been disinhibited, however, because the N-terminus is required for the down-regulation of Syx1 (Marx et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…The fourth is a GEF with a PDZ-binding motif (GEF720) that was recently identified in a human cDNA database (Kikuno et al, 2002) and classified as RhoA-specific (De Toledo et al, 2001). A rat orthologue of the same GEF (Tech, a transcript highly enriched in cortex and hippocampus) was independently identified and its catalytic properties were characterized (Marx et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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A PDZ-binding Motif as a Critical Determinant of Rho Guanine Exchange Factor Function and Cell Phenotype

Liu¹,

Horowitz²

2006

MBoC

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We identified a Rho guanine exchange factor (GEF) expressed as two splice variants, which differ only in either having or lacking a Postsynaptic density 95, Disk large, Zona occludens-1 (PDZ) motif. The PDZ adaptor protein synectin bound the longer splice variant, Syx1, which was targeted to the plasma membrane in a synectin-dependent manner. The shorter variant, Syx2, was diffusely distributed in the cytoplasm. Fluorescence resonance energy transfer (FRET) imaging revealed similar differences between the spatial patterns of active RhoA in Syx1 versus Syx2-expressing cells. Expression of Syx1 augmented endothelial cell (EC) migration and tube formation, whereas Syx2 expression did not. It appears, therefore, that synectin-dependent targeting of Syx is critical to its contribution to these EC functions. Although agonist-stimulated global RhoA activity was similar in Syx1-and Syx2-expressing cells, basal RhoA activity was surprisingly higher in the latter. Out of 23 cell types, we found a significant level of endogenous Syx2 expression only in brain tumor cells, which also exhibited high basal RhoA activity. We found that the activity level of JNK, which mediates transcriptional regulation downstream of RhoA, is elevated in a Syx2-dependent manner in these cells, possibly contributing to their tumorigenicity.

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“…However, these studies have not identified a consistent region of deletion. Furthermore, these and other studies have proposed over 20 genes within these regions as candidate neuroblastoma tumor suppressors, none of which have yet been proven to play a significant causative role in neuroblastoma tumor development (Ejeskar et al, 2000;Judson et al, 2000;De Toledo et al, 2001;Huang et al, 2001;Abel et al, 2002;Cerignoli et al, 2002;Krona et al, 2003;Thompson et al, 2003;Mathysen et al, 2004). Our current work was designed to determine the location and extent of 1p deletion in a very large primary tumor cohort by extensive genotyping, sequencing, gene identification, and transcript characterization.…”

Section: Discussionmentioning

confidence: 99%

Definition and characterization of a region of 1p36.3 consistently deleted in neuroblastoma

et al. 2004

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Substantial genomic and functional evidence from primary tumors and cell lines indicates that a consistent region of distal chromosome 1p is deleted in a sizable proportion of human neuroblastomas, suggesting that this region contains one or more tumor suppressor genes. To determine systematically and precisely the location and extent of 1p deletion in neuroblastomas, we performed allelic loss studies of 737 primary neuroblastomas and genotype analysis of 46 neuroblastoma cell lines. Together, the results defined a single region within 1p36.3 that was consistently deleted in 25% of tumors and 87% of cell lines. Two neuroblastoma patients had constitutional deletions of distal 1p36 that overlapped the tumor-defined region. The tumor-and constitutionally-derived deletions together defined a smallest region of consistent deletion (SRD) between D1S2795 and D1S253. The 1p36.3 SRD was deleted in all but one of the 184 tumors with 1p deletion. Physical mapping and DNA sequencing determined that the SRD minimally spans an estimated 729 kb. Genomic content and sequence analysis of the SRD identified 15 characterized, nine uncharacterized, and six predicted genes in the region. The RNA expression profiles of 21 of the genes were investigated in a variety of normal tissues. The SHREW1 and KCNAB2 genes both had tissue-restricted expression patterns, including expression in the nervous system. In addition, a novel gene (CHD5) with strong homology to proteins involved in chromatin remodeling was expressed mainly in neural tissues. Together, these results suggest that one or more genes involved in neuroblastoma tumorigenesis or tumor progression are likely contained within this region.

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The gene for a new brain specific RhoA exchange factor maps to the highly unstable chromosomal region 1p36.2–1p36.3.

Cited by 59 publications

References 63 publications

Requirement For C-terminal Sequences in Regulation of Ect2 Guanine Nucleotide Exchange Specificity and Transformation

Requirement For C-terminal Sequences in Regulation of Ect2 Guanine Nucleotide Exchange Specificity and Transformation

A PDZ-binding Motif as a Critical Determinant of Rho Guanine Exchange Factor Function and Cell Phenotype

Definition and characterization of a region of 1p36.3 consistently deleted in neuroblastoma

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