Cytohesins and centaurins: mediators of PI 3-kinase-regulated Arf signaling

Jackson, Trevor; Kearns, Brian G.; Theibert, Anne B.

doi:10.1016/s0968-0004(00)01644-3

Cited by 120 publications

(112 citation statements)

References 56 publications

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“…Interestingly, we have identi®ed the murine homologue to human centaurin g3 as upregulated in FGF2 transfectants. Centaurins, downstream mediators of phosphoinositide 3-kinase signaling cascades, have been proposed as involved in actin cytoskeletal organization (Jackson et al, 2000). Also, FGF2-T-MAE cells express high levels of collagen a2 type I and of the a 3 integrin receptor.…”

Section: Arrays (Clontech) a Typical Results Is Reported In (A) And (mentioning

confidence: 99%

Gene expression profile in fibroblast growth factor 2-transformed endothelial cells

et al. 2002

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Fibroblast growth factor-2 (FGF2) exerts paracrine and autocrine functions on endothelial cells. FGF2-overexpressing murine aortic endothelial cells (FGF2-T-MAE cells) induce opportunistic hemangioendothelioma-like tumors when inoculated in immunode®cient mice. To evaluate the impact of FGF2-mediated activation on gene expression pro®le in transformed endothelial cells, we performed subtractive suppression hybridization analysis between FGF2-T-MAE cells and parental MAE cells. The two cell populations were compared for di erential gene expression also by gene macroarray hybridization with 32 P-labeled cDNAs. The two approaches allowed the identi®cation of 27 transcripts whose expression was upregulated by FGF2 in endothelial cells. With the exception of one unknown gene, the di erentially expressed transcripts encoded for proteins involved in the modulation of cell cycle, di erentiation, and cell adhesion. Among them, the stress-inducible genes A170, GADD45 and GADD153 are upregulated by FGF2 transfection or recombinant growth factor treatment. Their expression was also induced in vascular tumors originated by parental or FGF2-transfected MAE cells in nude mice. This study extends the number of genes involved in tumor angiogenesis and/or endothelial cell transformation, a ®nding with possible implications for the discovery of novel targets for angiostatic therapy.

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Section: Arrays (Clontech) a Typical Results Is Reported In (A) And (mentioning

confidence: 99%

Gene expression profile in fibroblast growth factor 2-transformed endothelial cells

et al. 2002

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“…These proteins are known to play an important role in vesicular trafficking in all eukaryotic cells (34). Indeed, the overexpression of Msec7-1 up-regulates the levels of R1 ASA on the cell surface of COS-7 cells via an interaction with the dileucine motif.…”

Section: Discussionmentioning

confidence: 99%

-Aminobutyric Acid Type B (GABAB) Receptor Internalization Is Regulated by the R2 Subunit

Hannan

Wilkins

Dehghani-Tafti

et al. 2011

Journal of Biological Chemistry

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␥-Aminobutyric acid type B (GABA B ) receptors are important for slow synaptic inhibition in the CNS. The efficacy of inhibition is directly related to the stability of cell surface receptors. For GABA B receptors, heterodimerization between R1 and R2 subunits is critical for cell surface expression and signaling, but how this determines the rate and extent of receptor internalization is unknown. Here, we insert a high affinity ␣-bungarotoxin binding site into the N terminus of the R2 subunit and reveal its dominant role in regulating the internalization of GABA B receptors in live cells. To simultaneously study R1a and R2 trafficking, a new ␣-bungarotoxin binding site-labeling technique was used, allowing ␣-bungarotoxin conjugated to different fluorophores to selectively label R1a and R2 subunits. This approach demonstrated that R1a and R2 are internalized as dimers. In heterologous expression systems and neurons, the rates and extents of internalization for R1aR2 heteromers and R2 homomers are similar, suggesting a regulatory role for R2 in determining cell surface receptor stability. The fast internalization rate of R1a, which has been engineered to exit the endoplasmic reticulum, was slowed to that of R2 by truncating the R1a C-terminal tail or by removing a dileucine motif in its coiled-coil domain. Slowing the rate of internalization by co-assembly with R2 represents a novel role for GPCR heterodimerization whereby R2 subunits, via their C terminus coiled-coil domain, mask a dileucine motif on R1a subunits to determine the surface stability of the GABA B receptor.Metabotropic GABA B 2 receptors mediate a slow and prolonged phase of synaptic inhibition in the CNS. Their importance for neuronal function is evident when they become dysfunctional, which can lead to a range of diseases that includes epilepsy, sleep disorders, stress, depression, and substance abuse (1-3).Native GABA B receptors are considered to function as heterodimers formed from R1 and R2 subunits (4, 5) with the possibility that some higher order oligomeric assemblies (e.g. dimer of dimers) may also retain functionality (6, 7). Heterodimerization of GABA B receptors has profound consequences for their structural and functional properties, impacting on the efficiency of cell surface expression and the linkage between agonist binding and G-protein activation.Functional GABA B receptors require both R1 and R2 to coassemble because an endoplasmic reticulum (ER) retention motif, RSR, in the C-terminal coiled-coil domain of R1 subunits has to be masked by the R2 subunit to ensure surface expression (8, 9). Substitution of the retention motif with ASA allows R1 subunits to exit the ER and travel alone to the cell surface (8). Although the role of R2 in heterodimerization for forward trafficking has been reported, how heterodimerization, and in particular the R2 subunit, affects the cell surface stability and internalization of GABA B receptor subunits remains unresolved.This aspect is important because the cell surface stability and mobility of GA...

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“…It is, thus, conceivable that the invasive activity shown by breast carcinomas might be reminiscent of mechanisms used by epithelia in other stages such as during embryonic development, or used in other types of cells. The number of genes coding for Arf GEFs and Arf GAPs in humans is significantly larger than that for the Arf isoforms and Arf-like factors, and more than one type of GEF or GAP has been shown to act on Arf6 (6,30,31). Arf6 is versatile (6), and different GAPs and GEFs act on Arf6, perhaps depending on its different functions.…”

Section: Discussionmentioning

confidence: 99%

Requirement for Arf6 in breast cancer invasive activities

Hashimoto¹,

Onodera²,

Hashimoto³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

250

285

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In most human breast cancer cell lines, there is a direct correlation between their in vivo invasive phenotypes and in vitro invasion activities. Here, we found that ADP-ribosylation factor 6 (Arf6) is localized at the invadopodia of the cultured breast cancer cells MDA-MB-231, and its suppression by a small-interfering RNA duplex effectively blocks the invasive activities of the cells, such as invadopodia formation, localized matrix degradation and Matrigel transmigration but not the cell-adhesion activity. We also found that the GTP hydrolysis-defective mutant Arf6(Q67L) and the GTP-binding defective mutant Arf6(T27N) both blocked these invasive activities but not cell adhesion, suggesting the necessity of continued activation and cycling of the Arf6 GTPase cycle in invasion. Among the different human breast cancer cell lines that we examined, cell lines with high invasive activities expressed higher amounts of Arf6 protein than those in weakly invasive and noninvasive cell lines, although no notable correlation was found between Arf6 mRNA expression levels and invasive activities. Moreover, Matrigel-transmigration activity of all of these invasive cells was blocked effectively by an Arf6 small-interfering RNA duplex. Hence, Arf6 appears to be an integral component of breast cancer invasive activities, and we propose that Arf6 and the intracellular machinery regulating Arf6 during invasion should be considered as therapeutic targets for the prevention of breast cancer invasion.

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Cytohesins and centaurins: mediators of PI 3-kinase-regulated Arf signaling

Cited by 120 publications

References 56 publications

Gene expression profile in fibroblast growth factor 2-transformed endothelial cells

Gene expression profile in fibroblast growth factor 2-transformed endothelial cells

-Aminobutyric Acid Type B (GABAB) Receptor Internalization Is Regulated by the R2 Subunit

Requirement for Arf6 in breast cancer invasive activities

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