A novel family ofras-binding domains

Ponting, Chris P.; Benjamin, Dennis R.

doi:10.1016/s0968-0004(96)30038-8

Cited by 199 publications

(138 citation statements)

References 20 publications

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“…RA domains were first identified as effectors of small GTPases of the Ras family and have been found to play pivotal roles in transmitting signals to control many cellular processes (Ponting and Benjamin, 1996;Herrmann, 2003). Structurally, these conserved RA domains belong to the ubiquitin fold superfamily (Kiel and Serrano, 2006).…”

Section: Introductionmentioning

confidence: 99%

Binding the Atypical RA Domain of Ste50p to the Unfolded Opy2p Cytoplasmic Tail Is Essential for the High-Osmolarity Glycerol Pathway

Ekiel

Sulea

Jansen³

et al. 2009

MBoC

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Section: Introductionmentioning

confidence: 99%

Binding the Atypical RA Domain of Ste50p to the Unfolded Opy2p Cytoplasmic Tail Is Essential for the High-Osmolarity Glycerol Pathway

Ekiel

Sulea

Jansen³

et al. 2009

MBoC

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“…3), and was originally identified as a fusion partner of the ALL-1 gene involved in acute lymphoblastic leukaemia 4 . AF6 is a multi-domain protein, consisting (from the N to C terminus) of two Ras-associating domains, a forkhead-associated domain, a dilute domain, a PDZ (PSD95/Dlg1/ZO-1) domain and three proline-rich regions (Pro) [5][6][7] . In rodents and humans, AF6 is expressed in almost all epithelial tissues 8 mainly with two isoforms: a long isoform containing the F-actin-binding domain (FA) and a short isoform lacking the FA domain; these versions are referred to as l-and s-afadin, respectively.…”

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confidence: 99%

Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression

Chang

Peng

et al. 2015

Nat Commun

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Pancreatic cancer (PC) is a particularly lethal form of cancer with high potential for metastasis to distant organs. Disruption of cell polarity is a hallmark of advanced epithelial tumours. Here we show that the polarity protein AF6 (afadin and MLLT4) is expressed at low levels in PC. We demonstrate that depletion of AF6 markedly promotes proliferation and metastasis of PC cells through upregulation of the expression of Snail protein, and this requires the nuclear localization of AF6. Furthermore, AF6 deficiency in PC cells leads to increased formation of a Dishevelled 2 (Dvl2)-FOXE1 complex on the promoter region of Snail gene, and activation of Snail expression. Altogether, our data established AF6 as a potential inhibitor of metastasis in PC cells. Targeting the Dvl2-FOXE1-Snail signalling axis may thus represent a promising therapeutic strategy.

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“…The Ras-dependent membrane translocation has been shown to be prerequisite to activation of the Ras effectors, Raf-1 (7), phosphoinositide 3-kinase (8), and Ral guanine nucleotide dissociation stimulator (RalGDS) (9). Some of the candidate effectors of Ras, including RalGDS and AF-6/Afadin (10,11), have been shown to possess homologous motifs of about 100 amino acids in their Ras-associating (RA) regions (12). Recently, the RA domain of RalGDS was reported to share a * This work was supported by Ministry of Education, Science, Sports and Culture of Japan Grants 11470034, 12215098, 12670116, and 12670136 and by funds from the Sankyo Foundation of Life Science, Hyogo Science and Technology Association, and Kobe University.…”

mentioning

confidence: 99%

Regulation of a Novel Human Phospholipase C, PLCε, through Membrane Targeting by Ras

Song¹,

Hu²,

Masago³

et al. 2001

Journal of Biological Chemistry

309

268

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Phosphoinositide-specific phospholipase C (PI-PLC) plays a pivotal role in regulation of intracellular signal transduction from various receptor molecules. More than 10 members of human PI-PLC isoforms have been identified and classified into three classes ␤, ␥, and ␦, which are regulated by distinct mechanisms. Here we report identification of a novel class of human PI-PLC, named PLC⑀, which is characterized by the presence of a Ras-associating domain at its C terminus and a CDC25-like domain at its N terminus. The Ras-associating domain of PLC⑀ specifically binds to the GTP-bound forms of Ha-Ras and Rap1A. The dissociation constant for HaRas is estimated to be approximately 40 nM, comparable with those of other Ras effectors. Co-expression of an activated Ha-Ras mutant with PLC⑀ induces its translocation from the cytosol to the plasma membrane. Upon stimulation with epidermal growth factor, similar translocation of ectopically expressed PLC⑀ is observed, which is inhibited by co-expression of dominant-negative Ha-Ras. Furthermore, using a liposome-based reconstitution assay, it is shown that the phosphatidylinositol 4,5-bisphosphate-hydrolyzing activity of PLC⑀ is stimulated in vitro by Ha-Ras in a GTP-dependent manner. These results indicate that Ras directly regulates phosphoinositide breakdown through membrane targeting of PLC⑀.

show abstract

A novel family ofras-binding domains

Cited by 199 publications

References 20 publications

Binding the Atypical RA Domain of Ste50p to the Unfolded Opy2p Cytoplasmic Tail Is Essential for the High-Osmolarity Glycerol Pathway

Binding the Atypical RA Domain of Ste50p to the Unfolded Opy2p Cytoplasmic Tail Is Essential for the High-Osmolarity Glycerol Pathway

Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression

Regulation of a Novel Human Phospholipase C, PLCε, through Membrane Targeting by Ras

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