βArrestin1 Regulates the Guanine Nucleotide Exchange Factor RasGRF2 Expression and the Small GTPase Rac-mediated Formation of Membrane Protrusion and Cell Motility

Ma, Xiaojie; España‐Serrano, Laura; Kim, Wan-Ju; Purayil, Hamsa Thayele; Nie, Zhongzhen; Daaka, Yehia

doi:10.1074/jbc.m113.511360

Cited by 22 publications

(19 citation statements)

References 44 publications

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“…1G legend for detailed statistics). In a previous study, downregulation of RASGRF2 by 70% with RNAi resulted in a marked decrease of the RASGRF2 protein (30), suggesting that our observed down-regulation can be also significant at the translational level. Crucially, according to ENSEMBL, two protein-coding transcripts are produced from RASGRF2 (RASGRF2-201 and RASGRF2-206; Fig.…”

Section: Artificial Insertion Of the Hk2 Ltr Can Modulate Rasgrf2supporting

confidence: 69%

Human Endogenous Retrovirus-K HML-2 integration within RASGRF2 is associated with intravenous drug abuse and modulates transcription in a cell-line model

Karamitros

Hurst

Marchi

et al. 2018

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

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HERV-K HML-2 (HK2) has been proliferating in the germ line of humans at least as recently as 250,000 years ago, with some integrations that remain polymorphic in the modern human population. One of the solitary HK2 LTR polymorphic integrations lies between exons 17 and 18 of RASGRF2, a gene that affects dopaminergic activity and is thus related to addiction. Here we show that this antisense HK2 integration (namely RASGRF2-int) is found more frequently in persons who inject drugs compared with the general population. In a Greek HIV-1-positive population (n = 202), we found RASGRF2-int 2.5 times (14 versus 6%) more frequently in patients infected through i.v. drug use compared with other transmission route controls (P = 0.03). Independently, in a United Kingdom-based hepatitis C virus-positive population (n = 184), we found RASGRF2-int 3.6 times (34 versus 9.5%) more frequently in patients infected during chronic drug abuse compared with controls (P < 0.001). We then tested whether RASGRF2-int could be mechanistically responsible for this association by modulating transcription of RASGRF2. We show that the CRISPR/Cas9-mediated insertion of HK2 in HEK293 cells in the exact RASGRF2 intronic position found in the population resulted in significant transcriptional and phenotypic changes. We also explored mechanistic features of other intronic HK2 integrations and show that HK2 LTRs can be responsible for generation of cis-natural antisense transcripts, which could interfere with the transcription of nearby genes. Our findings suggest that RASGRF2-int is a strong candidate for dopaminergic manipulation, and emphasize the importance of accurate mapping of neglected HERV polymorphisms in human genomic studies.HERV-K HML-2 | endogenous retrovirus | RASGRF2 | persons who inject drugs | addiction

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Section: Artificial Insertion Of the Hk2 Ltr Can Modulate Rasgrf2supporting

confidence: 69%

Human Endogenous Retrovirus-K HML-2 integration within RASGRF2 is associated with intravenous drug abuse and modulates transcription in a cell-line model

Karamitros

Hurst

Marchi

et al. 2018

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

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“…The discrepancy of RasGRF2 expression between our results and the previous study is probably due to unelucidated mechanism. Several studies have reported aberrant methylation of RasGRF2 in different cancer, such as pancreatic cancers 27 , non-small cell lung cancer 8 and CRC 10 , which indicated that RasGRF2 expression may be suppressed in these tissues, based on an wide recognition that DNA methylation prevents gene Accumulating evidences suggests that RasGRF2 plays a critical role in movement, invasion and lung colonization of many kinds of cancer cells 5,7,29,30 . RasGRF2 has been shown to suppress rounded movement of melanoma cells 7 , whether RasGRF2 has a role in metastasis of CRC remains unclear.…”

Section: Discussionmentioning

confidence: 99%

“…RasGRF2 is a multi-domain protein that has dual Ras GEF and Rac GEF activities 4 . The Cdc25 homology domain at the C-terminus catalyzes exchange of GDP to GTP on Ras family proteins 5 . RasGRF2 is involved in regulating NMDA receptor signaling and synaptic plasticity in neuronal tissues 5 and in the control of T-cell proliferation and lymphomagenesis 6 .…”

Section: Introductionmentioning

confidence: 99%

“…The Cdc25 homology domain at the C-terminus catalyzes exchange of GDP to GTP on Ras family proteins 5 . RasGRF2 is involved in regulating NMDA receptor signaling and synaptic plasticity in neuronal tissues 5 and in the control of T-cell proliferation and lymphomagenesis 6 . Calvo et al demonstrated that RasGRF2 also plays a role in modulating tumor cell movement and invasion by inhibiting Cdc42 activation, a key component in actomyosin-contractility-dependent tumor cell movement 7 .…”

Section: Introductionmentioning

confidence: 99%

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RasGRF2 promotes migration and invasion of colorectal cancer cells by modulating expression of MMP9 through Src/Akt/NF-κB pathway

Chen

Yan

et al. 2018

Cancer Biology & Therapy

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Ras-specific guanine nucleotide-releasing factor 2 (RasGRF2) is a member of the guanine nucleotide exchange factors family which is expressed in a variety of tissues and cancer. However, the role of RasGRF2 in cancer is less reported, especially in colorectal cancer(CRC). Hence, the present study aimed to investigated the function of RasGRF2 and ways in which it affects tumor progression in CRC samples and cell lines. We first measured RasGRF2 mRNA level in 26 paired tumor and nontumor colon tissues after colon cancer surgical resection, and determined RasGRF2 protein level in 97 paired paraffinembedded colon cancer tissues, and found that levels of RasGRF2 mRNA and protein were increased in colorectal tumor tissues, compared with adjacent non-tumor tissues. We then examined the effects of RasGRF2 knockdown on proliferation, migration and invasion were analyzed in CRC cells (SW480, HCT116 and LS174T). HCT116 cells with RasGRF2 knockdown were injected into the tail vein in nude mice to yield metastatic model, and tumor metastasis was measured as well. We found that knockdown of RasGRF2 in CRC cells reduced their migration and invasion in vitro and metastasis in mice. Furthermore, we explored the underlying molecular mechanism for RasGRF2-mediated CRC migration and invasion. The results showed that knockdown of RasGRF2 in CRC cells impairing the expression of MMP9 and inhibiting the activation of Src/Akt and NF-κB signaling. We conclude that RasGRF2 plays a role in controlling migration and invasion of CRC and modulates the expression of MMP9 through Src/PI 3-kinase and the NF-κB pathways. ARTICLE HISTORY

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“…We have also shown that reduced expression of AnxA6 in TNBC cells is associated with increased expression of RasGRF2 (GRF2), a Ca 2+ activated Ras protein specific guanine nucleotide exchange factor (RasGEF) [17], with little effect on other RasGEFs such as SOS1. Meanwhile, GRF2 has been reported to promote cell growth via activation of Ras proteins and to inhibit cell motility via interaction with Cdc42 and Rac1 Rho GTPases [18,19]. Together, these studies suggest that the reciprocal expression of AnxA6 and GRF2 underlies the potential for TNBC cells to either grow rapidly or to become invasive.…”

Section: Introductionmentioning

confidence: 93%

Reciprocal expression of Annexin A6 and RasGRF2 discriminates rapidly growing from invasive triple negative breast cancer subsets

et al. 2020

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Actively growing tumors are often histologically associated with Ki67 positivity, while the detection of invasiveness relies on non-quantitative pathologic evaluation of mostly advanced tumors. We recently reported that reduced expression of the Ca 2+-dependent membrane-binding annexin A6 (AnxA6) is associated with increased expression of the Ca 2+ activated RasGRF2 (GRF2), and that the expression status of these proteins inversely influence the growth and motility of triple negative breast cancer (TNBC) cells. Here, we establish that the reciprocal expression of AnxA6 and GRF2 is at least in part, dependent on inhibition of non-selective Ca 2+ channels in AnxA6-low but not AnxA6-high TNBC cells. Immunohistochemical staining of breast cancer tissues revealed that compared to non-TNBC tumors, TNBC tumors express lower levels of AnxA6 and higher Ki67 expression. GRF2 expression levels strongly correlated with high Ki67 in pretreatment biopsies from patients with residual disease and with residual tumor size following chemotherapy. Elevated AnxA6 expression more reliably identified patients who responded to chemotherapy, while low AnxA6 levels were significantly associated with shorter distant relapse-free survival. Finally, the reciprocal expression of AnxA6 and GRF2 can delineate GRF2-low/ AnxA6-high invasive from GRF2-high/AnxA6-low rapidly growing TNBCs. These data suggest that AnxA6 may be a reliable biomarker for distant relapse-free survival and response of TNBC patients to chemotherapy, and that the reciprocal expression of AnxA6 and GRF2 can reliably delineate TNBCs into rapidly growing and invasive subsets which may be more relevant for subset-specific therapeutic interventions.

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βArrestin1 Regulates the Guanine Nucleotide Exchange Factor RasGRF2 Expression and the Small GTPase Rac-mediated Formation of Membrane Protrusion and Cell Motility

Cited by 22 publications

References 44 publications

Human Endogenous Retrovirus-K HML-2 integration within RASGRF2 is associated with intravenous drug abuse and modulates transcription in a cell-line model

Human Endogenous Retrovirus-K HML-2 integration within RASGRF2 is associated with intravenous drug abuse and modulates transcription in a cell-line model

RasGRF2 promotes migration and invasion of colorectal cancer cells by modulating expression of MMP9 through Src/Akt/NF-κB pathway

Reciprocal expression of Annexin A6 and RasGRF2 discriminates rapidly growing from invasive triple negative breast cancer subsets

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