When Overexpressed, a Novel Centrosomal Protein, RanBPM, Causes Ectopic Microtubule Nucleation Similar to γ-Tubulin

Nakamura, Masafumi; Masuda, Hisashi; Horii, Johji; Kuma, Kei-ichi; Yokoyama, Nobuhiko; Ohba, Tadashi; Nishitani, Hideo; Miyata, Takashi; Tanaka, Masao; Nishimoto, Tetsuya

doi:10.1083/jcb.143.4.1041

Cited by 182 publications

(159 citation statements)

References 92 publications

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“…RanBPM is a scaffold protein known to interact with different receptors including c-Met and to facilitate their activation (35), but it has also been reported to be incapable of interacting with the EGFR (36). In addition, although RanBPM was originally identified in a yeast two-hybrid screen using Ran as bait (37), thus far there is little evidence in the literature to support the idea that RanBPM is a bona fide Ran target, and we have not been able to detect an interaction between Ran and RanBPM in our stable cell lines (data not shown).…”

Section: Discussionmentioning

confidence: 38%

Activation of the Ran GTPase Is Subject to Growth Factor Regulation and Can Give Rise to Cellular Transformation

Wang

Pereira

et al. 2010

Journal of Biological Chemistry

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Although the small GTPase Ran is best known for its roles in nucleocytoplasmic transport, mitotic spindle assembly, and nuclear envelope formation, recent studies have demonstrated the overexpression of Ran in multiple tumor types and that its expression is correlated with a poor patient prognosis, providing evidence for the importance of this GTPase in cell growth regulation. Here we show that Ran is subject to growth factor regulation by demonstrating that it is activated in a serum-dependent manner in human breast cancer cells and, in particular, in response to heregulin, a growth factor that activates the Neu/ ErbB2 tyrosine kinase. The heregulin-dependent activation of Ran requires mTOR (mammalian target of rapamycin) and stimulates the capped RNA binding capability of the cap-binding complex in the nucleus, thus influencing gene expression at the level of mRNA processing. We further demonstrate that the excessive activation of Ran has important consequences for cell growth by showing that a novel, activated Ran mutant is sufficient to transform NIH-3T3 cells in an mTOR-and epidermal growth factor receptor-dependent manner and that Ran-transformed cells form tumors in mice.Ran is a unique member of the Ras superfamily of GTPases that utilizes a guanine nucleotide exchange factor (the chromatin-associated RCC1 protein), a GTPase-accelerating protein complex (RanGAP/RanBP1), and a single major class of effectors (the importins or karyopherins) to regulate the nucleocytoplasmic transport of various cargo as well as other nuclear functions (for review, see Ref. 1). In interphase cells, a Ran-GTP gradient is formed in response to the nuclear localization of RCC1 together with the cytoplasmic localization of RanGAP. As a result, Ran exists predominantly in an active, GTP-bound state in the nucleus where it is capable of engaging its primary biological effectors, the importins/karyopherins. GTP hydrolysis, catalyzed by RanGAP in the cytoplasm, then results in the dissociation of Ran-GDP from its effector proteins. The nucleocytoplasmic transport of a number of proteins is dependent upon the proper establishment of the Ran-GTP gradient, as best exemplified in the case of classical nuclear import (2). Protein cargo destined for the nucleus is identified by the presence of a nuclear localization sequence. The nuclear localization sequence is recognized by an adapter protein, importin-␣, in the cytosol, and upon binding the cargo, importin-␣ engages importin-␤ to form a complete import complex that translocates to the nucleus. Within the nucleus, Ran-GTP binds to importin-␤, causing it to dissociate from the import complex, which results in the subsequent release of cargo. Thus, the fact that Ran-GTP is predominantly a nuclear species is pivotal in the directional release of import cargo into the nucleus.Similarly, it has been suggested that Ran plays an essential role in the directional release of capped RNAs in the cytoplasm by regulating the interactions that occur between the nuclear cap-binding complex (CBC) 2 ...

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Section: Discussionmentioning

confidence: 38%

Activation of the Ran GTPase Is Subject to Growth Factor Regulation and Can Give Rise to Cellular Transformation

Wang

Pereira

et al. 2010

Journal of Biological Chemistry

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“…Although most of the Ran-binding proteins play an important role in nucleocytoplasmic transport, it is unlikely that RanBPM is involved in this process (Nishitani et al, 2001). Alternatively, Nakamura et al (1998) reported that RanBPM might be involved in reorganization of the microtubule network; however, the precise function of RanBPM remains unknown.…”

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confidence: 99%

“…Given that RanBPM is localized in both the cytoplasm and nucleus (Nakamura et al, 1998;Nishitani et al, 2001), it is probable that p73a might have an ability to promote nuclear translocation of RanBPM through the physical interaction between them. As described previously, wildtype p53 is predominantly localized in the cytoplasm of many neuroblastoma cells (Moll et al, 1996).…”

mentioning

confidence: 99%

“…After screening of approximately 5 Â 10 5 transformants, 12 independent clones exhibited a high level of b-galactosidase activity, and subsequent sequence analysis revealed that three out of them encoded the overlapping regions of RanBPM (Figure 1a). RanBPM was initially identified as a cellular protein that can interact with Ran nuclear-cytoplasmic transport protein (Nakamura et al, 1998;Nishitani et al, 2001), and contained the putative SPRY domain which might be involved in protein-protein interactions (Ponting et al, 1997). Although most of the Ran-binding proteins play an important role in nucleocytoplasmic transport, it is unlikely that RanBPM is involved in this process (Nishitani et al, 2001).…”

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confidence: 99%

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Protein stability and function of p73 are modulated by a physical interaction with RanBPM in mammalian cultured cells

et al. 2004

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Upon a certain DNA damage including cisplatin treatment, p73 is stabilized and exerts its growth-suppressive and/or proapoptotic function. However, the precise molecular basis by which the intracellular levels of p73 are regulated remains unclear. In the present study, we have identified RanBPM as a novel binding partner of p73a by yeastbased two-hybrid screening, and also found that RanBPM has an ability to stabilize p73a. GST pull-down assays and co-immunoprecipitation experiments revealed that RanBPM directly bound to the extreme COOH-terminal region of p73a, whereas it failed to interact with p53. Coexpression of RanBPM with p73a resulted in the nuclear translocation of RanBPM, and both proteins co-localized in cell nucleus as examined by indirect immunofluorescent staining. It is worth noting that the expression of RanBPM inhibited the ubiquitination of p73a, and thereby prolonged its half-life. Subsequent studies demonstrated that the proapoptotic activity of p73a was significantly enhanced in the presence of RanBPM. Taken together, our present findings implicate a novel role for RanBPM in the regulation of p73 stability and function. Oncogene (2005) 24, 938-944.

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“…Ran-BPM/RanBP9 was originally cloned as a Ran-binding protein and found to be localized in both the nucleus and cytoplasm (32,33). RanBPM contains a very conserved SPRY domain with unknown functions.…”

mentioning

confidence: 99%

Activation of Ras/Erk Pathway by a Novel MET-interacting Protein RanBPM

Wang

Messing

et al. 2002

Journal of Biological Chemistry

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144

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MET is a receptor protein-tyrosine kinase (RPTK) for hepatocyte growth factor (HGF), which is a multifunctional cytokine controlling cell growth, morphogenesis, and motility. MET overexpression has been identified in a variety of human cancers. Oncogenic missense mutations of the tyrosine kinase domain of the MET gene have been identified in human papillary renal cell carcinomas. In this study, RanBPM, also known as RanBP9, is identified as a novel interacting protein of MET through yeast two-hybrid screen. RanBPM contains a conserved SPRY (repeats in splA and RyR) domain. We demonstrate that RanBPM can interact with MET in vitro and in vivo, and the interaction can be strengthened by HGF stimulation. RanBPM interacts with the tyrosine kinase domain of MET through its SPRY domain. We show that RanBPM can induce GTP-Ras association and Erk phosphorylation and elevate serum response element-luciferase (SRE-LUC) expression, indicating that RanBPM can activate the Ras-Erk-SRE pathway. We demonstrate that RanBPM, which itself is not a guanine exchange protein, stimulates Ras activation by recruiting Sos. On the cellular level, A704 cells, a human renal carcinoma cell line, transfected with Ran-BPM exhibit increased migration ability. Our data suggest that RanBPM, functioning as an adaptor protein for the MET tyrosine kinase domain, can augment the HGF-MET signaling pathway and that RanBPM overexpression may cause constitutive activation of the Ras signaling pathway.

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When Overexpressed, a Novel Centrosomal Protein, RanBPM, Causes Ectopic Microtubule Nucleation Similar to γ-Tubulin

Cited by 182 publications

References 92 publications

Activation of the Ran GTPase Is Subject to Growth Factor Regulation and Can Give Rise to Cellular Transformation

Activation of the Ran GTPase Is Subject to Growth Factor Regulation and Can Give Rise to Cellular Transformation

Protein stability and function of p73 are modulated by a physical interaction with RanBPM in mammalian cultured cells

Activation of Ras/Erk Pathway by a Novel MET-interacting Protein RanBPM

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