Novel role of the muskelin–RanBP9 complex as a nucleocytoplasmic mediator of cell morphology regulation

Valiyaveettil, Manojkumar; Bentley, Amber A.; Gursahaney, Priya R.; Hussien, Rajaa; Chakravarti, Ritu; Kureishy, Nina; Prag, Søren; Adams, Josephine C.

doi:10.1083/jcb.200801133

Cited by 59 publications

(87 citation statements)

References 54 publications

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“…RanBPM has about 96% of high homology of amino acid sequence between human RanBPM (NM_005493) and mouse RanBPM (NM_019930). RanBPM is a multifunctional protein with a variety of intracellular interaction with proteins including MET (41), androgen receptor (43), HIPK2 (44), USP11 (45), Twa1 (25), calbindin D28K (47), p75NTR (48), TrkA (49), muskelin (50), LRP (26), and MOP (51), suggesting that RanBPM is involved in diverse biological processes. In particular, RanBPM was shown to interact with p73 and Ache to promote cell apoptosis (27,52).…”

Section: Discussionmentioning

confidence: 99%

Stability and Function of Mammalian Lethal Giant Larvae-1 Oncoprotein Are Regulated by the Scaffolding Protein RanBPM

Suresh

Ramakrishna

Kim

et al. 2010

Journal of Biological Chemistry

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The evolutionarily conserved lethal giant larvae (Lgl) tumor suppressor gene has an essential role in establishing apical-basal cell polarity, cell proliferation, differentiation, and tissue organization. However, the precise molecular mechanism by which the Lgl carries out its function remains obscure. In the current study, we have identified Ran-binding protein M (RanBPM) as a novel binding partner of Mgl-1, a mammalian homolog of Drosophila tumor suppressor protein lethal (2) giant larvae (L(2)gl) by yeast two-hybrid screening. RanBPM seems to act as a scaffolding protein with a modulatory function with respect to Mgl-1. The Mgl-1 and RanBPM association was confirmed by co-immunoprecipitation and GST pull-down experiments. Additionally, expression of RanBPM resulted in inhibition of Mgl-1 degradation, and thereby extended the half-life of Mgl-1. Furthermore, the ability of Mgl-1 activity in cell migration and colony formation assay was enhanced by RanBPM. Taken together, our findings reveal that RanBPM plays a novel role in regulating Mgl-1 stability and contributes to its biological function as a tumor suppressor.The lethal giant larvae (Lgl) 2 gene was identified as the first recessive oncogene in Drosophila (1-3). Lgl function is reported to be essential for the development of polarized epithelia (4, 5), localization of cell fate determinant Numb in Drosophila neuroblasts (6, 7) and association with cytoskeletal complex (8). It also has been reported that Lgl prevents tumor formation by antagonizing Decapentaplegic (Dpp) signaling by semaphonrin 5c in the brain (9). Lgl functions in concert with two other tumor suppressor genes: discs large (dlg) and scribble (scrib), primarily involved in maintenance of basolateral membrane domain and basal protein targeting (4, 5, 7). In addition, Lgl functions competitively with Par3 in order to make a complex with Par6-aPKC protein complexes that are crucial for the apical membrane domain (10, 11).Homologs of Lgl have been identified in many species including human, mouse, rat, bovine, insect, worm, slime mold, and yeast (12-15). The two Lgl homologs, Lgl1 and Lgl2 have conserved function in the maintenance of cell polarity and tissue homeostasis. In mouse, changes in Lgl1 activity leads to the loss of apical junctional complex in neuroblasts and hyperplasia (16). Hugl-l, a human homolog of Lgl is strongly down-regulated in malignant melanoma (17). A significant reduction in the expression of Hugl-1 was reported in tumor tissues from colorectal cancer patients. Thus, down-regulation of Hugl-1 correlates with occurrence of colorectal cancers whereas its expression leads to increase in cell adhesion and decreased cell migration (18). Hugl-1 plays a key role in the regulation of proteins, which are involved in epithelial-mesenchymal transition (EMT), a process that enables an epithelial cell to gain mesenchymal and migratory properties (17). In mouse embryonic fibroblasts, a mutant of Mgl-1 lacking five serine residues reduced cell polarization in an in vitro wounding ass...

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Section: Discussionmentioning

confidence: 99%

Stability and Function of Mammalian Lethal Giant Larvae-1 Oncoprotein Are Regulated by the Scaffolding Protein RanBPM

Suresh

Ramakrishna

Kim

et al. 2010

Journal of Biological Chemistry

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“…For example, it interacts with the Met tyrosine kinase receptor facilitating activation of the Ras-Erk pathway (Wang et al, 2002). It binds the kelch-repeat protein muskelin affecting cell morphology (Valiyaveettil et al, 2008). In the immune system, it interacts with the 2-integrin LFA1 (lymphocyte function-associated antigen 1) (Denti et al, 2004), whereas in the nervous system it modulates axonal and neurite outgrowth by affecting the plexin-A receptors, the neural cell adhesion molecule L1 signaling and the neurotrophin receptor TrkB (Cheng et al, 2005;Murrin and Talbot, 2007;Togashi et al, 2006;Yin et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

RanBPM is essential for mouse spermatogenesis and oogenesis

et al. 2011

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SUMMARYRanBPM is a recently identified scaffold protein that links and modulates interactions between cell surface receptors and their intracellular signaling pathways. RanBPM has been shown to interact with a variety of functionally unrelated proteins; however, its function remains unclear. Here, we show that RanBPM is essential for normal gonad development as both male and female RanBPM -/-mice are sterile. In the mutant testis there was a marked decrease in spermatogonia proliferation during postnatal development. Strikingly, the first wave of spermatogenesis was totally compromised, as seminiferous tubules of homozygous mutant animals were devoid of post-meiotic germ cells. We determined that spermatogenesis was arrested around the late pachytene-diplotene stages of prophase I; surprisingly, without any obvious defect in chromosome synapsis. Interestingly, RanBPM deletion led to a remarkably quick disappearance of all germ cell types at around one month of age, suggesting that spermatogonia stem cells are also affected by the mutation. Moreover, in chimeric mice generated with RanBPM -/-embryonic stem cells all mutant germ cells disappeared by 3 weeks of age suggesting that RanBPM is acting in a cell-autonomous way in germ cells. RanBPM homozygous mutant females displayed a premature ovarian failure due to a depletion of the germ cell pool at the end of prophase I, as in males. Taken together, our results highlight a crucial role for RanBPM in mammalian gametogenesis in both genders.

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“…Several recent reports have suggested that RanBPM contributes to the regulation of various cell signaling functions, including cell adhesion and migration (8)(9)(10)(11), microtubule regulation (12,13), as well as the regulation of gene transcription (14,15). There is also evidence for RanBPM involvement in signaling pathways elicited by environmental signals.…”

Section: Introductionmentioning

confidence: 99%

RanBPM Has Proapoptotic Activities That Regulate Cell Death Pathways in Response to DNA Damage

Atabakhsh

Bryce

Lefebvre

et al. 2009

Molecular Cancer Research

101

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Ran-binding protein M (RanBPM) is a nucleocytoplasmic protein previously implicated in various signaling pathways, but whose function remains enigmatic. Here, we provide evidence that RanBPM functions as an activator of apoptotic pathways induced by DNA damage. First, transient expression of RanBPM in HeLa cells induced cell death through caspase activation, and in the long-term, forced expression of RanBPM impaired cell viability. RanBPM COOH-terminal domain stimulated the ability of RanBPM to induce caspase activation, whereas this activity was negatively regulated by the central SPRY domain. Second, small interfering RNA-directed knockdown of RanBPM prevented DNA damage-induced apoptosis, as evidenced by the marked reduction in caspase-3 and caspase-2 activation. This correlated with a magnitude fold increase in the survival of RanBPM-depleted cells. Following ionizing radiation treatment, we observed a progressive relocalization of RanBPM from the nucleus to the cytoplasm, suggesting that the activation of apoptotic pathways by RanBPM in response to ionizing radiation may be regulated by nucleocytoplasmic trafficking. Finally, RanBPM downregulation was associated with a marked decrease of mitochondria-associated Bax, whereas Bcl-2 overall levels were dramatically upregulated. Overall, our results reveal a novel proapoptotic function for RanBPM in DNA damage-induced apoptosis through the regulation of factors involved in the mitochondrial apoptotic pathway.

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Novel role of the muskelin–RanBP9 complex as a nucleocytoplasmic mediator of cell morphology regulation

Cited by 59 publications

References 54 publications

Stability and Function of Mammalian Lethal Giant Larvae-1 Oncoprotein Are Regulated by the Scaffolding Protein RanBPM

Stability and Function of Mammalian Lethal Giant Larvae-1 Oncoprotein Are Regulated by the Scaffolding Protein RanBPM

RanBPM is essential for mouse spermatogenesis and oogenesis

RanBPM Has Proapoptotic Activities That Regulate Cell Death Pathways in Response to DNA Damage

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