Mapping nucleolar and spliceosome localization sequences of neuregulin1-β3

Golding, Matthew; Ruhrberg, Christiana; Sandle, J; Gullick, William J.

doi:10.1016/j.yexcr.2004.05.028

Cited by 23 publications

(29 citation statements)

References 29 publications

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“…Several of our HRGa 1-241 deletion constructs (such as HRGa DXhoI, HRGa 1-187 DXmnI, and HRGa 1-148 DBbsI) lacked a portion of the EGF-like domain, shown to be necessary and sufficient for receptor binding and activation (7), yet they were imported into the nucleus and able to form nuclear dot-like structures. Thus, it is conceivable that the nuclear translocation of our constructs did not depend on ErbB3 and ErbB4 binding and activation, confirming the data of Golding et al (20), showing nuclear localization of NRG1h 3 in a receptor-independent way. Our demonstration that HRGa 1-241 is translocated to the nucleus suggests that novel mechanisms of action of HRG different from receptor binding and activation might exist, whereby HRG may also act as an intracrine growth factor, potentially extending the biological functions of HRG proteins.…”

Section: Nuclear Translocation Of Hrga 1-241supporting

confidence: 89%

“…The interaction of HRGa 1-241 with the nuclear proteins RS cyclophilin, serine/arginine nuclear matrix protein, and RNA helicase, proteins required for pre-mRNA splicing, is supported by previous data showing that NRG1h 3 was found to associate with specific intranuclear compartments implicated in RNA splicing (20). Therefore, these findings serve as a control for the robustness of the data obtained by the yeast two-hybrid screen.…”

Section: Hrga 1-241 Interacts With Known Nuclear Proteinssupporting

confidence: 67%

“…We show here that HRGa 1-241 exhibits a pattern of subnuclear dot formation similar to Sp100 and PML proteins (26) and similar to neuregulin-1 (20). The Sp100 and PML proteins were shown to be covalently modified by the SUMO-1 protein, which was partly required for dot formation (27).…”

Section: Subnuclear Dot Formationmentioning

confidence: 64%

“…NRG1h 3 was shown recently to localize to the nuclei of human breast cancer cells in a receptor-independent way, supporting the idea that secretion and subsequent cell surface receptor binding of HRG proteins are not a prerequisite for nuclear localization and that nonsecreted ligands may have highly specific functions in defined nuclear compartments, such as the nucleoli and SC35-positive nuclear speckles (20). Further evidence for a nuclear function of HRG proteins during malignancy arises from studies showing that HRG is expressed in the nucleus of breast as well as thyroid cancer biopsies and medulloblastomas (14-16), whereas no nuclear HRG was found in normal tissues.…”

Section: Nuclear Translocation Of Hrga 1-241mentioning

confidence: 72%

“…Recently, it has been shown that NRG1h 3 localizes to two known intranuclear structures, nucleoli and SC35-positive nuclear speckles (20), independent of the receptor-binding domain or the previously predicted NLS.…”

Section: Introductionmentioning

confidence: 91%

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Heregulins Implicated in Cellular Functions Other Than Receptor Activation

Breuleux¹,

Schoumacher²,

Rehn³

et al. 2006

Molecular Cancer Research

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Heregulins (HRG) are known as soluble secreted growth factors that, on binding and activating ErbB3 and ErbB4 cell surface receptors, are involved in cell proliferation, metastasis, survival, and differentiation in normal and malignant tissues. Previous studies have shown that some HRG1 splice variants are translocated to the nucleus. By investigating the subcellular localization of HRGA 1-241 , nuclear translocation and accumulation in nuclear dot-like structures was shown in breast cancer cells. This subcellular distribution pattern depends on the presence of at least one of two nuclear localization sequences and on two domains on the HRG construct that were found to be necessary for nuclear dot formation. Focusing on the nuclear function of HRG, a mammary gland cDNA library was screened with the mature form of HRGA in a yeast two-hybrid system, and coimmunoprecipitation of endogenous HRG was done. The data reveal positive interactions of HRGA 1-241 with nuclear factors implicated in different biological functions, including transcriptional control as exemplified by interaction with the transcriptional repressor histone deacetylase 2. In addition, HRGA 1-241 showed transcriptional repression activity in a reporter gene assay. Furthermore, a potential of HRG proteins to form homodimers was reported and the HRG sequence responsible for dimerization was identified. These observations strongly support the notion that HRG1 splice variants have multifunctional properties, including previously unknown regulatory functions within the nucleus that are different from the activation of ErbB receptor signaling.

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Section: Nuclear Translocation Of Hrga 1-241supporting

confidence: 89%

Section: Hrga 1-241 Interacts With Known Nuclear Proteinssupporting

confidence: 67%

Section: Subnuclear Dot Formationmentioning

confidence: 64%

Section: Nuclear Translocation Of Hrga 1-241mentioning

confidence: 72%

Section: Introductionmentioning

confidence: 91%

See 3 more Smart Citations

Heregulins Implicated in Cellular Functions Other Than Receptor Activation

Breuleux¹,

Schoumacher²,

Rehn³

et al. 2006

Molecular Cancer Research

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Mechanisms of Neuregulin Action

Talmage¹

2008

Novartis Foundation Symposia

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Neuregulin 1 (Nrg1) and ErbB receptor tyrosine kinase signalling is essential for the formation and proper functioning of multiple organ systems and inappropriate Nrg1/ErbB signalling severely compromises health, contributing to such diverse pathologies as cancer and neuropsychiatric disorders. Numerous genetic modelling studies in mice demonstrate that Nrg1 signalling is important in the development of normal neuronal connectivity. Recent studies have identified novel signalling mechanisms and revealed unexpected roles of Nrg1 isoforms in both the developing and adult nervous system. Of particular interest to this discussion are findings linking deficits in Nrg1-ErbB4 signalling to perturbations of synaptic transmission, myelination, and the survival of particular sets of neurons and glia.

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Neuregulins in the Nucleus

McClelland¹,

Gullick²

2009

Breast Cancer in the Post-Genomic Era

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Mapping nucleolar and spliceosome localization sequences of neuregulin1-β3

Cited by 23 publications

References 29 publications

Heregulins Implicated in Cellular Functions Other Than Receptor Activation

Heregulins Implicated in Cellular Functions Other Than Receptor Activation

Mechanisms of Neuregulin Action

Neuregulins in the Nucleus

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