Interaction of the PA2G4 (EBP1) protein with ErbB-3 and regulation of this binding by heregulin

Yoo, Joo‐Yeon; Wang, Xin Wei; Rishi, Arun K.; Lessor, Tracy; Xia, Xi; Gustafson, Thomas A.; Hamburger, Anne W.

doi:10.1054/bjoc.1999.0981

Cited by 119 publications

(160 citation statements)

References 34 publications

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“…This extends previous observations made in tumor cell lines Yoo et al, 2000;Xia et al, 2001a), demonstrating that both normal and transformed cells are sensitive to EBP1 over- expression. Most importantly, we observed that the mutant K20A-K22A, which is only cytosolic and not nucleolar, is unable to inhibit proliferation.…”

Section: Discussionsupporting

confidence: 90%

EBP1 is a nucleolar growth-regulating protein that is part of pre-ribosomal ribonucleoprotein complexes

et al. 2004

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EBP1 was identified as a protein that interacts with the ErbB-3 receptor and possibly contributes to transducing growth regulatory signals. The existence of EBP1 homologs across species from simple eukaryotes to humans and its wide tissue expression pattern suggest that EBP1 acts as a general signaling molecule. We provide evidence that EBP1 is localized to the cytoplasm and to the nucleolus, and that its nucleolar localization requires amino-acid sequences present at both the aminoand carboxy-terminus of the molecule. We also show that EBP1 overexpression inhibits proliferation of human fibroblasts, and that this effect is linked to its nucleolar localization. Using mass spectrometry we demonstrate that EBP1 is part of ribonucleoprotein complexes and associates with different rRNA species. It is becoming clear that cell growth and proliferation are actively coordinated with rRNA processing and ribosome assembly. Our findings indicate that EBP1 is a nucleolar growth-regulating protein, and we propose that it could represent a new link between ribosome biosynthesis and cell proliferation.

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Section: Discussionsupporting

confidence: 90%

EBP1 is a nucleolar growth-regulating protein that is part of pre-ribosomal ribonucleoprotein complexes

et al. 2004

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“…Further study is needed of the involvement of non-NRG, non-ERBB regulators of ERBB3, such as CDK5, [122][123][124] BRK, 125 SRC, 126 and MET. 120 The fascinating and widely expressed ERBB3 effector EBP1 has thus far been examined mainly in mammary and prostate cells; [154][155][156][157][158][159][160][161][162][163][164] may it be important also in other cancers where ERBB3 is clearly a player, such as lung and melanoma? It is hoped that full understanding of the regulation and functions of ERBB3 will facilitate its integration into cancer management.…”

Section: Discussionmentioning

confidence: 99%

“…154 EBP1 is encoded by human gene PA2G4 (human homolog of the mouse p38-2G4 protein, a cell cycle-regulated DNA-binding protein), and is widely expressed. 155 It interacts with the first fifteen amino acids of the juxtamembrane domain of unphosphorylated ERBB3.…”

Section: Newly-identified Proteins Binding Erbb3 Phosphotyrosines-thementioning

confidence: 99%

“…158 Upon NRG stimulation, EBP1 is phosphorylated, independent of PKC, dissociates from ERBB3, and translocates to the nucleus. 154,155 Nuclear EBP1 interacts directly with the cell cycle regulator pRB, resulting in inhibition of transcription of E2F-regulated genes, including cyclin E, by a mechanism including recruitment of Sin3A and histone deacetylase. 157,[159][160][161][162] EBP1 contains an LXXLL motif mediating interactions with nuclear hormone receptors and binds androgen receptor, resulting in inhibition of activation of androgen-responsive gene promoters.…”

Section: Newly-identified Proteins Binding Erbb3 Phosphotyrosines-thementioning

confidence: 99%

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The ERBB3 receptor in cancer and cancer gene therapy

2008

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ERBB3, a member of the epidermal growth factor receptor (EGFR) family, is unique in that its tyrosine kinase domain is functionally defective. It is activated by neuregulins, by other ERBB and nonERBB receptors as well as by other kinases, and by novel mechanisms. Downstream it interacts prominently with the phosphoinositol 3-kinase/AKT survival/mitogenic pathway, but also with GRB, SHC, SRC, ABL, rasGAP, SYK and the transcription regulator EBP1. There are likely important but poorly understood roles for nuclear localization and for secreted isoforms. Studies of ERBB3 expression in primary cancers and of its mechanistic contributions in cultured cells have implicated it, with varying degrees of certainty, with causation or sustenance of cancers of the breast, ovary, prostate, certain brain cells, retina, melanocytes, colon, pancreas, stomach, oral cavity and lung. Recent results link high ERBB3 activity with escape from therapy targeting other ERBBs in lung and breast cancers. Thus a wide and centrally important role for ERBB3 in cancer is becoming increasingly apparent. Several approaches for targeting ERBB3 in cancers have been tested or proposed. Small inhibitory RNA (siRNA) to ERBB3 or AKT is showing promise as a therapeutic approach to treatment of lung adenocarcinoma.

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“…33), early growth response-1 (34), and the zinc finger protein ZNF207 (34). Yoo, Zhang, and others showed that treating AU565 breast cancer cells with the ErbB-3 ligand heregulin resulted in dissociation of Ebp1 from ErbB-3 and subsequent translocation of Ebp1 to the nucleus, where it suppressed androgen receptor-mediated gene transcription (35)(36)(37). Whether Ebp1 can interact with ErbB-3 in the nucleus and whether its transcriptional activity is regulated by nuclear ErbB-3 remain to be studied.…”

Section: Discussionmentioning

confidence: 99%

Bone Microenvironment and Androgen Status Modulate Subcellular Localization of ErbB3 in Prostate Cancer Cells

Cheng

Vakar-López³

et al. 2007

Molecular Cancer Research

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ErbB-3, an ErbB receptor tyrosine kinase, has been implicated in the pathogenesis of several malignancies, including prostate cancer. We found that ErbB-3 expression was up-regulated in prostate cancer cells within lymph node and bone metastases. Despite being a plasma membrane protein, ErbB-3 was also detected in the nuclei of the prostate cancer cells in the metastatic specimens. Because most metastatic specimens were from men who had undergone androgen ablation, we examined the primary tumors from patients who have undergone hormone deprivation therapy and found that a significant fraction of these specimens showed nuclear localization of ErbB3. We thus assessed the effect of androgens and the bone microenvironment on the nuclear translocation of ErbB-3 by using xenograft tumor models generated from bone-derived prostate cancer cell lines, MDA PCa 2b, and PC-3. In subcutaneous tumors, ErbB-3 was predominantly in the membrane/cytoplasm; however, it was present in the nuclei of the tumor cells in the femur. Castration of mice bearing subcutaneous MDA PCa 2b tumors induced a transient nuclear translocation of ErbB-3, with relocalization to the membrane/cytoplasm upon tumor recurrence. These findings suggest that the bone microenvironment and androgen status influence the subcellular localization of ErbB-3 in prostate cancer cells. We speculate that nuclear localization of ErbB-3 may aid prostate cancer cell survival during androgen ablation and progression of prostate cancer in bone. (Mol Cancer Res 2007;5(7):675 -84)

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Interaction of the PA2G4 (EBP1) protein with ErbB-3 and regulation of this binding by heregulin

Cited by 119 publications

References 34 publications

EBP1 is a nucleolar growth-regulating protein that is part of pre-ribosomal ribonucleoprotein complexes

EBP1 is a nucleolar growth-regulating protein that is part of pre-ribosomal ribonucleoprotein complexes

The ERBB3 receptor in cancer and cancer gene therapy

Bone Microenvironment and Androgen Status Modulate Subcellular Localization of ErbB3 in Prostate Cancer Cells

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