Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • Introduction Protein tyrosine phosphorylation plays key

    2022-08-08

    Introduction Protein-tyrosine phosphorylation plays key roles in a variety of intracellular signaling pathways involved in cell proliferation, differentiation, gene expression, cell adhesion, and metabolic changes [1]. While receptor-type tyrosine kinases localize to the plasma membrane, most of non-receptor-type tyrosine kinases are present in the cytoplasm but some are at various intracellular locations. We have shown that tyrosine kinases residing in the nucleus are capable of phosphorylating their nuclear substrates to regulate S63845 structural changes and gene expression [[2], [3], [4], [5], [6], [7], [8], [9]]. The receptor-type tyrosine kinase ErbB4 is a member of the epidermal growth factor receptor subfamily and is essential for development or maintenance of the heart, the mammary glands, and the nervous system [[10], [11], [12]]. Notably, ErbB4 has a unique characteristic that ligand stimulation generates the soluble ErbB4 intracellular kinase domain. Stimulation with neuregulin-1 (NRG-1) sequentially cleaves the ErbB4 extracellular domain (4ECD) by the tumor necrosis factor-α-converting enzyme (TACE) and the ErbB4 intracellular domain (4ICD) by γ-secretase, resulting in the release of 4ICD into the cytoplasm [13,14]. 4ICD acts as a non-receptor-type tyrosine kinase having one functional nuclear localization signal (NLS) and three putative nuclear export signals and can shuttle between the cytoplasm and the nucleus, suggesting the possibility of ErbB4's nuclear functions [14,15]. In fact, 4ICD was shown to act as a transcriptional regulator in the nucleus through protein-protein interactions [16,17]. Importantly, we showed that nuclear 4ICD enhances the levels of trimethylation of histone H3 at lysine 9 (H3K9me3), which is crucial for heterochromatin formation and epigenetic gene silencing [17]. These functions of nuclear ErbB4 depend on its kinase activity, suggesting the involvement of tyrosine phosphorylation of its unidentified substrate(s).
    Materials and methods
    Results
    Discussion Our previous study demonstrated for the first time that NRG-1/ErbB4 nuclear signaling enhances the levels of H3K9me3 in a manner dependent on 4ICD's tyrosine kinase activity [17]. Now, this study shows that NRG-1/ErbB4 nuclear signaling enhances H3K9me3 levels through SUV39H1 phosphorylation at Tyr-297, -303, and -308. Our previous study also showed that the enhanced levels of H3K9me3 by NRG-1/ErbB4 nuclear signaling further lead to transcriptional repression of the human telomerase reverse transcriptase gene and inhibition of cell proliferation [17]. Collectively, we can illustrate a model for the mechanism of NRG-1/ErbB4 nuclear signaling (Fig. 4). NRG-1 stimulation increases H3K9me3 levels through 4ICD-mediated tyrosine phosphorylation of SUV39H1, resulting in enhancement of heterochromatinization. We hypothesize that NRG-1 stimulation enhances H3K9me3 levels possibly at the 4ICD-target genes, leading to their transcriptional repression. Such genes are likely to include the telomerase reverse transcriptase gene [17], which is required to sustain cell proliferation [26]. Our findings may contribute to an understanding of NRG-1 → ErbB4 → SUV39H1 → H3K9me3 signaling in tumor suppression, because ErbB4 and SUV39H1 are known to have active roles in tumor suppression and cell differentiation [17,27,28]. SUV39H2 and SETDB1 are known as the other histone H3K9 trimethyltransferases [29,30]. Although SUV39H2 shares amino acid sequence homology with SUV39H1 and conserves the two tyrosine residues corresponding to Tyr-297 and Tyr-303 of SUV39H1 [25], SUV39H2 is restrictedly expressed in the testis [29]. Thus, SUV39H2 is unlikely to associate with NRG-1/ErbB4-induced H3K9me3 in T47D breast cancer cells. In addition, despite the fact that SETDB1 is expressed in T47D cells [30], SETDB1 does not have the sequence homologous to that containing Tyr-303 and Tyr-308 of SUV39H1. Together, it is plausible that, among these H3K9 trimethyltransferases, SUV39H1 plays a major role in NRG-1/ErbB4-induced H3K9me3 for enhancement of heterochromatinization.