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Signal transduction and exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Brendan Egan, Adam P. Sharples
Signal transduction also depends on the controlled movement of signal transduction proteins within the cell. One of the most important transport events is the bidirectional shuttling (i.e. translocation) of signal transduction proteins between the cytosol and the nucleus. In some cases, such movement depends on the activation of a nuclear localisation signal or sequence (NLS) on a protein. NLSs are recognised by proteins that transport protein cargo through nuclear pores from the cytosol into the nucleus of a cell. Usually, the activation of NLS involves protein modification or a change in protein-protein interaction, which exposes the NLS. For example, NF-κB is bound to its inhibitor, IκB, when it is in the cytosol. This is because IκB masks the NLS of NF-κB, which prevents it from transiting into the nucleus. In a similar manner, binding of class IIa histone deacetylases (HDACs) with the chaperone protein 14-3-3 masks the NLS and exposes the nuclear export sequence (NES) resulting in nuclear export and cytosolic retention of HDAC4. Phosphorylation of three serine residues (Ser246, Ser467 and Ser632) plays a key role in modulating HDAC4 translocation by increasing 14-3-3 binding and leading to nuclear export and the de-repression of gene transcription.
Transforming Growth Factor-β/Smad Signaling in Myocardial Disease
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Claudio Humeres, Nikolaos G. Frangogiannis
On a functional basis, the Smads are classified into three groups: (1) the receptor-activated Smads (R-Smads: Smad1, Smad2, Smad3, Smad5, and Smad8); (2) the common Smad (Co-Smad: Smad4); and (3) the inhibitory Smads (I-Smads: Smad6 and Smad7)12. Upon TGFβ-induced ALK5 activation, the R-Smads Smad2 and Smad3 are recruited to the TGF-β complex by the auxiliary adaptor protein SARA (SMAD anchor for receptor activation), which facilitates the interaction of the catalytic region of TβRI with the carboxyl MH2 domain of the R-Smads, leading to R-Smad phosphorylation in the C-terminal SXSS motif13. R-Smad phosphorylation induces a conformational change in the MH2 domain, enabling its dissociation from TβRI/SARA and subsequent association with Smad414. Finally, nuclear localization signal (NLS) motifs in the amino-terminal MH1 domain of the R-Smad/Smad4 complex allow its translocation to the nucleus, where it binds to Smad-binding elements or GC-rich sequences in the promoter regions of TGFβ effector genes, regulating the transcription of target genes15. Typically, ALK5 signaling triggers Smad2 and Smad3 activation, whereas ALK1 signaling activates Smad1/5; these two cascades have been suggested to play antagonistic roles in certain cell types16,17.
Engineered Nanoparticles for Drug Delivery in Cancer Therapy *
Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Tianmeng Sun, Yu Shrike Zhang, Pang Bo, Dong Choon Hyun, Miaoxin Yang, Younan Xia
Interestingly, the surface of nanoparticles can be functionalized with a ligand to target a specific organelle in the cell. For example, adding a nuclear localization signal (NLS) peptide motif to the surface of nanoparticles could lead to effective nuclear targeting. As reported by Mao and coworkers, liposome protamine/DNA complexes termed lipoplexes (LPDs) were accumulated in the nuclei of cells after their internalization when the surface of the particle was derivatized with NLS peptides [145]. Compared to LPDs with no nucleus-targeting ligand on the surface, the gene expression level was significantly elevated when DNA was delivered into the nuclei of the cells.
Screening and characterisation of a novel efficient tumour cell-targeting peptide derived from insulin-like growth factor binding proteins
Published in Journal of Drug Targeting, 2023
Min-Lin He, Jin Lei, Xue-Wei Cao, Jian Zhao, Fu-Jun Wang
We noticed that the C-terminal domain of the all six IGFBPs contain HBD sequences, the sequence composition of HBD is similar to that of cell-penetrating peptides due to its richness in cations and hydrophobic amino acid residues, and is an important source for screening human cell-penetrating peptides [53,54]. Therefore, we evaluated the endogenous ability and efficiency of HBD sequences with highly homologous C-terminal domains of six IGFBPs molecules (IHPs for short) to a variety of tested cells. Results showed that IHP3 and IHP5 had the strongest transmembrane activity. Moreover, these two small peptides show very high penetration efficiency than that of the classical cell-penetrating peptide TAT, respectively (Figures 2B,C). It has been shown that IGFBP-2, IGFBP-3, IGFBP-5, and IGFBP-6 all contain functional nuclear localisation sequences (NLS) by which they are introduced into the nucleus of certain cell types [55–58]. Unlike other IGFBPs, the C-terminal domains of IGFBP-3 and IGFBP-5 also function in binding to the ALS [59,60] and are involved in cellular uptake and nuclear localisation [61,62], which may explain the strong binding capacity and high membrane-penetrating activity of IHP3 and IHP5. Recent in vitro studies have demonstrated that both recombinant IGFBP-3 and IGFBP-5 can translocate from the extracellular compartment to the nucleus in rapidly dividing human breast cancer cells [63], while the IGFBP-3 and IGFBP-5 derived NLS peptides can help to improve the transfection efficiency of chitosan-based non-viral gene delivery systems [64].
Detection of endocrine and metabolism disrupting xenobiotics in milk-derived fat samples by fluorescent protein-tagged nuclear receptors and live cell imaging
Published in Toxicology Mechanisms and Methods, 2023
Keshav Thakur, Emmagouni Sharath Kumar Goud, Yashika Jawa, Chetan Keswani, Suneel Onteru, Dheer Singh, Surya P. Singh, Partha Roy, Rakesh K. Tyagi
Estrogen receptor α (ERα) also belongs to the steroid hormone receptor family. However, unlike AR, ligand-free ERα is predominantly localized in the nuclear compartment. This nuclear localized ERα cannot be used for studying ligand response via nuclear translocation assays as was possible with AR. However, specific mutations in the nuclear localization signal (NLS), region of NRs are reported to shift the localization of some ligand-free receptors (Guiochon-Mantel et al. 1989; Burns et al. 2011; Mavinakere et al. 2012; Rana et al. 2018; Lu et al. 2021). To obtain a cytoplasmic-shifted ERα chimera capable of responding to hormones and xenobiotics, we replaced selected residues (R263A, K266A, K268A, R269A, R271A) in the DNA binding domain-hinge region (DBD-Hinge) of GFP-ERα. This GFP-ERαcy was characterized by immunoblotting, immunocytochemistry, and transcription assays (data not shown). The cytoplasmic-shifted ERα mutant was found to be suitable for assessing the presence of (anti-)estrogenic xenobiotics by observing its nuclear translocation.
14-3-3 proteins at the crossroads of neurodevelopment and schizophrenia
Published in The World Journal of Biological Psychiatry, 2022
André S. L. M. Antunes, Verônica M. Saia-Cereda, Fernanda Crunfli, Daniel Martins-de-Souza
14-3-3 proteins regulate their targets through inhibition, activation, structural stabilisation, translocation and regulation of target degradation (reviewed in Rosenquist 2003; Fan et al. 2019). The structural effects of 14-3-3 proteins binding to their targets are: conformational changes and physical occlusion of sequence-specific or structural protein features (reviewed in Alastair Aitken 2006). Regarding their physiological functions, 14-3-3 proteins may exert effects on the subcellular localisation, activity and stability of their targets. They may regulate ubiquitination and degradation or block the action of phosphatases on their target by occlusion (Tzivion and Avruch 2002). For instance, occlusion by 14-3-3 proteins has been shown to block protein-DNA interactions and to prevent nuclear localisation signal (NLS)-mediated translocation (Brunet et al. 2002; Obsil et al. 2003). In addition, 14-3-3 proteins can serve as rigid scaffolding structures that are able to induce direct conformational alterations in their targets (Obsil et al. 2001) and to bind targets, promoting the formation of protein complexes (Ottmann et al. 2007) (Figure 1).