The third cleavage, mediated by γ-secretase, acts on the intracellular region near the membrane and results in liberation and translocation of the active segment of Notch (NICD, Notch intracellular domain) to the nucleus. The extracelluar N-terminal cleavage products are endocytosed by the signal-sending cell. The second cleavage by a metalloproteinase, a disintegrin and metallop 17 (ADAM17), occurs at the extracellular region near the membrane. With the interactions between a transmembrane ligand of the Delta-Serrate Lag family and EGF-like repeats of the extracellular domain of Notch receptors, conformational changes in the receptor expose critical sides for next two steps of cleavage. It is then anchored in the plasma membrane. Notch precursor is first cleaved by a furin-like convertase to generate two subunits within the Golgi apparatus. ER membrane-bound proteins are translocated into the nucleus directly or by trafficking first to the Golgi from the ER, but both routes give rise to the fragments of the proteins finally entering the nucleus. PM proteins are translocated into the nucleus directly or by Golgi to ER retrograde trafficking, either in their full-length or in their cytosolic fragmented form. We separate MTFs into two groups: plasma membrane-bound (PM) transcription factors and ER membrane-bound transcription factors. In this review, we mainly focus on how MTFs move within the cell and whether they turn to other organelle membranes during their nuclear translocation.
Nuclear translocation signals that have been established include ligand-receptor binding response signals as well as many types of stress, such as nerve injury stress, temperature stress, endoplasmic reticulum (ER) stress, and oxidative stress, among others. Cellular stimuli can activate transcription factor precursors and induce their nuclear translocation. Once they are anchored in the cell membrane, MTFs remain in a dormant state. Full-length MTFs are synthesized in the cytoplasm and are rapidly transported to the cellular membrane. As a result, membrane-bound transcription factors can respond rapidly to stresses from either extracellular or intracellular stimuli. According to the activation routes of general transcription factors, these molecules are regulated at many points throughout signal transduction in an exquisite process. Membrane-bound transcription factors (MTFs) have been observed in many types of organisms, such as plants, animals and microorganisms. Some membrane proteins play a transcription regulatory role after being translocated into the nucleus. Conversely, one gene can be regulated by many transcription factors. A transcription factor usually has one or more DNA-binding domains, and therefore can regulate the expression of multiple genes. After receiving a signal from the cell membrane signal transduction, transcription factors are activated and then translocated from the cytoplasm into the nucleus where they interact with the corresponding DNA frame (cis-acting elements). Most transcription factors are located in the cytoplasm. Many long non-coding RNAs have been found to play important roles in the regulation of gene expression. Existing research shows that transcription factors are not only proteins but numerous non-coding RNAs act as regulators of transcription. Gene expression is controlled by specific interactions between transcription factors, regulatory proteins, and cis-elements in the gene regulatory regions. Moreover, targeting intracellular movement pathways of disease-associated MTFs may significantly improve the survival of patients. Several different nuclear trafficking modes of MTFs are summarized in this review, providing an effective supplement to the mechanisms of signal transduction and gene regulation. In both of these pathways, only the fragments of the ER membrane-bound TFs transit to the nucleus. In contrast, the ER membrane-bound TFs relocate to the nucleus directly or by trafficking to the Golgi. In addition, some PM-bound TFs exist as full-length proteins in cell nucleus via trafficking to the Golgi and the ER, where membrane-releasing mechanisms rely on endocytosis.
#Nuclear envelope fragments meaning full#
However, lipid-anchored PM-bound proteins enter the nucleus in their full length for depalmitoylation. Upon specific signal recognition cues, some PM-bound TFs undergo proteolytic cleavage to liberate the intracellular fragments that enter the nucleus to control gene transcription. Existing research indicates that some plasma membrane (PM)-bound proteins and some endoplasmic reticulum (ER) membrane-bound proteins have the ability to enter the nucleus.
Activated by external or internal stimuli, MTFs are released from parent membranes and are transported to the nucleus. Membrane-bound transcription factors (MTFs) are transcription factors (TFs) that are anchored in membranes in a dormant state.