Ubiquitin links to cytoskeletal dynamics, cell adhesion and migration

Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands.
Biochemical Journal (Impact Factor: 4.4). 02/2012; 442(1):13-25. DOI: 10.1042/BJ20111815
Source: PubMed


Post-translational modifications are used by cells to link additional information to proteins. Most modifications are subtle and concern small moieties such as a phosphate group or a lipid. In contrast, protein ubiquitylation entails the covalent attachment of a full-length protein such as ubiquitin. The protein ubiquitylation machinery is remarkably complex, comprising more than 15 Ubls (ubiquitin-like proteins) and several hundreds of ubiquitin-conjugating enzymes. Ubiquitin is best known for its role as a tag that induces protein destruction either by the proteasome or through targeting to lysosomes. However, addition of one or more Ubls also affects vesicular traffic, protein-protein interactions and signal transduction. It is by now well established that ubiquitylation is a component of most, if not all, cellular signalling pathways. Owing to its abundance in controlling cellular functions, ubiquitylation is also of key relevance to human pathologies, including cancer and inflammation. In the present review, we focus on its role in the control of cell adhesion, polarity and directional migration. It will become clear that protein modification by Ubls occurs at every level from the receptors at the plasma membrane down to cytoskeletal components such as actin, with differential consequences for the pathway's final output. Since ubiquitylation is fast as well as reversible, it represents a bona fide signalling event, which is used to fine-tune a cell's responses to receptor agonists.

Download full-text


Available from: Micha Nethe, Dec 24, 2013
  • Source
    • "The proteins of the ubiquitination machinery comprise several ubiquitin-like proteins and hundreds of ubiquitin-conjugating enzymes. Ubiquitin is mainly known for its role as a tag that induces protein degradation either by the proteasome or through targeting to lysosomes, but it is well established that ubiquitination is also a component of most cellular signaling pathways for the control of cell adhesion, polarity and directional migration (Schaefer et al. 2012). Most of the in silico predicted functions of RPHM21 such as reorganization of cytoskeleton, cell migration, cell cycle control, chromatin remodeling, and transcriptional control are shared with MK3 (Ronkina et al. 2008; Milani, Ghiselli, Guerra, et al. 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondrial ORFans (Open Reading Frames having no detectable homology and with unknown function) were discovered in bivalve molluscs with Doubly Uniparental Inheritance (DUI) of mitochondria. In these animals two mitochondrial lineages are present, one transmitted through eggs (F-type), the other through sperm (M-type), each showing a specific ORFan. In the present study, we used in situ hybridization and immunocytochemistry to provide evidence for the expression of Ruditapes philippinarum male-specific ORFan (orf21): both the transcript and the protein (RPHM21) were localized in spermatogenetic cells and mature spermatozoa; the protein was localized in sperm mitochondria and nuclei, and in early embryos. Also, in silico analyses of orf21 flanking region and RPHM21 structure supported its derivation from viral sequence endogenization. We propose that RPHM21 prevents the recognition of M-type mitochondria by the degradation machinery, allowing their survival in the zygote. The process might involve a mechanism similar to that of Modulators of Immune Recognition, viral proteins involved in the immune recognition pathway, to which RPHM21 showed structural similarities. A viral origin of RPHM21 may also support a developmental role, since some integrated viral elements are involved in development and sperm differentiation of their host. Mitochondrial ORFans could be responsible for or participate in the DUI mechanism and their viral origin could explain the acquired capability of M-type mitochondria to avoid degradation and invade the germ line, that is what viruses do best: to elude host immune system and proliferate.
    Genome Biology and Evolution 02/2014; 6(2). DOI:10.1093/gbe/evu021 · 4.23 Impact Factor
  • Source
    • "Thus, it is the balance between the opposing actions of specific E3 ligases and DUBs which ultimately determines the ubiquitination status of a given target, rendering protein ubiquitination a versatile and dynamic posttranslational modification. The list of cellular processes where ubiquitination plays a regulatory role is continuously expanding, and includes gene expression [16], cell cycle progression [17], apoptosis [18], DNA repair [19] and cell motility [20], among others. Many of these ubiquitination-regulated processes are essential for maintaining cellular homeostasis, and their alteration contributes to tumor development. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Reversible protein ubiquitination is emerging as a key process for maintaining cell homeostasis, and the enzymes that participate in this process, in particular E3 ubiquitin ligases and deubiquitinases (DUBs), are increasingly being regarded as candidates for drug discovery. Human DUBs are a group of approximately 100 proteins, whose cellular functions and regulatory mechanisms remain, with some exceptions, poorly characterized. One of the best-characterized human DUBs is ubiquitin-specific protease 1 (USP1), which plays an important role in the cellular response to DNA damage. USP1 levels, localization and activity are modulated through several mechanisms, including protein-protein interactions, autocleavage/degradation and phosphorylation, ensuring that USP1 function is carried out in a properly regulated spatio-temporal manner. Importantly, USP1 expression is deregulated in certain types of human cancer, suggesting that USP1 could represent a valid target in cancer therapy. This view has gained recent support with the finding that USP1 inhibition may contribute to revert cisplatin resistance in an in vitro model of non-small cell lung cancer (NSCLC). Here, we describe the current knowledge on the cellular functions and regulatory mechanisms of USP1. We also summarize USP1 alterations found in cancer, combining data from the literature and public databases with our own data. Finally, we discuss the emerging potential of USP1 as a target, integrating published data with our novel findings on the effects of the USP1 inhibitor pimozide in combination with cisplatin in NSCLC cells.
    Molecular Cancer 08/2013; 12(1):91. DOI:10.1186/1476-4598-12-91 · 4.26 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Using in silico analysis a number of potential sites for post-translational modifications has been revealed within the human O6-methylguanine-DNA methyltransferase (MGMT) protein. In particular these were the acetylation of Gly3 residue in the N-terminus of protein and internal residues Lys132 and Lys135; Arg166 residue methylation; Lys63 SUMOylation and ubiquitination of Lys31, Lys39, Lys49, Lys63, Lys67, Lys135, Lys156, Lys196, Lys209. Also it has been predicted 16 novel potential phosphorylation sites of serine residues (positions 13, 124, 144, 182, 183, 190, 215, 216 and 230), tyrosine residues (positions 100 and 189) and threonine residues (positions 23, 69, 94, 126 and 229), as well as five binding sites for kinases and other proteins (Serl3 with 14-3-3, Val21 and Ile172 with D-domain, Pro78 and Pro111 with SH3-domain, Pro111 with MAPK3). Some kinases predicted by the authors are known as partners of the MGMT protein, that confirms the probability of modification of the given sites. Potential sites require further experimental confirmation of modifications and investigation of their influence on stability and DNA-repair activity of this protein.
    Ukrainskii biokhimicheskii zhurnal 01/2012; 84(6):74-85.
Show more