Browsing by Subject "CELL-ADHESION"

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  • Liu, Yixin; Kaljunen, Heidi; Pavic, Ana; Saarenpää, Tuulia; Himanen, Juha P.; Nikolov, Dimitar B.; Goldman, Adrian (2018)
    Eph/Ephrin signaling pathways are crucial in regulating a large variety of physiological processes during development, such as cell morphology, proliferation, migration and axonal guidance. EphrinA (efn-A) ligands, in particular, can be activated by EphA receptors at cellcell interfaces and have been proposed to cause reverse signaling via RET receptor tyrosine kinase. Such association has been reported to mediate spinal motor axon navigation, but conservation of the interactive signaling pathway and the molecular mechanism of the interaction are unclear. Here, we found Danio rerio efn-A5b bound to Mus musculus EphA4 with high affinity, revealing structurally and functionally conserved EphA/efn-A signaling. Interestingly, we observed no interaction between efn-A5b and RET from zebrafish, unlike earlier cell-based assays. Their lack of association indicates how complex efn-A signaling is and suggests that there may be other molecules involved in efn-A5-induced RET signaling.
  • Int Headache Genetics Consortium (2018)
    Background The biological mechanisms of headache chronification are poorly understood. We aimed to identify changes in DNA methylation associated with the transformation from episodic to chronic headache. Methods Participants were recruited from the population-based Norwegian HUNT Study. Thirty-six female headache patients who transformed from episodic to chronic headache between baseline and follow-up 11 years later were matched against 35 controls with episodic headache. DNA methylation was quantified at 485,000 CpG sites, and changes in methylation level at these sites were compared between cases and controls by linear regression analysis. Data were analyzed in two stages (Stages 1 and 2) and in a combined meta-analysis. Results None of the top 20 CpG sites identified in Stage 1 replicated in Stage 2 after multiple testing correction. In the combined meta-analysis the strongest associated CpG sites were related to SH2D5 and NPTX2, two brain-expressed genes involved in the regulation of synaptic plasticity. Functional enrichment analysis pointed to processes including calcium ion binding and estrogen receptor pathways. Conclusion In this first genome-wide study of DNA methylation in headache chronification several potentially implicated loci and processes were identified. The study exemplifies the use of prospectively collected population cohorts to search for epigenetic mechanisms of disease.
  • Polley, Anirban; Orlowski, Adam; Danne, Reinis; Gurtovenko, Andrey A.; de la Serna, Jorge Bernardino; Eggeling, Christian; Davis, Simon J.; Rog, Tomasz; Vattulainen, Ilpo (2017)
    Proteins embedded in the plasma membrane mediate interactions with the cell environment and play decisive roles in many signaling events. For cell-cell recognition molecules, it is highly likely that their structures and behavior have been optimized in ways that overcome the limitations of membrane tethering. In particular, the ligand binding regions of these proteins likely need to be maximally exposed. Here we show by means of atomistic simulations of membrane-bound CD2, a small cell adhesion receptor expressed by human T-cells and natural killer cells, that the presentation of its ectodomain is highly dependent on membrane lipids and receptor glycosylation acting in apparent unison. Detailed analysis shows that the underlying mechanism is based on electrostatic interactions complemented by steric interactions between glycans in the protein and the membrane surface. The findings are significant for understanding the factors that render membrane receptors accessible for binding and signaling.
  • Pekkonen, Pirita; Alve, Sanni; Balistreri, Giuseppe; Gramolelli, Silvia; Tatti-Bugaeva, Olga; Paatero, Ilkka; Niiranen, Otso; Tuohinto, Krista; Perala, Nina; Taiwo, Adewale; Zinovkina, Nadezhda; Repo, Pauliina; Icay, Katherine; Ivaska, Joanna; Saharinen, Pipsa; Hautaniemi, Sampsa; Lehti, Kaisa; Ojala, Paivi M. (2018)
    Lymphatic invasion and lymph node metastasis correlate with poor clinical outcome in melanoma. However, the mechanisms of lymphatic dissemination in distant metastasis remain incompletely understood. We show here that exposure of expansively growing human WM852 melanoma cells, but not singly invasive Bowes cells, to lymphatic endothelial cells (LEC) in 3D co-culture facilitates melanoma distant organ metastasis in mice. To dissect the underlying molecular mechanisms, we established LEC co-cultures with different melanoma cells originating from primary tumors or metastases. Notably, the expansively growing metastatic melanoma cells adopted an invasively sprouting phenotype in 3D matrix that was dependent on MMP14, Notch3 and beta 1-integrin. Unexpectedly, MMP14 was necessary for LEC-induced Notch3 induction and coincident beta 1-integrin activation. Moreover, MMP14 and Notch3 were required for LEC-mediated metastasis of zebrafish xenografts. This study uncovers a unique mechanism whereby LEC contact promotes melanoma metastasis by inducing a reversible switch from 3D growth to invasively sprouting cell phenotype.
  • Biggs, Leah C.; Kim, Christine S.; Miroshnikova, Yekaterina A.; Wickström, Sara A. (2020)
    Tissue shape emerges from the collective mechanical properties and behavior of individual cells and the ways by which they integrate into the surrounding tissue. Tissue architecture and its dynamic changes subsequently feed back to guide cell behavior. The skin is a dynamic, self-renewing barrier that is subjected to large-scale extrinsic mechanical forces throughout its lifetime. The ability to withstand this constant mechanical stress without compromising its integrity as a barrier requires compartment-specific structural specialization and the capability to sense and adapt to mechanical cues. This review discusses the unique mechanical properties of the skin and the importance of signals that arise from mechanical communication between cells and their environment.
  • Miihkinen, Mitro; Grönloh, Max L. B.; Popovic, Ana; Vihinen, Helena; Jokitalo, Eija; Goult, Benjamin T.; Ivaska, Johanna; Jacquemet, Guillaume (2021)
    Filopodia assemble unique integrin-adhesion complexes to sense the extracellular matrix. However, the mechanisms of integrin regulation in filopodia are poorly defined. Here, we report that active integrins accumulate at the tip of myosin-X (MYO10)-positive filopodia, while inactive integrins are uniformly distributed. We identify talin and MYO10 as the principal integrin activators in filopodia. In addition, deletion of MYO10's FERM domain, or mutation of its b1-integrin-binding residues, reveals MYO10 as facilitating integrin activation, but not transport, in filopodia. However, MYO10's isolated FERM domain alone cannot activate integrins, potentially because of binding to both integrin tails. Finally, because a chimera construct generated by swapping MYO10-FERM by talin-FERM enables integrin activation in filopodia, our data indicate that an integrin-binding FERM domain coupled to a myosin motor is a core requirement for integrin activation in filopodia. Therefore, we propose a two-step integrin activation model in filopodia: receptor tethering by MYO10 followed by talin-mediated integrin activation.
  • Glerup, Simon; Lume, Maria; Olsen, Ditte; Nyengaard, Jens R.; Vaegter, Christian B.; Gustafsen, Camilla; Christensen, Erik I.; Kjolby, Mads; Hay-Schmidt, Anders; Bender, Dirk; Madsen, Peder; Saarma, Mart; Nykjaer, Anders; Petersen, Claus M. (2013)
  • Kukkurainen, Sampo; Azizi, Latifeh; Zhang, Pingfeng; Jacquier, Marie-Claude; Baikoghli, Mo; von Essen, Magdalena; Tuukkanen, Anne; Laitaoja, Mikko; Liu, Xiaonan; Rahikainen, Rolle; Orlowski, Adam; Jänis, Janne; Määttä, Juha A. E.; Varjosalo, Markku; Vattulainen, Ilpo; Rog, Tomasz; Svergun, Dmitri; Cheng, R. Holland; Wu, Jinhua; Hytönen, Vesa P.; Wehrle-Haller, Bernhard (2020)
    Integrin activation and clustering by talin are early steps of cell adhesion. Membrane-bound talin head domain and kindlin bind to the beta integrin cytoplasmic tail, cooperating to activate the heterodimeric integrin, and the talin head domain induces integrin clustering in the presence of Mn2+. Here we show that kindlin-1 can replace Mn2+ to mediate beta 3 integrin clustering induced by the talin head, but not that induced by the F2-F3 fragment of talin. Integrin clustering mediated by kindlin-1 and the talin head was lost upon deletion of the flexible loop within the talin head F1 subdomain. Further mutagenesis identified hydrophobic and acidic motifs in the F1 loop responsible for beta 3 integrin clustering. Modeling, computational and cysteine crosslinking studies showed direct and catalytic interactions of the acidic F1 loop motif with the juxtamembrane domains of alpha- and beta 3-integrins, in order to activate the beta 3 integrin heterodimer, further detailing the mechanism by which the talin-kindlin complex activates and clusters integrins. Moreover, the F1 loop interaction with the beta 3 integrin tail required the newly identified compact FERM fold of the talin head, which positions the F1 loop next to the inner membrane clasp of the talin-bound integrin heterodimer. This article has an associated First Person interview with the first author of the paper.