sh.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
A conserved mechanism for extracellular signaling in eukaryotes and prokaryotes
Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
Case Western Reserve University School of Medicine, Cleveland, USA.
Case Western Reserve University School of Medicine, Cleveland, USA.
Södertörn University, Avdelning Naturvetenskap.
2002 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 99, no 19, 12208-12213 p.Article in journal (Refereed) Published
Abstract [en]

Epidermal growth factor receptor (EGFr) is a key mediator of cell communication during animal development and homeostasis. In Drosophila, the signaling event is commonly regulated by the polytopic membrane protein Rhomboid (RHO), which mediates the proteolytic activation of EGFr ligands, allowing the secretion of the active signal. Until very recently, the biochemical function of RHO had remained elusive. It is now believed that Drosophila RHO is the founder member of a previously undescribed family of serine proteases, and that it could be directly responsible for the unusual, intramembranous cleavage of EGFr ligands. Here we show that the function of RHO is conserved in Gram-negative bacteria. AarA, a Providencia stuartii RHO-related protein, is active in Drosophila on the fly EGFr ligands. Vice versa, Drosophila RHO-1 can effectively rescue the bacterium's ability to produce or release the signal that activates density-dependent gene regulation (or quorum sensing). This study provides the first evidence that prokaryotic and eukaryotic RHOs could have a conserved role in cell communication and that their biochemical properties could be more similar than previously anticipated.

Place, publisher, year, edition, pages
2002. Vol. 99, no 19, 12208-12213 p.
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:sh:diva-15786DOI: 10.1073/pnas.192138799ISI: 000178187000040PubMedID: 12221285Scopus ID: 2-s2.0-0037126036OAI: oai:DiVA.org:sh-15786DiVA: diva2:508383
Available from: 2012-03-08 Created: 2012-03-07 Last updated: 2017-07-19Bibliographically approved
In thesis
1. The Rhomboid family of intramembrane proteases, conserved regulators of cell communication
Open this publication in new window or tab >>The Rhomboid family of intramembrane proteases, conserved regulators of cell communication
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The development of multicellular organisms relies heavily on cell communication. Cells send and receive complex sets of signals, harmonising their growth and differentiation with that of other, often distant, cell populations. In animals, the Epidermal Growth Factor Receptor (EGFR) is an important mediator of cell communication. EGFR activation regulates various developmental events in nematodes, insects and vertebrates. In addition, mutations in human EGFRs have been associated with a number of cancers. In Drosophila, a key event triggering EGFR signalling is the regulated release of the extracellular portion of EGFR ligands. Rhomboid (Rho), an unusual polytopic protease, cleaves the transmembrane, inactive ligand precursor into an active, soluble form. Both the target sequence and Rho s catalytic site are embedded within the membrane bilayer and for this reason the reaction has been described as regulated intramembrane proteolysis. The work presented in this thesis begins with the characterisation of a classical fly mutation, roughoid (ru). Our results indicate that ru acts as a novel, positive regulator of EGFR signalling during eye development in Drosophila. ru was subsequently identified as rhomboid-3, one of seven rhomboid related genes encoded in the fly genome. Unexpectedly, we found that sequences related to Rhomboid are also common in unicellular organisms. A single microbial Rho has been previously studied, the aarA gene from the human pathogen Providencia stuartii. Strikingly, AarA appears to have a corresponding function to that of the Drosophila Rho: it is necessary for the release of a peptide-signal, which mediates cell communication in P. stuartii. AarA was indeed capable of substituting for the fly Rho in vivo. Vice versa, the fly Rho-1 restored the ability of aarA mutant bacteria to produce the extracellular signal mediating cell communication. These results suggest that Rho-mediated proteolysis might represent a very ancient mechanism for cell communication. The Drosophila genome contains seven Rhomboids. We began to investigate the possibility of additional substrates by analyzing the respiratory system phenotype observed in ru/rho-3 mutant embryos. During embryogenesis, specialised tracheal branches target and invade the ventral nerve cord, part of the central nervous system (CNS). In ru/rho-3 mutants, these branches are misrouted, and inappropriately cross the CNS midline. Also in this context Rho-3 functions to activate an EGFR ligand. Yet, the results reveal an unusual role for the pathway in the repulsion of migrating epithelial cells. EGFR ligands act as chemoattractants for a variety of cells in vivo and in vitro, including tumors. Our results provide a proof of principle that the EGFR can also mediate repulsion from the signal source.

Place, publisher, year, edition, pages
Stockholm: Karolinska Instiutet, 2004. 61 p.
National Category
Biological Sciences
Identifiers
urn:nbn:se:sh:diva-32067 (URN)91-7349-951-X (ISBN)
Public defence
2004-06-04, MB 503, Alfred Nobels allé 7, Huddinge, 11:00 (English)
Opponent
Supervisors
Available from: 2017-02-15 Created: 2017-02-15 Last updated: 2017-02-15Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMedScopusPMC Full text

Search in DiVA

By author/editor
Gallio, MarcoKylsten, Per
By organisation
Avdelning Naturvetenskap
In the same journal
Proceedings of the National Academy of Sciences of the United States of America
Natural Sciences

Search outside of DiVA

GoogleGoogle Scholar

Altmetric score

Total: 50 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf