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The Rhomboid family of intramembrane proteases, conserved regulators of cell communication
Södertörn University, School of Chemistry, Biology, Geography and Environmental Science. Karolinska Institutet.
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: urn:nbn:se:sh:diva-32067ISBN: 91-7349-951-X (print)OAI: oai:DiVA.org:sh-32067DiVA: diva2:1074627
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
List of papers
1. The roughoid locus identifies a novel function involved in epidermal growth factor receptor signalling in Drosophila
Open this publication in new window or tab >>The roughoid locus identifies a novel function involved in epidermal growth factor receptor signalling in Drosophila
(English)Manuscript (preprint) (Other academic)
National Category
Biological Sciences
Identifiers
urn:nbn:se:sh:diva-32066 (URN)
Note

Som manuskript i avhandling. As manuscript in dissertation.

Available from: 2017-02-15 Created: 2017-02-15 Last updated: 2017-02-15Bibliographically approved
2. Providencia may help find a function for a novel, widespread protein family
Open this publication in new window or tab >>Providencia may help find a function for a novel, widespread protein family
2000 (English)In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 10, no 19, R693-R694 p.Article in journal (Refereed) Published
National Category
Biochemistry and Molecular Biology Cell Biology
Identifiers
urn:nbn:se:sh:diva-15733 (URN)10.1016/S0960-9822(00)00722-3 (DOI)000089988600005 ()11050401 (PubMedID)2-s2.0-0034609723 (Scopus ID)
Available from: 2012-03-07 Created: 2012-03-07 Last updated: 2017-02-15Bibliographically approved
3. A conserved mechanism for extracellular signaling in eukaryotes and prokaryotes
Open this publication in new window or tab >>A conserved mechanism for extracellular signaling in eukaryotes and prokaryotes
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.

National Category
Natural Sciences
Identifiers
urn:nbn:se:sh:diva-15786 (URN)10.1073/pnas.192138799 (DOI)000178187000040 ()12221285 (PubMedID)2-s2.0-0037126036 (Scopus ID)
Available from: 2012-03-08 Created: 2012-03-07 Last updated: 2017-07-19Bibliographically approved
4. Rhomboid 3 orchestrates Slit-independent repulsion of tracheal branches at the CNS midline
Open this publication in new window or tab >>Rhomboid 3 orchestrates Slit-independent repulsion of tracheal branches at the CNS midline
2004 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 131, no 15, 3605-3614 p.Article in journal (Refereed) Published
Abstract [en]

EGF-receptor ligands act as chemoattractants for migrating epithelial cells during organogenesis and wound healing. We present evidence that Rhomboid 3/EGF signalling, which originates from the midline of the Drosophila ventral nerve cord, repels tracheal ganglionic branches and prevents them from crossing it. rho3 acts independently from the main midline repellent Slit, and originates from a different sub-population of midline cells: the VUM neurons. Expression of dominant-negative Egfr or Ras induces midline crosses, whereas activation of the Egfr or Ras in the leading cell of the ganglionic branch can induce premature turns away from the midline. This suggests that the level of Egfr intracellular signalling, rather than the asymmetric activation of the receptor on the cell surface, is an important determinant in ganglionic branch repulsion. We propose that Egfr activation provides a necessary switch for the interpretation of a yet unknown repellent function of the midline.

National Category
Developmental Biology
Identifiers
urn:nbn:se:sh:diva-15472 (URN)10.1242/dev.01242 (DOI)000223517400010 ()15229181 (PubMedID)2-s2.0-4444361021 (Scopus ID)
Available from: 2012-02-21 Created: 2012-02-20 Last updated: 2017-02-15Bibliographically approved

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