Disease relevance of rho

• Although nothing is known about the function of the approximately 100 currently known rhomboid genes conserved throughout evolution, a recent analysis suggests that a Rhomboid from the pathogenic bacterium Providencia stuartii is involved in the production of a quorum-sensing factor [1].
• In the abdominal epidermis, Serrate promotes denticle diversity by precisely localizing a single cell stripe of rhomboid expression, which generates a source of EGF signal that is not produced in thoracic epidermis [2].
• We have solved the structure of the rhomboid peptidase from Haemophilus influenzae (hiGlpG) to 2.2-A resolution [3].

High impact information on rho

• In accordance with the putative Rhomboid active site being in the membrane bilayer, Spitz is cleaved within its transmembrane domain, and thus is, to our knowledge, the first example of a growth factor activated by regulated intramembrane proteolysis [4].
• Drosophila rhomboid-1 defines a family of putative intramembrane serine proteases [4].
• Both Star and Rhomboid-1 have been assumed to work at the cell surface to control ligand activation [5].
• The membrane proteins Star and Rhomboid-1 have been genetically defined as the primary regulators of EGF receptor activation in Drosophila, but their molecular mechanisms have been elusive [5].
• Ectopic expression of mirr in the posterior follicle cells induces a stripe of rhomboid (rho) expression and represses pipe (pip), a gene with a role in the establishment of the dorsal-ventral axis, at a distance [6].

Chemical compound and disease context of rho

• On the basis of experimental studies with the developmental regulator rhomboid from Drosophila and the AarA protein from the bacterium Providencia stuartii, the rhomboids are thought to be intramembrane serine proteases whose signaling function is conserved in eukaryotes and prokaryotes [7].

Biological context of rho

• The rate limiting component of Drosophila Egfr signaling is Rhomboid, a seven transmembrane domain protein, whose expression prefigures Egfr signaling [8].
• To gain insights into the mechanisms underlying Rho and Star function, we developed a mutagenesis scheme to isolate novel overexpression activity (NOVA) alleles [9].
• Despite differences in the primary structure of Rhomboid proteins, the proteolytic activity and substrate specificity of these enzymes has been conserved in diverse organisms [10].
• Second, lateral inhibition, mediated by the neurogenic genes, acts within this cluster of cells to segregate the tip cell precursor, in which proneural gene expression strengthens to initiate rhomboid expression [11].
• A second group of target genes (e.g. rhomboid (rho)) is induced only at later stages of oogenesis, and may require additional inputs by signals emanating from the anterior, stretch follicle cells [12].

Anatomical context of rho

• Immunoelectron microscopy reveals that Rho plaques are composed of a highly localized patch of plasma membrane and a densely staining underlying structure [13].
• In some cells Rho plaques colocalize with Armadillo at adherens junctions, while in other cells plaques are only found basal to the adherens junction [13].
• By looking for mutations that modify the phenotype caused by ectopic expression of the rhomboid gene in the eye, I have discovered that the spitz gene is required for photoreceptor determination [14].
• We show that rhomboid (rho), a novel member of this group, encodes a protein that is localized on the apical surface of the dorsal-anterior follicle cells surrounding the oocyte [15].
• Mitochondrial membrane remodelling regulated by a conserved rhomboid protease [16].

Associations of rho with chemical compounds

• Modeling a tetrapeptide substrate in the context of the rhomboid structure reveals an oxyanion hole comprising the side chain of a second conserved histidine and the main-chain NH of the nucleophilic serine residue [3].
• The UDP-sugar transporter FRINGE-CONNECTION (FRC) is localized to a subset of the Golgi units distinct from those harboring SULFATELESS (SFL), which modifies glucosaminoglycans (GAGs), and from those harboring the protease RHOMBOID (RHO), which processes the glycoprotein SPITZ (SPI) [17].
• In contrast, shedding of TgAMA1 from the surface of extracellular tachyzoites occurs exclusively via cleavage within the luminal half of its transmembrane domain by a rhomboid-like protease [18].

Enzymatic interactions of rho

• The Drosophila EGF receptor ligand Spitz is cleaved by Rhomboid to generate an active secreted molecule [19].

Regulatory relationships of rho

• Patterned expression of the Drosophila rhomboid (rho) gene is thought to promote signaling by the EGF receptor (EGFR) in specific cell types [13].
• In the anterior cells, the target genes wingless and patched are activated whereas posterior cells respond to Hh by expressing rhomboid and patched [20].
• We showed that the argos transcripts are expressed transiently in the cells surrounding the Ch organ precursor and that the gene rhomboid (rho), which is involved in the regulation of the number of Ch organs, acts epistatically to argos in this event [21].
• Vein primordia are specified by the positional information provided by hedgehog and decapentaplegic in the wing imaginal disc and express the key regulatory gene rhomboid [22].

Other interactions of rho

• The Drosophila rhomboid gene mediates the localized formation of wing veins and interacts genetically with components of the EGF-R signaling pathway [23].
• This observation suggests a sequential activity of Star and Rho in mSpi processing [24].
• Thus, Serrate and veinlet (rhom) partake in the last layer of the segmentation cascade [25].
• Serrate accomplishes this task by activating Notch in a discrete domain, the main purpose of which is to broaden the spatially regulated expression of Rhomboid [26].
• Processing is confined to the cell row posterior to the Engrailed domain by the restricted expression of Rhomboid [27].

Analytical, diagnostic and therapeutic context of rho

• Expression in mammalian cell cultures reveals interdependent, but distinct, functions for Star and Rhomboid proteins in the processing of the Drosophila transforming-growth-factor-alpha homologue Spitz [28].
• Using a polymerase chain reaction (PCR)-based strategy, we have cloned a human cDNA which encodes a protein that has high sequence similarity to Rhomboid [29].

References