scholarly journals A family of rhomboid-like genes: Drosophila rhomboid-1 and roughoid/rhomboid-3 cooperate to activate EGF receptor signaling

2000 ◽  
Vol 14 (13) ◽  
pp. 1651-1663 ◽  
Author(s):  
Jonathan D. Wasserman ◽  
Sinisa Urban ◽  
Matthew Freeman
Keyword(s):  
Molecular Mechanism ◽  
Growth And Development ◽  
Egf Receptor ◽  
Transmembrane Domain ◽  
Large Family ◽  
Egfr Signaling ◽  
Apparent Lack ◽  
Cell Determination ◽  
Domain Protein ◽  
Rate Limiting

As in mammals, the Drosophila EGF receptor controls many aspects of growth and development. The rate limiting component ofDrosophila Egfr signaling is Rhomboid, a seven transmembrane domain protein, whose expression prefigures Egfr signaling. Little is known about the molecular mechanism of Rhomboid function but genetic evidence suggests that it controls the activation of the ligand Spitz, a TGFα-like factor. Spitz/Egfr signaling regulates cell determination in the eye but here there is no apparent function for Rhomboid, an observation that casts doubt on this prevailing model of Rhomboid function. We describe our identification of six newrhomboid-like genes in Drosophila, and a large family of related genes present in organisms as diverse as bacteria and mammals; a human rhomboid homolog has also recently been described. Drosophila rhomboid-3 corresponds to theroughoid mutation; it cooperates with rhomboid-1 to control Egfr signaling in the eye, thereby solving the puzzle of the apparent lack of Rhomboid-1 function there. Rhomboid-1 and Roughoid/Rhomboid-3 act in the signal-emitting not signal-receiving cell, supporting the idea that Spitz activation is regulated by Rhomboid-like molecules.

scholarly journals iRhoms 1 and 2 are essential upstream regulators of ADAM17-dependent EGFR signaling

2015 ◽  
Vol 112 (19) ◽  
pp. 6080-6085 ◽  
Author(s):  
Xue Li ◽  
Thorsten Maretzky ◽  
Gisela Weskamp ◽  
Sébastien Monette ◽  
Xiaoping Qing ◽  
...  
Keyword(s):  
Heart Valves ◽  
Egf Receptor ◽  
Transmembrane Domain ◽  
Intestinal Barrier ◽  
Underlying Mechanism ◽  
Egfr Signaling ◽  
Mouse Development ◽  
Double Knockout ◽  
Egfr Ligands ◽  
And Function

The metalloproteinase ADAM17 (a disintegrin and metalloprotease 17) controls EGF receptor (EGFR) signaling by liberating EGFR ligands from their membrane anchor. Consequently, a patient lacking ADAM17 has skin and intestinal barrier defects that are likely caused by lack of EGFR signaling, and Adam17−/− mice die perinatally with open eyes, like Egfr−/− mice. A hallmark feature of ADAM17-dependent EGFR ligand shedding is that it can be rapidly and posttranslationally activated in a manner that requires its transmembrane domain but not its cytoplasmic domain. This suggests that ADAM17 is regulated by other integral membrane proteins, although much remains to be learned about the underlying mechanism. Recently, inactive Rhomboid 2 (iRhom2), which has seven transmembrane domains, emerged as a molecule that controls the maturation and function of ADAM17 in myeloid cells. However, iRhom2−/− mice appear normal, raising questions about how ADAM17 is regulated in other tissues. Here we report that iRhom1/2−/− double knockout mice resemble Adam17−/− and Egfr−/− mice in that they die perinatally with open eyes, misshapen heart valves, and growth plate defects. Mechanistically, we show lack of mature ADAM17 and strongly reduced EGFR phosphorylation in iRhom1/2−/− tissues. Finally, we demonstrate that iRhom1 is not essential for mouse development but regulates ADAM17 maturation in the brain, except in microglia, where ADAM17 is controlled by iRhom2. These results provide genetic, cell biological, and biochemical evidence that a principal function of iRhoms1/2 during mouse development is to regulate ADAM17-dependent EGFR signaling, suggesting that iRhoms1/2 could emerge as novel targets for treatment of ADAM17/EGFR-dependent pathologies.

scholarly journals Three Subfamilies of Pheromone and Receptor Genes Generate Multiple B Mating Specificities in the Mushroom Coprinus cinereus

Genetics ◽  
2000 ◽  
Vol 154 (3) ◽  
pp. 1115-1123 ◽  
Author(s):  
John R Halsall ◽  
Michael J Milner ◽  
Lorna A Casselton
Keyword(s):  
Southern Blotting ◽  
Transmembrane Domain ◽  
Functional Unit ◽  
Large Family ◽  
Coprinus Cinereus ◽  
Multidrug Transporter ◽  
Type Locus ◽  
Allele Specific ◽  
Unique Specificity ◽  
Major Facilitator

Abstract The B mating type locus of the basidiomycete Coprinus cinereus encodes a large family of lipopeptide pheromones and their seven transmembrane domain receptors. Here we show that the B42 locus, like the previously described B6 locus, derives its unique specificity from nine multiallelic genes that are organized into three subgroups each comprising a receptor and two pheromone genes. We show that the three genes within each group are kept together as a functional unit by being embedded in an allele-specific DNA sequence. Using a combination of sequence analysis, Southern blotting, and DNA-mediated transformation with cloned genes, we demonstrate that different B loci may share alleles of one or two groups of genes. This is consistent with the prediction that the three subgroups of genes are functionally redundant and that it is the different combinations of their alleles that generate the multiple B mating specificities found in nature. The B42 locus was found to contain an additional gene, mfs1, that encodes a putative multidrug transporter belonging to the major facilitator family. In strains with other B mating specificities, this gene, whose functional significance was not established, lies in a region of shared homology flanking the B locus.

FRET detects lateral interaction between transmembrane domain of EGF receptor and ganglioside GM3 in lipid bilayers

2021 ◽  
pp. 183623
Author(s):  
Mikito Nakano ◽  
Shinya Hanashima ◽  
Toshiaki Hara ◽  
Kazuya Kabayama ◽  
Yuya Asahina ◽  
...  
Keyword(s):  
Lipid Bilayers ◽  
Egf Receptor ◽  
Transmembrane Domain ◽  
Lateral Interaction ◽  
Ganglioside Gm3

scholarly journals Notch signaling coordinates ommatidial rotation in the Drosophila eye via transcriptional regulation of the EGF-Receptor ligand Argos

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yildiz Koca ◽  
Benjamin E. Housden ◽  
William J. Gault ◽  
Sarah J. Bray ◽  
Marek Mlodzik
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Planar Cell Polarity ◽  
Egf Receptor ◽  
Control Cell ◽  
Loss Of Function ◽  
Egfr Signaling ◽  
Specific Expression ◽  
Egfr Signaling Pathway ◽  
Ommatidial Rotation

AbstractIn all metazoans, a small number of evolutionarily conserved signaling pathways are reiteratively used during development to orchestrate critical patterning and morphogenetic processes. Among these, Notch (N) signaling is essential for most aspects of tissue patterning where it mediates the communication between adjacent cells to control cell fate specification. In Drosophila, Notch signaling is required for several features of eye development, including the R3/R4 cell fate choice and R7 specification. Here we show that hypomorphic alleles of Notch, belonging to the Nfacet class, reveal a novel phenotype: while photoreceptor specification in the mutant ommatidia is largely normal, defects are observed in ommatidial rotation (OR), a planar cell polarity (PCP)-mediated cell motility process. We demonstrate that during OR Notch signaling is specifically required in the R4 photoreceptor to upregulate the transcription of argos (aos), an inhibitory ligand to the epidermal growth factor receptor (EGFR), to fine-tune the activity of EGFR signaling. Consistently, the loss-of-function defects of Nfacet alleles and EGFR-signaling pathway mutants are largely indistinguishable. A Notch-regulated aos enhancer confers R4 specific expression arguing that aos is directly regulated by Notch signaling in this context via Su(H)-Mam-dependent transcription.

scholarly journals Glycosphingolipids are required for sorting melanosomal proteins in the Golgi complex

2001 ◽  
Vol 155 (3) ◽  
pp. 369-380 ◽  
Author(s):  
Hein Sprong ◽  
Sophie Degroote ◽  
Tijs Claessens ◽  
Judith van Drunen ◽  
Viola Oorschot ◽  
...  
Keyword(s):  
Golgi Complex ◽  
Protein Transport ◽  
Transmembrane Domain ◽  
Direct Pathway ◽  
Mouse Melanoma Cell ◽  
Multicellular Organisms ◽  
Rate Limiting ◽  
Tyrosinase Related Protein ◽  
Mouse Melanoma Cell Line

A;lthough glycosphingolipids are ubiquitously expressed and essential for multicellular organisms, surprisingly little is known about their intracellular functions. To explore the role of glycosphingolipids in membrane transport, we used the glycosphingolipid-deficient GM95 mouse melanoma cell line. We found that GM95 cells do not make melanin pigment because tyrosinase, the first and rate-limiting enzyme in melanin synthesis, was not targeted to melanosomes but accumulated in the Golgi complex. However, tyrosinase-related protein 1 still reached melanosomal structures via the plasma membrane instead of the direct pathway from the Golgi. Delivery of lysosomal enzymes from the Golgi complex to endosomes was normal, suggesting that this pathway is not affected by the absence of glycosphingolipids. Loss of pigmentation was due to tyrosinase mislocalization, since transfection of tyrosinase with an extended transmembrane domain, which bypassed the transport block, restored pigmentation. Transfection of ceramide glucosyltransferase or addition of glucosylsphingosine restored tyrosinase transport and pigmentation. We conclude that protein transport from Golgi to melanosomes via the direct pathway requires glycosphingolipids.

Transcriptomic Analysis of MSTN Knockout in the Early Differentiation of Chicken Fetal Myoblasts

Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 58
Author(s):  
Ke Xu ◽  
Hao Zhou ◽  
Chengxiao Han ◽  
Zhong Xu ◽  
Jinmei Ding ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Molecular Mechanism ◽  
Growth And Development ◽  
Biological Effects ◽  
Muscle Growth ◽  
Negative Regulator ◽  
Myoblast Differentiation ◽  
Fatty Acid Binding ◽  
Knock Out ◽  
Early Differentiation

In mammals, Myostatin (MSTN) is a known negative regulator of muscle growth and development, but its role in birds is poorly understood. To investigate the molecular mechanism of MSTN on muscle growth and development in chickens, we knocked out MSTN in chicken fetal myoblasts (CFMs) and sequenced the mRNA transcriptomes. The amplicon sequencing results show that the editing efficiency of the cells was 76%. The transcriptomic results showed that 296 differentially expressed genes were generated after down-regulation of MSTN, including angiotensin I converting enzyme (ACE), extracellular fatty acid-binding protein (EXFABP) and troponin T1, slow skeletal type (TNNT1). These genes are closely associated with myoblast differentiation, muscle growth and energy metabolism. Subsequent enrichment analysis showed that DEGs of CFMs were related to MAPK, P13K/AKT, and STAT3 signaling pathways. The MAPK and P13K/AKT signaling pathways are two of the three known signaling pathways involved in the biological effects of MSTN in mammals, and the STAT3 pathway is also significantly enriched in MSTN knock out chicken leg muscles. The results of this study will help to understand the possible molecular mechanism of MSTN regulating the early differentiation of CFMs and lay a foundation for further research on the molecular mechanism of MSTN involvement in muscle growth and development.

Characterization of Star and its interactions with sevenless and EGF receptor during photoreceptor cell development in Drosophila

Development ◽  
1994 ◽  
Vol 120 (7) ◽  
pp. 1731-1745 ◽  
Author(s):  
A.L. Kolodkin ◽  
A.T. Pickup ◽  
D.M. Lin ◽  
C.S. Goodman ◽  
U. Banerjee
Keyword(s):  
Genetic Background ◽  
Egf Receptor ◽  
Transmembrane Domain ◽  
Loss Of Function ◽  
Morphogenetic Furrow ◽  
Eye Disc ◽  
Son Of Sevenless ◽  
Photoreceptor Development ◽  
Star Gene

Loss-of-function mutations in Star impart a dominant rough eye phenotype and, when homozygous, are embryonic lethal with ventrolateral cuticular defects. We have cloned the Star gene and show that it encodes a novel protein with a putative transmembrane domain. Star transcript is expressed in a dynamic pattern in the embryo including in cells of the ventral midline. In the larval eye disc, Star is expressed first at the morphogenetic furrow, then in the developing R2, R5, and R8 cells as well as in the posterior clusters of the disc in additional R cells. Star interacts with Drosophila EGF receptor in the eye and mosaic analysis of Star in the larval eye disc reveals that homozygous Star patches contain no developing R cells. Taken together with the expression pattern at the morphogenetic furrow, these results demonstrate an early role for Star in photoreceptor development. Additionally, loss-of-function mutations in Star act as suppressors of R7 development in a sensitized genetic background involving the Son of sevenless (Sos) locus, and overexpression of Star enhances R7 development in this genetic background. Based on the genetic interactions with Sos, we suggest that Star also has a later role in photoreceptor development including the recruitment of the R7 cell through the sevenless pathway.

scholarly journals Molecular Mechanism for the Shp-2 Tyrosine Phosphatase Function in Promoting Growth Factor Stimulation of Erk Activity

2000 ◽  
Vol 20 (5) ◽  
pp. 1526-1536 ◽  
Author(s):  
Zhong-Qing Shi ◽  
De-Hua Yu ◽  
Morag Park ◽  
Mark Marshall ◽  
Gen-Sheng Feng
Keyword(s):  
Growth Factor ◽  
Molecular Mechanism ◽  
Egf Receptor ◽  
Tyrosine Phosphatase ◽  
Mouse Fibroblast ◽  
Positive Role ◽  
Extracellular Signal ◽  
Biochemical Analyses ◽  
Erk Activity ◽  
Mutant Cells

ABSTRACT We have previously shown that activation of extracellular signal-regulated kinase (Erk) by epidermal growth factor (EGF) treatment was significantly decreased in mouse fibroblast cells expressing a mutant Shp-2 molecule lacking 65 amino acids in the SH2-N domain, Shp-2Δ46-110. To address the molecular mechanism for the positive role of Shp-2 in mediating Erk induction, we evaluated the activation of signaling components upstream of Erk in Shp-2 mutant cells. EGF-stimulated Ras, Raf, and Mek activation was significantly attenuated in Shp-2 mutant cells, suggesting that Shp-2 acts to promote Ras activation or to suppress the down-regulation of activated Ras. Biochemical analyses indicate that upon EGF stimulation, Shp-2 is recruited into a multiprotein complex assembled on the Gab1 docking molecule and that Shp-2 seems to exert its biological function by specifically dephosphorylating an unidentified molecule of 90 kDa in the complex. The mutant Shp-2Δ46-110 molecule failed to participate in the Gab1-organized complex for dephosphorylation of p90, correlating with a defective activation of the Ras-Raf-Mek-Erk cascade in EGF-treated Shp-2 mutant cells. Evidence is also presented that Shp-2 does not appear to modulate the signal relay from EGF receptor to Ras through the Shc, Grb2, and Sos proteins. These results begin to elucidate the mechanism of Shp-2 function downstream of a receptor tyrosine kinase to promote the activation of the Ras-Erk pathway, with potential therapeutic applications in cancer treatment.

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