scholarly journals The CHORD protein CHP-1 regulates EGF receptor trafficking and signaling in C. elegans and in human cells

2019 ◽  
Author(s):  
Andrea Haag ◽  
Michael Walser ◽  
Adrian Henggeler ◽  
Alex Hajnal
Keyword(s):  
Intracellular Trafficking ◽  
Egf Receptor ◽  
Mapk Signaling ◽  
Human Cells ◽  
Receptor Trafficking ◽  
Independent Function ◽  
Vulval Development ◽  
C Elegans ◽  
Downstream Signaling

AbstractThe intracellular trafficking of growth factor receptors determines the activity of their downstream signaling pathways. The putative co-chaperone CHP-1 acts as a regulator of EGFR trafficking during C.elegans vulval development. Loss of chp-1 causes the retention of the EGFR in the ER and decreased MAPK signaling. CHP-1 functions specifically, as the localization of other receptors is unaltered in chp-1(lf) mutants, and inhibiting other co-chaperones does not affect EGFR localization. The role of CHP-1 during EGFR trafficking is conserved in humans. Analogous to C.elegans, the response of CHP-1-deficient human cells to EGF stimulation is attenuated, the EGFR accumulates in the ER and ERK2 activity is decreased. Although CHP-1 has been proposed to act as a co-chaperone for HSP90, our data indicate an HSP90-independent function of CHP-1. The identification of CHP-1 as a regulator of EGFR trafficking opens the possibility to identify small molecule chaperone inhibitors targeting the EGFR pathway with increased selectivity.

scholarly journals The CHORD protein CHP-1 regulates EGF receptor trafficking and signaling in C. elegans and in human cells

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Andrea Haag ◽  
Michael Walser ◽  
Adrian Henggeler ◽  
Alex Hajnal
Keyword(s):  
Egf Receptor ◽  
Mapk Signaling ◽  
Human Cells ◽  
Receptor Trafficking ◽  
A431 Cells ◽  
Transmembrane Receptors ◽  
C Elegans ◽  
Downstream Signaling ◽  
Hsp 90

The intracellular trafficking of growth factor receptors determines the activity of their downstream signaling pathways. Here, we show that the putative HSP-90 co-chaperone CHP-1 acts as a regulator of EGFR trafficking in C. elegans. Loss of chp-1 causes the retention of the EGFR in the ER and decreases MAPK signaling. CHP-1 is specifically required for EGFR trafficking, as the localization of other transmembrane receptors is unaltered in chp-1(lf) mutants, and the inhibition of hsp-90 or other co-chaperones does not affect EGFR localization. The role of the CHP-1 homolog CHORDC1 during EGFR trafficking is conserved in human cells. Analogous to C. elegans, the response of CHORDC1-deficient A431 cells to EGF stimulation is attenuated, the EGFR accumulates in the ER and ERK2 activity decreases. Although CHP-1 has been proposed to act as a co-chaperone for HSP90, our data indicate that CHP-1 plays an HSP90-independent function in controlling EGFR trafficking through the ER.

scholarly journals Syndecan Transmembrane Domain Specifically Regulates Downstream Signaling Events of the Transmembrane Receptor Cytoplasmic Domain

2021 ◽  
Vol 22 (15) ◽  
pp. 7918
Author(s):  
Jisun Hwang ◽  
Bohee Jang ◽  
Ayoung Kim ◽  
Yejin Lee ◽  
Joonha Lee ◽  
...  
Keyword(s):  
Transmembrane Domain ◽  
Growth Factor Receptor ◽  
Cytoplasmic Domain ◽  
Nih3t3 Cells ◽  
C Elegans ◽  
Downstream Signaling ◽  
Downstream Effectors ◽  
Signaling Events

Despite the known importance of the transmembrane domain (TMD) of syndecan receptors in cell adhesion and signaling, the molecular basis for syndecan TMD function remains unknown. Using in vivo invertebrate models, we found that mammalian syndecan-2 rescued both the guidance defects in C. elegans hermaphrodite-specific neurons and the impaired development of the midline axons of Drosophila caused by the loss of endogenous syndecan. These compensatory effects, however, were reduced significantly when syndecan-2 dimerization-defective TMD mutants were introduced. To further investigate the role of the TMD, we generated a chimera, 2eTPC, comprising the TMD of syndecan-2 linked to the cytoplasmic domain of platelet-derived growth factor receptor (PDGFR). This chimera exhibited SDS-resistant dimer formation that was lost in the corresponding dimerization-defective syndecan-2 TMD mutant, 2eT(GL)PC. Moreover, 2eTPC specifically enhanced Tyr 579 and Tyr 857 phosphorylation in the PDGFR cytoplasmic domain, while the TMD mutant failed to support such phosphorylation. Finally, 2eTPC, but not 2eT(GL)PC, induced phosphorylation of Src and PI3 kinase (known downstream effectors of Tyr 579 phosphorylation) and promoted Src-mediated migration of NIH3T3 cells. Taken together, these data suggest that the TMD of a syndecan-2 specifically regulates receptor cytoplasmic domain function and subsequent downstream signaling events controlling cell behavior.

scholarly journals Cell fate-specific regulation of EGF receptor trafficking during Caenorhabditis elegans vulval development

2006 ◽  
Vol 25 (11) ◽  
pp. 2347-2357 ◽  
Author(s):  
Attila Stetak ◽  
Erika Fröhli Hoier ◽  
Assunta Croce ◽  
Giuseppe Cassata ◽  
Pier Paolo Di Fiore ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Cell Fate ◽  
Egf Receptor ◽  
Receptor Trafficking ◽  
Vulval Development ◽  
Specific Regulation

scholarly journals Reciprocal EGFR signaling in the Anchor Cell ensures precise inter-organ connection during C. elegans vulval morphogenesis

2021 ◽  
Author(s):  
Silvan Spiri ◽  
Simon Berger ◽  
Louisa Mereu ◽  
Andrew DeMello ◽  
Alex Hajnal
Keyword(s):  
Egf Receptor ◽  
Adherens Junctions ◽  
Egfr Signaling ◽  
Cell Fates ◽  
Vulval Development ◽  
C Elegans ◽  
Sequence Of Events ◽  
Epidermal Growth ◽  
Short And Long Term ◽  
Anchor Cell

During C. elegans vulval development, the uterine anchor cell (AC) first secretes an epidermal growth factor (EGF) to specify the vulval cell fates and then invades into the underlying vulval epithelium. Thereby, the AC establishes direct contact with the invaginating primary vulF cells and attaches the developing uterus to the vulva. The signals involved and the exact sequence of events joining these two organs are not fully understood. Using a conditional let-23 egf receptor (EGFR) allele along with novel microfluidic short- and long-term imaging methods, we discovered a specific function of the EGFR in the AC during vulval lumen morphogenesis. Tissue-specific inactivation of let-23 in the AC resulted in imprecise alignment of the AC with the primary vulval cells, delayed AC invasion and disorganized adherens junctions at the newly forming contact site between the AC and the dorsal vulF toroid. We propose that EGFR signaling, activated by a reciprocal EGF cue from the primary vulval cells, positions the AC at the vulval midline, guides it during invasion and assembles a cytoskeletal scaffold organizing the adherens junctions that connect the developing uterus to the dorsal vulF toroid. EGFR signaling in the AC thus ensures the precise alignment of the two developing organs.

scholarly journals Role of the Sec61 Translocon in EGF Receptor Trafficking to the Nucleus and Gene Expression

2007 ◽  
Vol 18 (3) ◽  
pp. 1064-1072 ◽  
Author(s):  
Hong-Jun Liao ◽  
Graham Carpenter
Keyword(s):  
Gene Expression ◽  
Endoplasmic Reticulum ◽  
Growth Factor ◽  
Egf Receptor ◽  
Transmembrane Proteins ◽  
Receptor Trafficking ◽  
Cyclin D ◽  
Egf Receptors ◽  
Epidermal Growth

The epidermal growth factor (EGF)-dependent trafficking of the intact EGF receptor to the nucleus and its requirement for growth factor induction of cyclin D and other genes has been reported. Unresolved is the mechanism by which this or other transmembrane proteins are excised from a lipid bilayer before nuclear translocalization. We report that, after the addition of EGF, the cell surface EGF receptor is trafficked to the endoplasmic reticulum (ER) where it associates with Sec61β, a component of the Sec61 translocon, and is retrotranslocated from the ER to the cytoplasm. Abrogation of Sec61β expression prevents EGF-dependent localization of EGF receptors to the nucleus and expression of cyclin D. This indicates that EGF receptors are trafficked from the ER to the nucleus by a novel pathway that involves the Sec61 translocon.

scholarly journals ENPL-1, the Caenorhabditis elegans homolog of GRP94, promotes insulin secretion via regulation of proinsulin processing and maturation

Development ◽  
2020 ◽  
Vol 147 (20) ◽  
pp. dev190082
Author(s):  
Agnieszka Podraza-Farhanieh ◽  
Balasubramanian Natarajan ◽  
Dorota Raj ◽  
Gautam Kao ◽  
Peter Naredi
Keyword(s):  
Insulin Secretion ◽  
Caenorhabditis Elegans ◽  
Growth Control ◽  
Specific Domain ◽  
C Elegans ◽  
Downstream Signaling ◽  
Dauer Larva ◽  
Proinsulin Processing

ABSTRACTInsulin/IGF signaling in Caenorhabditis elegans is crucial for proper development of the dauer larva and growth control. Mutants disturbing insulin processing, secretion and downstream signaling perturb this process and have helped identify genes that affect progression of type 2 diabetes. Insulin maturation is required for its proper secretion by pancreatic β cells. The role of the endoplasmic reticulum (ER) chaperones in insulin processing and secretion needs further study. We show that the C. elegans ER chaperone ENPL-1/GRP94 (HSP90B1), acts in dauer development by promoting insulin secretion and signaling. Processing of a proinsulin likely involves binding between the two proteins via a specific domain. We show that, in enpl-1 mutants, an unprocessed insulin exits the ER lumen and is found in dense core vesicles, but is not secreted. The high ER stress in enpl-1 mutants does not cause the secretion defect. Importantly, increased ENPL-1 levels result in increased secretion. Taken together, our work indicates that ENPL-1 operates at the level of insulin availability and is an essential modulator of insulin processing and secretion.

How do histone modifications contribute to transgenerational epigenetic inheritance in C. elegans?

2020 ◽  
Vol 48 (3) ◽  
pp. 1019-1034 ◽  
Author(s):  
Rachel M. Woodhouse ◽  
Alyson Ashe
Keyword(s):  
Histone Modifications ◽  
Molecular Mechanisms ◽  
Epigenetic Inheritance ◽  
Nematode Caenorhabditis Elegans ◽  
Histone Methyltransferases ◽  
Transgenerational Epigenetic Inheritance ◽  
C Elegans ◽  
Recent Developments ◽  
Gene Regulatory

Gene regulatory information can be inherited between generations in a phenomenon termed transgenerational epigenetic inheritance (TEI). While examples of TEI in many animals accumulate, the nematode Caenorhabditis elegans has proven particularly useful in investigating the underlying molecular mechanisms of this phenomenon. In C. elegans and other animals, the modification of histone proteins has emerged as a potential carrier and effector of transgenerational epigenetic information. In this review, we explore the contribution of histone modifications to TEI in C. elegans. We describe the role of repressive histone marks, histone methyltransferases, and associated chromatin factors in heritable gene silencing, and discuss recent developments and unanswered questions in how these factors integrate with other known TEI mechanisms. We also review the transgenerational effects of the manipulation of histone modifications on germline health and longevity.

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