scholarly journals LIN-10 can promote LET-23 EGFR signaling and trafficking independently of LIN-2 and LIN-7

2020 ◽  
Author(s):  
Kimberley D. Gauthier ◽  
Christian E. Rocheleau
Keyword(s):  
Signal Transmission ◽  
Basolateral Membrane ◽  
Pdz Domain ◽  
Growth Factor Receptor ◽  
Egfr Signaling ◽  
Independent Function ◽  
Cell Fates ◽  
Recycling Endosomes ◽  
C Elegans ◽  
Epidermal Growth

AbstractDuring C. elegans larval development, an inductive signal mediated by LET-23 EGFR (Epidermal Growth Factor Receptor) specifies three of six vulva precursor cells (VPCs) to adopt vulval cell fates. An evolutionarily conserved complex consisting of PDZ domain-containing scaffold proteins LIN-2 (CASK), LIN-7 (Lin7 or Veli), and LIN-10 (APBA1 or Mint1) (LIN-2/7/10) mediates basolateral LET-23 EGFR localization in the VPCs to permit signal transmission and development of the vulva. We recently found that the LIN-2/7/10 complex likely forms at Golgi ministacks or recycling endosomes; however, the mechanism through which the complex targets the receptor to the basolateral membrane remains unknown. Here we found that overexpression of LIN-10 or LIN-7 can compensate for loss of their complex components by promoting LET-23 EGFR signaling through previously unknown complex-independent and receptor-dependent pathways. In particular, LIN-10 can independently promote basolateral LET-23 EGFR localization, and its complex-independent function uniquely requires its PDZ domains that also regulate its localization to Golgi ministacks and recycling endosomes. These studies point to a novel complex-independent function for LIN-7 and LIN-10 that broadens our understanding of how this complex regulates targeted sorting of membrane proteins.

scholarly journals LIN-10 can promote LET-23 EGFR signaling and trafficking independently of LIN-2 and LIN-7

2021 ◽  
pp. mbc.E20-07-0490
Author(s):  
Kimberley D. Gauthier ◽  
Christian E. Rocheleau
Keyword(s):  
Signal Transmission ◽  
Basolateral Membrane ◽  
Pdz Domain ◽  
Growth Factor Receptor ◽  
Pdz Domains ◽  
Egfr Signaling ◽  
Independent Function ◽  
Cell Fates ◽  
C Elegans ◽  
Epidermal Growth

During C. elegans larval development, an inductive signal mediated by LET-23 EGFR (Epidermal Growth Factor Receptor) specifies three of six vulva precursor cells (VPCs) to adopt vulval cell fates. An evolutionarily conserved complex consisting of PDZ domain-containing scaffold proteins LIN-2 (CASK), LIN-7 (Lin7 or Veli), and LIN-10 (APBA1 or Mint1) (LIN-2/7/10) mediates basolateral LET-23 EGFR localization in the VPCs to permit signal transmission and development of the vulva. We recently found that the LIN-2/7/10 complex likely forms at Golgi ministacks; however, the mechanism through which the complex targets the receptor to the basolateral membrane remains unknown. Here we found that overexpression of LIN-10 or LIN-7 can compensate for loss of their complex components by promoting LET-23 EGFR signaling through previously unknown complex-independent and receptor-dependent pathways. In particular, LIN-10 can independently promote basolateral LET-23 EGFR localization, and its complex-independent function uniquely requires its PDZ domains that also regulate its localization to Golgi. These studies point to a novel complex-independent function for LIN-7 and LIN-10 that broadens our understanding of how this complex regulates targeted sorting of membrane proteins.

scholarly journals Rab8 and Rabin8-Mediated Tumor Formation by Hyperactivated EGFR Signaling via FGFR Signaling

2020 ◽  
Vol 21 (20) ◽  
pp. 7770
Author(s):  
Junghwa Choi ◽  
Jee Young Sung ◽  
Saerom Lee ◽  
Jungyoen Yoo ◽  
Christopher Rongo ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Tumor Model ◽  
Tumor Formation ◽  
Rab Proteins ◽  
Egfr Signaling ◽  
Vulval Development ◽  
C Elegans ◽  
Exon 19 Deletion ◽  
Epidermal Growth ◽  
Egfr Tki

The epidermal growth factor receptor (EGFR) signaling is important for normal development, such as vulval development in Caenorhabditis elegans, and hyperactivation of the EGFR is often associated with cancer development. Our previous report demonstrated the multivulva (Muv) phenotype, a tumor model in C. elegans (jgIs25 strain) by engineering LET-23/EGFR with a TKI-resistant human EGFR T790-L858 mutant. Because Rab proteins regulate vesicle transport, which is important for receptor signaling, we screened the RNAi in the jgIs25 strain to find the Rabs critical for Muv formation. Herein, we show that rab-8 RNAi and the rab-8 (-/-) mutation effectively reduce Muv formation. We demonstrate that RABN-8, an ortholog of Rabin8, known as a GEF for Rab8, is also required for Muv formation by promoting the secretion of EGL-17/FGF from vulval precursor cells. In addition, FGFR inhibitors decreased Muv formation mediated by mutant EGFR. Our data suggest that Rab8 and Rabin8 mediate Muv formation through FGF secretion in the EGFR-TKI-resistant nematode model. Furthermore, FGFR-TKIs more effectively inhibit the growth of lung cancer cell lines in H1975 (EGFR T790M-L858R; EGFR-TKI-resistant) than H522 (wild-type EGFR) and H1650 (EGFR exon 19 deletion; EGFR-TKI-sensitive) cells, suggesting that FGFR-TKIs could be used to control cancers with EGFR-TKI-resistant mutations.

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 Golgi localization of the LIN-2/7/10 complex points to a role in basolateral secretion of LET-23 EGFR in the C. elegans vulval precursor cells

Development ◽  
2021 ◽  
pp. dev.194167
Author(s):  
Kimberley D. Gauthier ◽  
Christian E. Rocheleau
Keyword(s):  
Cell Fate ◽  
Spatial Organization ◽  
Basolateral Membrane ◽  
Growth Factor Receptor ◽  
Precursor Cells ◽  
C Elegans ◽  
Receptor Localization ◽  
Epidermal Growth ◽  
Complex Forms

The evolutionarily conserved LIN-2 (CASK)/LIN-7 (Lin7A-C)/LIN-10 (APBA1) complex plays an important role in regulating spatial organization of membrane proteins and signaling components. In C. elegans, the complex is essential for development of the vulva by promoting the localization of the sole Epidermal Growth Factor Receptor (EGFR) orthologue, LET-23, to the basolateral membrane of the vulva precursor cells (VPCs) where it can specify the vulval cell fate. To understand how the LIN-2/7/10 complex regulates receptor localization, we determined its expression and localization during vulva development. We found that LIN-7 colocalizes with LET-23 EGFR at the basolateral membrane, whereas the LIN-2/7/10 complex colocalizes with LET-23 EGFR at cytoplasmic punctae, that mostly overlap with the Golgi. Furthermore, LIN-10 recruits LIN-2, which in turn recruits LIN-7. We demonstrate that the complex forms in vivo with particularly strong interaction and colocalization between LIN-2 and LIN-7 consistent with their forming a subcomplex. Thus, the LIN-2/7/10 complex forms on the Golgi where it likely targets LET-23 EGFR trafficking to the basolateral membrane rather than functioning as a tether.

scholarly journals Dynamic expression and localization of the LIN-2/7/10 protein scaffolding complex during C. elegans vulval development

2020 ◽  
Author(s):  
Kimberley D. Gauthier ◽  
Christian E. Rocheleau
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Spatial Organization ◽  
Basolateral Membrane ◽  
Growth Factor Receptor ◽  
C Elegans ◽  
Epidermal Growth ◽  
Complex Forms

AbstractThe evolutionarily conserved LIN-2 (CASK)/LIN-7 (Lin7A-C)/LIN-10 (APBA1) complex plays an important role in regulating spatial organization of membrane proteins and signaling components. In C. elegans, the complex is essential for development of the vulva by promoting the localization of the sole Epidermal Growth Factor Receptor (EGFR) orthologue, LET-23, to the basolateral membrane of the vulva precursor cells (VPCs) where it can specify the vulval cell fate. However, the expression and localization of the LIN-2/7/10 complex, and how the complex regulates receptor localization, are not known. Here we describe an in vivo analysis of the complex in C. elegans VPCs. Only LIN-7 colocalizes with LET-23 EGFR at the basolateral membrane, while the LIN-2/7/10 complex components instead colocalize at cytoplasmic foci, consistent with Golgi or endosomes. LIN-10 recruits LIN-2, which in turn recruits LIN-7. We demonstrate that the complex forms in vivo with particularly strong interaction and colocalization between LIN-2 and LIN-7. Our data suggest that the LIN-2/7/10 complex forms on endomembrane compartments where it likely targets LET-23 EGFR to the basolateral membrane, and point to distinct regulation between LIN-2/7 and LIN-10.Summary StatementLIN-10 recruits LIN-2 and LIN-7 to Golgi or recycling endosomes, consistent with targeting rather than tethering the epidermal growth factor receptor to the basolateral membrane in C. elegans.

scholarly journals Updated Insights on EGFR Signaling Pathways in Glioma

2021 ◽  
Vol 22 (2) ◽  
pp. 587
Author(s):  
Alexandru Oprita ◽  
Stefania-Carina Baloi ◽  
Georgiana-Adeline Staicu ◽  
Oana Alexandru ◽  
Daniela Elise Tache ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Standard Of Care ◽  
Egfr Signaling ◽  
Current Standard ◽  
Egfr Amplification ◽  
Epidermal Growth ◽  
New Diagnosis ◽  
Clear Clinical Benefit

Nowadays, due to recent advances in molecular biology, the pathogenesis of glioblastoma is better understood. For the newly diagnosed, the current standard of care is represented by resection followed by radiotherapy and temozolomide administration, but because median overall survival remains poor, new diagnosis and treatment strategies are needed. Due to the quick progression, even with aggressive multimodal treatment, glioblastoma remains almost incurable. It is known that epidermal growth factor receptor (EGFR) amplification is a characteristic of the classical subtype of glioma. However, targeted therapies against this type of receptor have not yet shown a clear clinical benefit. Many factors contribute to resistance, such as ineffective blood–brain barrier penetration, heterogeneity, mutations, as well as compensatory signaling pathways. A better understanding of the EGFR signaling network, and its interrelations with other pathways, are essential to clarify the mechanisms of resistance and create better therapeutic agents.

scholarly journals Dominant Enhancers of Egfr in Drosophila melanogaster: Genetic Links Between the Notch and Egfr Signaling Pathways

Genetics ◽  
1997 ◽  
Vol 147 (3) ◽  
pp. 1139-1153 ◽  
Author(s):  
James V Price ◽  
Edward D Savenye ◽  
David Lum ◽  
Ashton Breitkreutz
Keyword(s):  
Notch Signaling ◽  
Signaling Pathways ◽  
Growth Factor Receptor ◽  
Compound Eyes ◽  
Egfr Signaling ◽  
Wing Vein ◽  
Developmental Context ◽  
Epidermal Growth ◽  
Hypomorphic Alleles ◽  
Complex Signaling

The Drosophila epidermal growth factor receptor (EGFR) is a key component of a complex signaling pathway that participates in multiple developmental processes. We have performed and F1 screen for mutations that cause dominant enhancement of wing vein phenotypes associated with mutations in Egfr. With this screen, we have recovered mutations in Hairless (H), vein, groucho (gro), and three apparently novel loci. All of the E(Egfr)s we have identified show dominant interactions in transheterozygous combinations with each other and with alleles of N or Su(H), suggesting that they are involved in cross-talk between the N and EGFR signaling pathways. Further examination of the phenotypic interactions between Egfr, H, and gro revealed that reductions in Egfr activity enhanced both the bristle loss associated with H mutations, and the bristle hyperplasia and ocellar hypertrophy associated with gro mutations. Double mutant combinations of Egfr and gro hypomorphic alleles led to the formation of ectopic compound eyes in a dosage sensitive manner. Our findings suggest that these E(Egfr)s represent links between the Egfr and Notch signaling pathways, and that Egfr activity can either promote or suppress Notch signaling, depending on its developmental context.

scholarly journals Mdm2-Mediated Downmodulation of GRK2 Restricts Centrosome Separation for Proper Chromosome Congression

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 729
Author(s):  
Clara Reglero ◽  
Belén Ortiz del Castillo ◽  
Verónica Rivas ◽  
Federico Mayor ◽  
Petronila Penela
Keyword(s):  
Hippo Pathway ◽  
Growth Factor Receptor ◽  
Receptor Kinase ◽  
Egfr Signaling ◽  
Polyubiquitin Chains ◽  
Centrosome Separation ◽  
Chromosome Congression ◽  
Epidermal Growth ◽  
The Hippo Pathway ◽  
G Protein Coupled

The timing of centrosome separation and the distance moved apart influence the formation of the bipolar spindle, affecting chromosome stability. Epidermal growth factor receptor (EGFR) signaling induces early centrosome separation through downstream G protein-coupled receptor kinase GRK2, which phosphorylates the Hippo pathway component MST2 (Mammalian STE20-like protein kinase 2), in turn allowing NIMA kinase Nek2A activation for centrosomal linker disassembly. However, the mechanisms that counterbalance centrosome disjunction and separation remain poorly understood. We unveil that timely degradation of GRK2 by the E3 ligase Mdm2 limits centrosome separation in the G2. Both knockout expression and catalytic inhibition of Mdm2 result in GRK2 accumulation and enhanced centrosome separation before mitosis onset. Phosphorylation of GRK2 on residue S670 enables a complex pattern of non-K48-linked polyubiquitin chains assembled by Mdm2, which correlate with kinase protein degradation. Remarkably, GRK2-S670A protein fails to phosphorylate MST2 despite overcoming Mdm2-dependent degradation, which results in defective centrosome separation, shorter spindles, and abnormal chromosome congression. Conversely, extra levels of wild-type kinase in the G2 cause increased inter-centrosome distances with longer spindles, also converging in congression issues. Our findings show that the signals enabling activity of the GRK2/MST2/Nek2A axis for separation also switches on Mdm2 degradation of GRK2 to ensure accurate centrosome dynamics and proper mitotic spindle functionality.

scholarly journals CG6015 controls spermatogonia transit-amplifying divisions by epidermal growth factor receptor signaling in Drosophila testes

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Jun Yu ◽  
Qianwen Zheng ◽  
Zhiran Li ◽  
Yunhao Wu ◽  
Yangbo Fu ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Stem Cell ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Gene Set Enrichment Analysis ◽  
Germline Stem Cell ◽  
Egfr Signaling ◽  
Egfr Signaling Pathway ◽  
Epidermal Growth

AbstractSpermatogonia transit-amplifying (TA) divisions are crucial for the differentiation of germline stem cell daughters. However, the underlying mechanism is largely unknown. In the present study, we demonstrated that CG6015 was essential for spermatogonia TA-divisions and elongated spermatozoon development in Drosophila melanogaster. Spermatogonia deficient in CG6015 inhibited germline differentiation leading to the accumulation of undifferentiated cell populations. Transcriptome profiling using RNA sequencing indicated that CG6015 was involved in spermatogenesis, spermatid differentiation, and metabolic processes. Gene Set Enrichment Analysis (GSEA) revealed the relationship between CG6015 and the epidermal growth factor receptor (EGFR) signaling pathway. Unexpectedly, we discovered that phosphorylated extracellular regulated kinase (dpERK) signals were activated in germline stem cell (GSC)-like cells after reduction of CG6015 in spermatogonia. Moreover, Downstream of raf1 (Dsor1), a key downstream target of EGFR, mimicked the phenotype of CG6015, and germline dpERK signals were activated in spermatogonia of Dsor1 RNAi testes. Together, these findings revealed a potential regulatory mechanism of CG6015 via EGFR signaling during spermatogonia TA-divisions in Drosophila testes.

scholarly journals Assessment of epidermal growth factor receptor (EGFR) signaling in paired colorectal cancer and normal colon tissue samples using computer-aided immunohistochemical analysis

2005 ◽  
Vol 4 (12) ◽  
pp. 1381-1386 ◽  
Author(s):  
Wells Messersmith ◽  
Darin Oppenheimer ◽  
Josep Peralba ◽  
Valeria Sebastiani ◽  
Maria Amador ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Immunohistochemical Analysis ◽  
Egfr Signaling ◽  
Normal Colon ◽  
Colon Tissue ◽  
Tissue Samples ◽  
Computer Aided ◽  
Epidermal Growth
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