An ionic lock and a hydrophobic zipper mediate the coupling between an insect pheromone receptor BmOR3 and downstream effectors

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.

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Extracellular Modulation of the Silkmoth Sex Pheromone Receptor Activity by Cyclic Nucleotides

PLoS ONE ◽

10.1371/journal.pone.0063774 ◽

2013 ◽

Vol 8 (6) ◽

pp. e63774 ◽

Cited By ~ 6

Author(s):

Tatsuro Nakagawa ◽

Kazushige Touhara

Keyword(s):

Sex Pheromone ◽

Cyclic Nucleotides ◽

Receptor Activity ◽

Pheromone Receptor

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Potential targeted therapy and diagnosis based on novel insight into growth factors, receptors, and downstream effectors in acute kidney injury and acute kidney injury-chronic kidney disease progression

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-020-0106-1 ◽

2020 ◽

Vol 5 (1) ◽

Cited By ~ 6

Author(s):

Li Gao ◽

Xiang Zhong ◽

Juan Jin ◽

Jun Li ◽

Xiao-ming Meng

Keyword(s):

Chronic Kidney Disease ◽

Acute Kidney Injury ◽

Growth Factors ◽

Targeted Therapy ◽

Kidney Injury ◽

Chronic Kidney Disease Progression ◽

Downstream Effectors ◽

Kidney Disease Progression ◽

Therapy And Diagnosis ◽

Insight Into

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The noncoding MIR100HG RNA enhances the autocrine function of transforming growth factor β signaling

Oncogene ◽

10.1038/s41388-021-01803-8 ◽

2021 ◽

Author(s):

Panagiotis Papoutsoglou ◽

Dorival Mendes Rodrigues-Junior ◽

Anita Morén ◽

Andrew Bergman ◽

Fredrik Pontén ◽

...

Keyword(s):

Growth Factor ◽

Target Genes ◽

Rna Binding ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Tgfβ Signaling ◽

Ribonucleoprotein Complexes ◽

Expression Of Genes ◽

Downstream Effectors ◽

Human Carcinomas

AbstractActivation of the transforming growth factor β (TGFβ) pathway modulates the expression of genes involved in cell growth arrest, motility, and embryogenesis. An expression screen for long noncoding RNAs indicated that TGFβ induced mir-100-let-7a-2-mir-125b-1 cluster host gene (MIR100HG) expression in diverse cancer types, thus confirming an earlier demonstration of TGFβ-mediated transcriptional induction of MIR100HG in pancreatic adenocarcinoma. MIR100HG depletion attenuated TGFβ signaling, expression of TGFβ-target genes, and TGFβ-mediated cell cycle arrest. Moreover, MIR100HG silencing inhibited both normal and cancer cell motility and enhanced the cytotoxicity of cytostatic drugs. MIR100HG overexpression had an inverse impact on TGFβ signaling responses. Screening for downstream effectors of MIR100HG identified the ligand TGFβ1. MIR100HG and TGFB1 mRNA formed ribonucleoprotein complexes with the RNA-binding protein HuR, promoting TGFβ1 cytokine secretion. In addition, TGFβ regulated let-7a-2–3p, miR-125b-5p, and miR-125b-1–3p expression, all encoded by MIR100HG intron-3. Certain intron-3 miRNAs may be involved in TGFβ/SMAD-mediated responses (let-7a-2–3p) and others (miR-100, miR-125b) in resistance to cytotoxic drugs mediated by MIR100HG. In support of a model whereby TGFβ induces MIR100HG, which then enhances TGFβ1 secretion, analysis of human carcinomas showed that MIR100HG expression correlated with expression of TGFB1 and its downstream extracellular target TGFBI. Thus, MIR100HG controls the magnitude of TGFβ signaling via TGFβ1 autoinduction and secretion in carcinomas.

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