A miR‐29a‐driven negative feedback loop regulates peripheral glucocorticoid receptor signaling

Activation of the EGF receptor tyrosine kinase by ligand indirectly activates a series of other cellular enzymes, including protein kinase C. To test the hypothesis that phosphorylation of the EGF receptor by protein kinase C provides an intracellular negative feedback loop to attenuate EGF receptor signaling, we used scanning EM to follow the characteristic EGF-induced retraction of lamellipodia and concomitant cell shape changes. Wild type and mutant EGF receptors were expressed in receptor-deficient NR6 cells. The mutant receptors were prepared by truncation at C' terminal residue 973 (c'973) to provide resistance to ligand-induced down regulation that strongly attenuates receptor signaling and by replacement of threonine 654 (T654) with alanine (A654) to remove the site of phosphorylation by protein kinase C. Cells expressing WT and c'973 EGF receptors demonstrated characteristic lamellipodial retraction after exposure to EGF, with the non-down regulating c'973 EGF receptors responding more rapidly. Exposure of cells to TPA blocked this response. Replacement of T654 by alanine resulted in EGF receptors that were resistant to TPA. Cells expressing the A654 mutation underwent more rapid and more extensive morphologic changes than cells with the corresponding T654 EGF receptor. In cells expressing T654 EGF receptors, down regulation of protein kinase C resulted in more rapid and extensive EGF-induced changes similar to those seen in cells expressing A654 EGF receptors. These data indicate that activation of protein kinase C and subsequent phosphorylation of the EGF receptor at T654 lead to rapid physiological attenuation of EGF receptor signaling.

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Faculty Opinions recommendation of NF-κB induction of the SUMO protease SENP2: A negative feedback loop to attenuate cell survival response to genotoxic stress.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.12315958.13489058 ◽

2011 ◽

Author(s):

Andreas Villunger ◽

Florian Bock

Keyword(s):

Cell Survival ◽

Negative Feedback ◽

Feedback Loop ◽

Genotoxic Stress ◽

Negative Feedback Loop ◽

Sumo Protease

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Faculty Opinions recommendation of REVEILLE8 and PSEUDO-REPONSE REGULATOR5 form a negative feedback loop within the Arabidopsis circadian clock.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718048365.793488625 ◽

2013 ◽

Author(s):

C Robertson McClung

Keyword(s):

Circadian Clock ◽

Negative Feedback ◽

Feedback Loop ◽

Negative Feedback Loop

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Faculty Opinions recommendation of EFA6 controls Arf1 and Arf6 activation through a negative feedback loop.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718528121.793498466 ◽

2014 ◽

Author(s):

Chris Fromme

Keyword(s):

Negative Feedback ◽

Feedback Loop ◽

Negative Feedback Loop

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Smad2/3 Activation Regulates Smad1/5/8 Signaling via a Negative Feedback Loop to Inhibit 3T3-L1 Adipogenesis

International Journal of Molecular Sciences ◽

10.3390/ijms22168472 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8472

Author(s):

Senem Aykul ◽

Jordan Maust ◽

Vijayalakshmi Thamilselvan ◽

Monique Floer ◽

Erik Martinez-Hackert

Keyword(s):

Negative Feedback ◽

Feedback Loop ◽

Negative Feedback Loop ◽

Adipose Tissues ◽

Family Growth ◽

Simultaneous Activation ◽

Adipocyte Hypertrophy ◽

Adipocyte Development ◽

Energy Surplus

Adipose tissues (AT) expand in response to energy surplus through adipocyte hypertrophy and hyperplasia. The latter, also known as adipogenesis, is a process by which multipotent precursors differentiate to form mature adipocytes. This process is directed by developmental cues that include members of the TGF-β family. Our goal here was to elucidate, using the 3T3-L1 adipogenesis model, how TGF-β family growth factors and inhibitors regulate adipocyte development. We show that ligands of the Activin and TGF-β families, several ligand traps, and the SMAD1/5/8 signaling inhibitor LDN-193189 profoundly suppressed 3T3-L1 adipogenesis. Strikingly, anti-adipogenic traps and ligands engaged the same mechanism of action involving the simultaneous activation of SMAD2/3 and inhibition of SMAD1/5/8 signaling. This effect was rescued by the SMAD2/3 signaling inhibitor SB-431542. By contrast, although LDN-193189 also suppressed SMAD1/5/8 signaling and adipogenesis, its effect could not be rescued by SB-431542. Collectively, these findings reveal the fundamental role of SMAD1/5/8 for 3T3-L1 adipogenesis, and potentially identify a negative feedback loop that links SMAD2/3 activation with SMAD1/5/8 inhibition in adipogenic precursors.

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