Revisiting the Role of TGFβ Receptor Internalization for Smad Signaling: It is Not Required in Optogenetic TGFβ Signaling Systems

Transforming growth factor (TGF)β is an important physiological regulator of cellular growth and differentiation. It activates a receptor threonine/serine kinase that phosphorylates the transcription factor Smad2, which then translocates into the nucleus to trigger specific transcriptional events. Here we show that activated type I and II TGFβ receptors internalize into endosomes containing the early endosomal protein EEA1. The extent of TGFβ-stimulated Smad2 phosphorylation, Smad2 nuclear translocation, and TGFβ-stimulated transcription correlated closely with the extent of internalization of the receptor. TGFβ signaling also requires SARA (Smad anchor for receptor activation), a 135-kD polypeptide that contains a FYVE Zn++ finger motif. Here we show that SARA localizes to endosomes containing EEA1, and that disruption of this localization inhibits TGFβ-induced Smad2 nuclear translocation. These results indicate that traffic of the TGFβ receptor into the endosome enables TGFβ signaling, revealing a novel function for the endosome as a compartment specialized for the amplification of certain extracellular signals.

Download Full-text

Faculty Opinions recommendation of The role of receptor internalization in CD95 signaling.

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

10.3410/f.1031197.363587 ◽

2006 ◽

Author(s):

Harald Stenmark

Keyword(s):

Receptor Internalization

Download Full-text

Chemical Genetics Reveals a Role of Squalene Synthase in TGFβ Signaling and Cardiomyogenesis

Angewandte Chemie International Edition ◽

10.1002/anie.202100523 ◽

2021 ◽

Author(s):

Yasushi Takemoto ◽

Shin Kadota ◽

Itsunari Minami ◽

Shinya Otsuka ◽

Satoshi Okuda ◽

...

Keyword(s):

Chemical Genetics ◽

Squalene Synthase ◽

Tgfβ Signaling

Download Full-text

Skeletal Deformities in Osterix-Cre;Tgfbr2f/f Mice May Cause Postnatal Death

Genes ◽

10.3390/genes12070975 ◽

2021 ◽

Vol 12 (7) ◽

pp. 975

Author(s):

Kara Corps ◽

Monica Stanwick ◽

Juliann Rectenwald ◽

Andrew Kruggel ◽

Sarah B. Peters

Keyword(s):

Transforming Growth Factor ◽

Skeletal Development ◽

Transforming Growth Factor Β ◽

Tgfβ Signaling ◽

Skeletal Deformities ◽

Tooth Abnormalities ◽

Pathological Analysis ◽

Diaphragmatic Muscle ◽

Proliferation And Differentiation ◽

Tgfβ Receptor

Transforming growth factor β (TGFβ) signaling plays an important role in skeletal development. We previously demonstrated that the loss of TGFβ receptor II (Tgfbr2) in Osterix-Cre-expressing mesenchyme results in defects in bones and teeth due to reduced proliferation and differentiation in pre-osteoblasts and pre-odontoblasts. These Osterix-Cre;Tgfbr2f/f mice typically die within approximately four weeks for unknown reasons. To investigate the cause of death, we performed extensive pathological analysis on Osterix-Cre- (Cre-), Osterix-Cre+;Tgfbr2f/wt (HET), and Osterix-Cre+;Tgfbr2f/f (CKO) mice. We also crossed Osterix-Cre mice with the ROSA26mTmG reporter line to identify potential off-target Cre expression. The findings recapitulated published skeletal and tooth abnormalities and revealed previously unreported osteochondral dysplasia throughout both the appendicular and axial skeletons in the CKO mice, including the calvaria. Alterations to the nasal area and teeth suggest a potentially reduced capacity to sense and process food, while off-target Cre expression in the gastrointestinal tract may indicate an inability to absorb nutrients. Additionally, altered nasal passages and unexplained changes in diaphragmatic muscle support the possibility of hypoxia. We conclude that these mice likely died due to a combination of breathing difficulties, malnutrition, and starvation resulting primarily from skeletal deformities that decreased their ability to sense, gather, and process food.

Download Full-text

Recapitulation of the Function and Role of ROS Generated in Response to Heat Stress in Plants

Plants ◽

10.3390/plants10020371 ◽

2021 ◽

Vol 10 (2) ◽

pp. 371

Author(s):

Emily Medina ◽

Su-Hwa Kim ◽

Miriam Yun ◽

Won-Gyu Choi

Keyword(s):

Heat Stress ◽

Plant Growth ◽

Intracellular Signaling ◽

Oxygen Species ◽

Natural Ecosystems ◽

Signaling Molecule ◽

Signaling Systems ◽

Cell Compartments ◽

Tropical Area

In natural ecosystems, plants are constantly exposed to changes in their surroundings as they grow, caused by a lifestyle that requires them to live where their seeds fall. Thus, plants strive to adapt and respond to changes in their exposed environment that change every moment. Heat stress that naturally occurs when plants grow in the summer or a tropical area adversely affects plants’ growth and poses a risk to plant development. When plants are subjected to heat stress, they recognize heat stress and respond using highly complex intracellular signaling systems such as reactive oxygen species (ROS). ROS was previously considered a byproduct that impairs plant growth. However, in recent studies, ROS gained attention for its function as a signaling molecule when plants respond to environmental stresses such as heat stress. In particular, ROS, produced in response to heat stress in various plant cell compartments such as mitochondria and chloroplasts, plays a crucial role as a signaling molecule that promotes plant growth and triggers subsequent downstream reactions. Therefore, this review aims to address the latest research trends and understandings, focusing on the function and role of ROS in responding and adapting plants to heat stress.

Download Full-text

Parathyroid hormone induces bone formation in phosphorylation-deficient PTHR1 knockin mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00380.2011 ◽

2012 ◽

Vol 302 (10) ◽

pp. E1183-E1188 ◽

Cited By ~ 6

Author(s):

Nabanita S. Datta ◽

Tareq A. Samra ◽

Abdul B. Abou-Samra

Keyword(s):

Parathyroid Hormone ◽

Bone Formation ◽

Physiological Role ◽

Receptor Internalization ◽

Mineral Density ◽

Trabecular Thickness ◽

Receptor Complexes ◽

Diaphyseal Bone ◽

Anabolic Action

Activation of G protein-coupled receptors by agonists leads to receptor phosphorylation, internalization of ligand receptor complexes, and desensitization of hormonal response. The role of parathyroid hormone (PTH) receptor 1, PTHR1, is well characterized and known to regulate cellular responsiveness in vitro. However, the role of PTHR1 phosphorylation in bone formation is yet to be investigated. We have previously demonstrated that impaired internalization and sustained cAMP stimulation of phosphorylation-deficient (PD) PTHR1 leads to exaggerated cAMP response to subcutaneous PTH infusion in a PD knockin mouse model. To understand the physiological role of receptor internalization on PTH bone anabolic action, we examined bone parameters of wild-type (WT) and PD knockin female and male mice following PTH treatment. We found a decrease in total and diaphyseal bone mineral density in female but not in male PD mice compared with WT controls at 3–6 mo of age. This effect was attenuated at older age groups. PTH administration displayed increased bone volume and trabecular thickness in the vertebrae and distal femora of both WT and PD animals. These results suggest that PTHR1 phosphorylation does not play a major role in the anabolic action of PTH.

Download Full-text