βarrestin2 interacts with TβRII to regulate Smad-dependent and Smad-independent signal transduction.
The Transforming Growth Factor beta (TGFβ) signaling pathway is necessary for a variety of normal cellular processes. However, the distinct mechanisms involved in TGFβ receptor turnover and the effect on signal transduction have yet to be fully elucidated. We have previously shown that TβRIII is able to interact with the TβRII/TβRI complex to increase clathrin-dependent endocytosis and receptor half-life. Others have shown that βarrestin2 binds TβRIII to mediate TβRII/TβRIII endocytosis. To further understand the mechanism regulating TGFβ receptor signaling, we evaluated the role of βarrestin2 in TGFβ receptor signal transduction, half-life and trafficking. We have found that TβRII binds βarrestin2 in the absence of TβRIII. Furthermore, using immunofluorescence microscopy we show that βarrestin2 traffics to the early endosome with TβRII. We investigated the effect of loss of βarrestin2 on TβRII dynamics and found that loss of βarrestin2 increases steady-state levels of TβRII at the cell surface. The interaction of TβRII with βarrestin2 is involved in modulating TGFβ signal transduction, as loss of βarrestin2 increases the phosphorylation of p38 and modestly affects pSmad levels. Using a luciferase assay to assess TGFβ-dependent transcription we show that loss of βarrestin2 decreases Smad-dependent TGFβ-stimulated transcription. Furthermore, loss of βarrestin2 increases p38 signal transduction, which correlated with increased cell death via apoptosis. Overall, our results suggest a role for βarrestin2 in the regulation of Smad-dependent and independent TGFβ pathways.
Department of Physiology and Pharmacology, Western University, London, Ontario, Canada.
Sarah
S
McLean
Moshmi
M
Bhattacharya
Gianni M
GM
Di Guglielmo
D017209:Apoptosis; D019390:Arrestins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011509:Proteoglycans / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D000071557:beta-Arrestins; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D019390:Arrestins; D047908:Intracellular Signaling Peptides and Proteins; D011509:Proteoglycans; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D000071557:beta-Arrestins; C071736:betaglycan; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; C116420:ZFYVE16 protein, human; D012697:Serine Endopeptidases