title: Regulation of TGFβ receptor trafficking and signaling by atypical protein kinase C.
abstract: Transforming growth factor beta (TGFβ) signaling is linked to the membrane trafficking of TGFβ receptors. The Protein Kinase C (PKC) family of serine/threonine kinases have been implicated in modulating the endocytic processes of various receptors. The present study investigated whether PKC activity plays a role in the trafficking, and signaling of TGFβ receptors, and further explored which PKC isoforms may be responsible for altered TGFβ signaling patterns. Using immunofluorescence microscopy and (125)I-TGFβ internalization assays, we show that the pharmacological inhibition of PKC activity alters TGFβ receptor trafficking and delays TGFβ receptor degradation. Consistent with these findings, we demonstrate that PKC inhibition extends TGFβ-dependent Smad2 phosphorylation. Previous studies have shown that PKCζ associates with TGFβ receptors to modulate cell plasticity. We therefore used siRNA directed at the atypical PKC isoforms to investigate if reducing PKCι and PKCζ protein levels would delay TGFβ receptor degradation and extend TGFβ signaling. Our findings suggest that atypical PKC isoforms regulate TGFβ signaling by altering cell surface TGFβ receptor trafficking and degradation.
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada.
authors.forename: Adrian
authors.initials: A
authors.lastname: Gunaratne
authors.forename: Hassina
authors.initials: H
authors.lastname: Benchabane
authors.forename: Gianni M
authors.initials: GM
authors.lastname: Di Guglielmo
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D021941:Caveolae / Q000378:metabolism; D002460:Cell Line; D011992:Endosomes / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006207:Half-Life; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008301:Maleimides / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D059748:Proteolysis; D034622:RNA Interference; D051381:Rats; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology
chemical_list: D002227:Carbazoles; D007211:Indoles; D007527:Isoenzymes; D008301:Maleimides; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; C081021:Go 6976; C115015:PKC-3 protein; D011493:Protein Kinase C; C070515:bisindolylmaleimide I