CIN85 modulates TGF beta signaling by promoting the presentation of TGF beta receptors on the cell surface
2015 (English)In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 210, no 2, 319-332 p.Article in journal (Refereed) Published
Members of the transforming growth factor beta (TGF beta) family initiate cellular responses by binding to TGF beta receptor type II (Tf3R11) and type I (TpRI) serine/threonine kinases, whereby Srnad2 and Smad3 are phosphorylated and activated, promoting their association with Smadzi. We report here that T beta RI interacts with the SH3 domains of the adaptor protein CIN85 in response to TGF beta stimulation in a TRAF6-dependent manner. Small interfering RNA mediated knockdown of CIN85 resulted in accumulation of T beta RI in intracellular compartments and diminished TGF beta-stimulated Sniad2 phosphorylation. Overexpression of CIN85 instead increased the amount of T beta RI at the cell surface. This effect was inhibited by a dominant-negative mutant of Rab11, suggesting that CIN85 promoted recycling of TGF beta receptors. CIN85 enhanced TGF beta-stimulated Smad2 phosphorylation, transcriptional responses, and cell migration. CIN85 expression correlated with the degree of malignancy of prostate cancers. Collectively, our results reveal that CIN85 promotes recycling of TGF beta receptors and thereby positively regulates TGF beta signaling.
Place, publisher, year, edition, pages
2015. Vol. 210, no 2, 319-332 p.
Cancer and Oncology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
IdentifiersURN: urn:nbn:se:uu:diva-260622DOI: 10.1083/jcb.201411025ISI: 000358457300012OAI: oai:DiVA.org:uu-260622DiVA: diva2:848131
FunderKnut and Alice Wallenberg Foundation, 2012.0090Swedish Cancer Society, 13 0688
Funding: Ludwig Institute for Cancer Research, Swedish Medical Research Council K2013-66X-15284-04-42015-08-242015-08-212016-01-14Bibliographically approved