title: CIN85 modulates TGFβ signaling by promoting the presentation of TGFβ receptors on the cell surface.
abstract: Members of the transforming growth factor β (TGFβ) family initiate cellular responses by binding to TGFβ receptor type II (TβRII) and type I (TβRI) serine/threonine kinases, whereby Smad2 and Smad3 are phosphorylated and activated, promoting their association with Smad4. We report here that TβRI interacts with the SH3 domains of the adaptor protein CIN85 in response to TGFβ stimulation in a TRAF6-dependent manner. Small interfering RNA-mediated knockdown of CIN85 resulted in accumulation of TβRI in intracellular compartments and diminished TGFβ-stimulated Smad2 phosphorylation. Overexpression of CIN85 instead increased the amount of TβRI at the cell surface. This effect was inhibited by a dominant-negative mutant of Rab11, suggesting that CIN85 promoted recycling of TGFβ receptors. CIN85 enhanced TGFβ-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 TGFβ receptors and thereby positively regulates TGFβ signaling.
authors.affiliation: Science for Life Laboratory, Ludwig Institute for Cancer Research Ltd., Uppsala University, SE-75124 Uppsala, Sweden.
authors.forename: Ihor
authors.initials: I
authors.lastname: Yakymovych
authors.affiliation: Science for Life Laboratory, Ludwig Institute for Cancer Research Ltd., Uppsala University, SE-75124 Uppsala, Sweden.
authors.forename: Mariya
authors.initials: M
authors.lastname: Yakymovych
authors.affiliation: Department of Medical Biosciences and Pathology, Umeå University, SE-90185 Umeå, Sweden.
authors.forename: Guangxiang
authors.initials: G
authors.lastname: Zang
authors.affiliation: Department of Medical Biosciences and Pathology, Umeå University, SE-90185 Umeå, Sweden.
authors.forename: Yabing
authors.initials: Y
authors.lastname: Mu
authors.affiliation: Department of Medical Biosciences and Pathology, Umeå University, SE-90185 Umeå, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Bergh
authors.affiliation: Science for Life Laboratory, Ludwig Institute for Cancer Research Ltd., Uppsala University, SE-75124 Uppsala, Sweden Department of Medical Biosciences and Pathology, Umeå University, SE-90185 Umeå, Sweden.
authors.forename: Maréne
authors.initials: M
authors.lastname: Landström
authors.affiliation: Science for Life Laboratory, Ludwig Institute for Cancer Research Ltd., Uppsala University, SE-75124 Uppsala, Sweden c-h.heldin@licr.uu.se.
authors.forename: Carl-Henrik
authors.initials: CH
authors.lastname: Heldin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D011471:Prostatic Neoplasms / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D021381:Protein Transport; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000502:physiology*; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018125:Receptors, Transforming Growth Factor beta; D048029:TNF Receptor-Associated Factor 6; D016212:Transforming Growth Factor beta; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C433810:SH3KBP1 protein, human