CIN85 modulates TGFβ signaling by promoting the presentation of TGFβ receptors on the cell surface.
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Yakymovych I, Yakymovych M, Zang G, Mu Y, Bergh A, Landström M, Heldin CH
J. Cell Biol. 210 (2) 319-332 [2015-07-20; online 2015-07-13]
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.
PubMed 26169354
DOI 10.1083/jcb.201411025
Crossref 10.1083/jcb.201411025
pii: jcb.201411025
pmc: PMC4508896
RefSeq: NM_031892
SWISSPROT: P20338
SWISSPROT: P36897
SWISSPROT: P37173
SWISSPROT: P62491
SWISSPROT: P70196
SWISSPROT: Q96B97