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SNX25 regulates TGF-beta signaling by enhancing the receptor degradation

Abstract: SNXs (sorting nexin), a family of proteins playing roles in cargo sorting and signaling from compartments within the endocytic network, regulate traffic of membrane proteins including TGF-beta receptors. Here we report that the full length human and mouse SNX25, a SNX member with PX, PXA and RGS domains, colocalizes with TGF-beta receptors, and forms internalized cytosolic punctae upon treatment with TGF-beta. While overexpression of SNX25 inhibits TGF-beta induced luciferase reporter activity, knocking down endogenous SNX25 by siRNA in NIH3T3 cells elevates the TGF-beta receptor levels and facilitates TGF-beta signaling. Immunoprecipitation experiments demonstrate that SNX25 interacts with T beta RI. Western blot analyses indicate that SNX25 enhances the degradation of TGF-beta receptors. SNX25 induced TGF-beta receptor degradation is shown via the clathrin dependent endocytosis pathway into lysosome. We have characterized that PXA domain of SNX25 is required for the degradation of T beta RI. Our findings demonstrate that SNX25 negatively regulates TGF-beta signaling by enhancing the receptor degradation through lysosome pathway.