Pin1 Down-regulates Transforming Growth Factor-β (TGF-β) Signaling by Inducing Degradation of Smad Proteins*

Transforming growth factor-β (TGF-β) is crucial in numerous cellular processes, such as proliferation, differentiation, migration, and apoptosis. TGF-β signaling is transduced by intracellular Smad proteins that are regulated by the ubiquitin-proteasome system. Smad ubiquitin regulatory factor 2 (Smurf2) prevents TGF-β and bone morphogenetic protein signaling by interacting with Smads and inducing their ubiquitin-mediated degradation. Here we identified Pin1, a peptidylprolyl cis-trans isomerase, as a novel protein binding Smads. Pin1 interacted with Smad2 and Smad3 but not Smad4; this interaction was enhanced by the phosphorylation of (S/T)P motifs in the Smad linker region. (S/T)P motif phosphorylation also enhanced the interaction of Smad2/3 with Smurf2. Pin1 reduced Smad2/3 protein levels in a manner dependent on its peptidyl-prolyl cis-trans isomerase activity. Knockdown of Pin1 increased the protein levels of endogenous Smad2/3. In addition, Pin1 both enhanced the interaction of Smurf2 with Smads and enhanced Smad ubiquitination. Pin1 inhibited TGF-β-induced transcription and gene expression, suggesting that Pin1 negatively regulates TGF-β signaling by down-regulating Smad2/3 protein levels via induction of Smurf2-mediated ubiquitin-proteasomal degradation.

[1]  K. Miyazawa,et al.  Smurf2 Induces Ubiquitin-dependent Degradation of Smurf1 to Prevent Migration of Breast Cancer Cells* , 2008, Journal of Biological Chemistry.

[2]  H. Aburatani,et al.  Pitx2 Prevents Osteoblastic Transdifferentiation of Myoblasts by Bone Morphogenetic Proteins* , 2008, Journal of Biological Chemistry.

[3]  Elisabeth S Yeh,et al.  PIN1, the cell cycle and cancer , 2007, Nature Reviews Cancer.

[4]  A. Brivanlou,et al.  Balancing BMP signaling through integrated inputs into the Smad1 linker. , 2007, Molecular cell.

[5]  J. Massagué,et al.  Smad transcription factors. , 2005, Genes & development.

[6]  H. Akiyama,et al.  Pin1 promotes production of Alzheimer's amyloid beta from beta-cleaved amyloid precursor protein. , 2005, Biochemical and biophysical research communications.

[7]  A. Mauviel,et al.  Crosstalk mechanisms between the mitogen-activated protein kinase pathways and Smad signaling downstream of TGF-β: implications for carcinogenesis , 2005, Oncogene.

[8]  Fang Liu,et al.  Identification and characterization of ERK MAP kinase phosphorylation sites in Smad3. , 2005, Biochemistry.

[9]  K. Miyazono,et al.  NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) negatively regulates TGF-β (transforming growth factor-β) signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-β type I receptor , 2005 .

[10]  Anita B. Roberts,et al.  Role of Rho/ROCK and p38 MAP Kinase Pathways in Transforming Growth Factor-β-mediated Smad-dependent Growth Inhibition of Human Breast Carcinoma Cells in Vivo* , 2004, Journal of Biological Chemistry.

[11]  Priti Garg,et al.  Modeling breast cancer in vivo and ex vivo reveals an essential role of Pin1 in tumorigenesis , 2004, The EMBO journal.

[12]  Philippe Soriano,et al.  In vivo convergence of BMP and MAPK signaling pathways: impact of differential Smad1 phosphorylation on development and homeostasis. , 2004, Genes & development.

[13]  J. Sowadski,et al.  Prevalent overexpression of prolyl isomerase Pin1 in human cancers. , 2004, The American journal of pathology.

[14]  Joseph R. Nevins,et al.  A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells , 2004, Nature Cell Biology.

[15]  T. Yokota,et al.  Involvement of Ras in extraembryonic endoderm differentiation of embryonic stem cells. , 2004, Biochemical and biophysical research communications.

[16]  J. Massagué.  Integration of Smad and MAPK pathways: a link and a linker revisited. , 2003, Genes & development.

[17]  J. Massagué,et al.  Cytostatic and apoptotic actions of TGF-β in homeostasis and cancer , 2003, Nature Reviews Cancer.

[18]  Ying E. Zhang,et al.  Smad-dependent and Smad-independent pathways in TGF-β family signalling , 2003, Nature.

[19]  K. Miyazono,et al.  Cooperative inhibition of bone morphogenetic protein signaling by Smurf1 and inhibitory Smads. , 2003, Molecular biology of the cell.

[20]  J. Massagué,et al.  Mechanisms of TGF-β Signaling from Cell Membrane to the Nucleus , 2003, Cell.

[21]  J. Gurdon,et al.  Nuclear exclusion of Smad2 is a mechanism leading to loss of competence , 2002, Nature Cell Biology.

[22]  Tianhua Niu,et al.  Pin1 is overexpressed in breast cancer and cooperates with Ras signaling in increasing the transcriptional activity of c‐Jun towards cyclin D1 , 2001, The EMBO journal.

[23]  Tomoki Chiba,et al.  Smurf1 Interacts with Transforming Growth Factor-β Type I Receptor through Smad7 and Induces Receptor Degradation* , 2001, The Journal of Biological Chemistry.

[24]  R. Derynck,et al.  Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[25]  J. Wrana,et al.  Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. , 2000, Molecular cell.

[26]  Xia Lin,et al.  Smurf2 Is a Ubiquitin E3 Ligase Mediating Proteasome-dependent Degradation of Smad2 in Transforming Growth Factor-β Signaling* 210 , 2000, The Journal of Biological Chemistry.

[27]  K. Miyazono,et al.  c-Ski Acts as a Transcriptional Co-repressor in Transforming Growth Factor-β Signaling through Interaction with Smads* , 1999, The Journal of Biological Chemistry.

[28]  C. Uchida,et al.  Mice lacking Pin1 develop normally, but are defective in entering cell cycle from G(0) arrest. , 1999, Biochemical and biophysical research communications.

[29]  Jeffrey L. Wrana,et al.  A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation , 1999, Nature.

[30]  J. Massagué,et al.  A mechanism of repression of TGFbeta/ Smad signaling by oncogenic Ras. , 1999, Genes & development.

[31]  K. Miyazono,et al.  Role of p300, a transcriptional coactivator, in signalling of TGF‐β , 1998, Genes to cells : devoted to molecular & cellular mechanisms.

[32]  Denis Vivien,et al.  Direct binding of Smad3 and Smad4 to critical TGFβ‐inducible elements in the promoter of human plasminogen activator inhibitor‐type 1 gene , 1998, The EMBO journal.

[33]  M. Kirschner,et al.  Sequence-specific and phosphorylation-dependent proline isomerization: a potential mitotic regulatory mechanism. , 1997, Science.

[34]  Kohei Miyazono,et al.  TGF-β signalling from cell membrane to nucleus through SMAD proteins , 1997, Nature.

[35]  M. Kretzschmar,et al.  Opposing BMP and EGF signalling pathways converge on the TGF-β family mediator Smad1 , 1997, Nature.

[36]  R. Ranganathan,et al.  Structural and Functional Analysis of the Mitotic Rotamase Pin1 Suggests Substrate Recognition Is Phosphorylation Dependent , 1997, Cell.

[37]  Activation of (cid:2) -Catenin Signaling in Prostate Cancer by Peptidyl-Prolyl Isomerase Pin1-Mediated Abrogation of the Androgen Receptor– (cid:2) -Catenin Interaction , 2022 .