title: SENP1 deSUMOylates and regulates Pin1 protein activity and cellular function.
abstract: The Pin1 prolyl isomerase regulates phosphorylation signaling by controlling protein conformation after phosphorylation, and its upregulation promotes oncogenesis via acting on numerous oncogenic molecules. SUMOylation and deSUMOylation are dynamic mechanisms regulating a spectrum of protein activities. The SUMO proteases (SENP) remove SUMO conjugate from proteins, and their expression is deregulated in cancers. However, nothing is known about the role of SUMOylation in regulating Pin1 function. Here, we show that Pin1 is SUMOylated on Lys6 in the WW domain and on Lys63 in the PPIase domain. Pin1 SUMOylation inhibits its protein activity and oncogenic function. We further identify that SENP1 binds to and deSUMOylates Pin1. Importantly, either overexpression of SENP1 or disruption of Pin1 SUMOylation promotes the ability of Pin1 to induce centrosome amplification and cell transformation. Moreover, SENP1 also increases Pin1 protein stability in cell cultures, and Pin1 levels are positively correlated with SENP1 levels in human breast cancer specimens. These results not only uncover Pin1 SUMOylation on Lys6/63 as a novel mechanism to inhibit its activity and function but also identify a critical role for SENP1-mediated deSUMOylation in promoting Pin1 function during tumorigenesis.
authors: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors: Chun-Hau
authors: CH
authors: Chen
authors: Che-Chang
authors: CC
authors: Chang
authors: Tae Ho
authors: TH
authors: Lee
authors: Manli
authors: M
authors: Luo
authors: Pengyu
authors: P
authors: Huang
authors: Pei-Hsin
authors: PH
authors: Liao
authors: Shuo
authors: S
authors: Wei
authors: Fu-An
authors: FA
authors: Li
authors: Ruey-Hwa
authors: RH
authors: Chen
authors: Xiao Zhen
authors: XZ
authors: Zhou
authors: Hsiu-Ming
authors: HM
authors: Shih
authors: Kun Ping
authors: KP
authors: Lu
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D018385:Centrosome / Q000378:metabolism; D043171:Chromosomal Instability; D019938:Cyclin D1; D003546:Cysteine Endopeptidases; D010450:Endopeptidases / Q000378:metabolism*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D018384:Oxidative Stress; D019696:Peptidylprolyl Isomerase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D015398:Signal Transduction; D058207:Sumoylation
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019938:Cyclin D1; D010450:Endopeptidases; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse
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