Pin1 promotes transforming growth factor-β-induced migration and invasion

Isao Matsuura, Keng Nan Chiang, Chen Yu Lai, Dongming He, Guannan Wang, Romila Ramkumar, Takafumi Uchida, Akihide Ryo, Kunping Lu, Fang Liu

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

Transforming growth factor-β(TGF-β) regulates a wide variety of biological activities. It induces potent growth-inhibitory responses in normal cells but promotes migration and invasion of cancer cells. Smads mediate the TGF-β responses. TGF-β binding to the cell surface receptors leads to the phosphorylation of Smad2/3 in their Cterminus as well as in the proline-rich linker region. The serine/threonine phosphorylation sites in the linker region are followed by the proline residue. Pin1, a peptidyl-prolyl cis/trans isomerase, recognizes phosphorylated serine/threonine-proline motifs. Here we show that Smad2/3 interacts with Pin1 in a TGF-β-dependent manner. We further show that the phosphorylated threonine 179-proline motif in the Smad3 linker region is the major binding site for Pin1. Although epidermal growth factor also induces phosphorylation of threonine 179 and other residues in the Smad3 linker region the same as TGF-β, Pin1 is unable to bind to the epidermal growth factor-stimulated Smad3. Further analysis suggests that phosphorylation of Smad3 in the C terminus is necessary for the interaction with Pin1. Depletion of Pin1 by small hairpin RNA does not significantly affect TGF-β-induced growth-inhibitory responses and a number of TGF-β/Smad target genes analyzed. In contrast, knockdown of Pin1 in human PC3 prostate cancer cells strongly inhibited TGF-β-mediated migration and invasion. Accordingly, TGF-β induction of N-cadherin, which plays an important role in migration and invasion, is markedly reduced when Pin1 is depleted in PC3 cells. Because Pin1 is overexpressed in many cancers, our findings highlight the importance of Pin1 in TGF-β-induced migration and invasion of cancer cells.

Original languageEnglish (US)
Pages (from-to)1754-1764
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number3
DOIs
StatePublished - Jan 15 2010

Fingerprint

Phosphorylation
Transforming Growth Factors
Threonine
Proline
Cells
Epidermal Growth Factor
Serine
Peptidylprolyl Isomerase
Neoplasms
Cell Surface Receptors
Cadherins
Growth
Bioactivity
Small Interfering RNA
Cell Movement
Prostatic Neoplasms
Genes
Binding Sites

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Biochemistry
  • Cell Biology

Cite this

Matsuura, Isao ; Chiang, Keng Nan ; Lai, Chen Yu ; He, Dongming ; Wang, Guannan ; Ramkumar, Romila ; Uchida, Takafumi ; Ryo, Akihide ; Lu, Kunping ; Liu, Fang. / Pin1 promotes transforming growth factor-β-induced migration and invasion. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 3. pp. 1754-1764.
@article{60eba693a0a445e09ccdc180b41c3062,
title = "Pin1 promotes transforming growth factor-β-induced migration and invasion",
abstract = "Transforming growth factor-β(TGF-β) regulates a wide variety of biological activities. It induces potent growth-inhibitory responses in normal cells but promotes migration and invasion of cancer cells. Smads mediate the TGF-β responses. TGF-β binding to the cell surface receptors leads to the phosphorylation of Smad2/3 in their Cterminus as well as in the proline-rich linker region. The serine/threonine phosphorylation sites in the linker region are followed by the proline residue. Pin1, a peptidyl-prolyl cis/trans isomerase, recognizes phosphorylated serine/threonine-proline motifs. Here we show that Smad2/3 interacts with Pin1 in a TGF-β-dependent manner. We further show that the phosphorylated threonine 179-proline motif in the Smad3 linker region is the major binding site for Pin1. Although epidermal growth factor also induces phosphorylation of threonine 179 and other residues in the Smad3 linker region the same as TGF-β, Pin1 is unable to bind to the epidermal growth factor-stimulated Smad3. Further analysis suggests that phosphorylation of Smad3 in the C terminus is necessary for the interaction with Pin1. Depletion of Pin1 by small hairpin RNA does not significantly affect TGF-β-induced growth-inhibitory responses and a number of TGF-β/Smad target genes analyzed. In contrast, knockdown of Pin1 in human PC3 prostate cancer cells strongly inhibited TGF-β-mediated migration and invasion. Accordingly, TGF-β induction of N-cadherin, which plays an important role in migration and invasion, is markedly reduced when Pin1 is depleted in PC3 cells. Because Pin1 is overexpressed in many cancers, our findings highlight the importance of Pin1 in TGF-β-induced migration and invasion of cancer cells.",
author = "Isao Matsuura and Chiang, {Keng Nan} and Lai, {Chen Yu} and Dongming He and Guannan Wang and Romila Ramkumar and Takafumi Uchida and Akihide Ryo and Kunping Lu and Fang Liu",
year = "2010",
month = "1",
day = "15",
doi = "https://doi.org/10.1074/jbc.M109.063826",
language = "English (US)",
volume = "285",
pages = "1754--1764",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "3",

}

Matsuura, I, Chiang, KN, Lai, CY, He, D, Wang, G, Ramkumar, R, Uchida, T, Ryo, A, Lu, K & Liu, F 2010, 'Pin1 promotes transforming growth factor-β-induced migration and invasion', Journal of Biological Chemistry, vol. 285, no. 3, pp. 1754-1764. https://doi.org/10.1074/jbc.M109.063826

Pin1 promotes transforming growth factor-β-induced migration and invasion. / Matsuura, Isao; Chiang, Keng Nan; Lai, Chen Yu; He, Dongming; Wang, Guannan; Ramkumar, Romila; Uchida, Takafumi; Ryo, Akihide; Lu, Kunping; Liu, Fang.

In: Journal of Biological Chemistry, Vol. 285, No. 3, 15.01.2010, p. 1754-1764.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Pin1 promotes transforming growth factor-β-induced migration and invasion

AU - Matsuura, Isao

AU - Chiang, Keng Nan

AU - Lai, Chen Yu

AU - He, Dongming

AU - Wang, Guannan

AU - Ramkumar, Romila

AU - Uchida, Takafumi

AU - Ryo, Akihide

AU - Lu, Kunping

AU - Liu, Fang

PY - 2010/1/15

Y1 - 2010/1/15

N2 - Transforming growth factor-β(TGF-β) regulates a wide variety of biological activities. It induces potent growth-inhibitory responses in normal cells but promotes migration and invasion of cancer cells. Smads mediate the TGF-β responses. TGF-β binding to the cell surface receptors leads to the phosphorylation of Smad2/3 in their Cterminus as well as in the proline-rich linker region. The serine/threonine phosphorylation sites in the linker region are followed by the proline residue. Pin1, a peptidyl-prolyl cis/trans isomerase, recognizes phosphorylated serine/threonine-proline motifs. Here we show that Smad2/3 interacts with Pin1 in a TGF-β-dependent manner. We further show that the phosphorylated threonine 179-proline motif in the Smad3 linker region is the major binding site for Pin1. Although epidermal growth factor also induces phosphorylation of threonine 179 and other residues in the Smad3 linker region the same as TGF-β, Pin1 is unable to bind to the epidermal growth factor-stimulated Smad3. Further analysis suggests that phosphorylation of Smad3 in the C terminus is necessary for the interaction with Pin1. Depletion of Pin1 by small hairpin RNA does not significantly affect TGF-β-induced growth-inhibitory responses and a number of TGF-β/Smad target genes analyzed. In contrast, knockdown of Pin1 in human PC3 prostate cancer cells strongly inhibited TGF-β-mediated migration and invasion. Accordingly, TGF-β induction of N-cadherin, which plays an important role in migration and invasion, is markedly reduced when Pin1 is depleted in PC3 cells. Because Pin1 is overexpressed in many cancers, our findings highlight the importance of Pin1 in TGF-β-induced migration and invasion of cancer cells.

AB - Transforming growth factor-β(TGF-β) regulates a wide variety of biological activities. It induces potent growth-inhibitory responses in normal cells but promotes migration and invasion of cancer cells. Smads mediate the TGF-β responses. TGF-β binding to the cell surface receptors leads to the phosphorylation of Smad2/3 in their Cterminus as well as in the proline-rich linker region. The serine/threonine phosphorylation sites in the linker region are followed by the proline residue. Pin1, a peptidyl-prolyl cis/trans isomerase, recognizes phosphorylated serine/threonine-proline motifs. Here we show that Smad2/3 interacts with Pin1 in a TGF-β-dependent manner. We further show that the phosphorylated threonine 179-proline motif in the Smad3 linker region is the major binding site for Pin1. Although epidermal growth factor also induces phosphorylation of threonine 179 and other residues in the Smad3 linker region the same as TGF-β, Pin1 is unable to bind to the epidermal growth factor-stimulated Smad3. Further analysis suggests that phosphorylation of Smad3 in the C terminus is necessary for the interaction with Pin1. Depletion of Pin1 by small hairpin RNA does not significantly affect TGF-β-induced growth-inhibitory responses and a number of TGF-β/Smad target genes analyzed. In contrast, knockdown of Pin1 in human PC3 prostate cancer cells strongly inhibited TGF-β-mediated migration and invasion. Accordingly, TGF-β induction of N-cadherin, which plays an important role in migration and invasion, is markedly reduced when Pin1 is depleted in PC3 cells. Because Pin1 is overexpressed in many cancers, our findings highlight the importance of Pin1 in TGF-β-induced migration and invasion of cancer cells.

UR - http://www.scopus.com/inward/record.url?scp=76249090037&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=76249090037&partnerID=8YFLogxK

U2 - https://doi.org/10.1074/jbc.M109.063826

DO - https://doi.org/10.1074/jbc.M109.063826

M3 - Article

C2 - 19920136

VL - 285

SP - 1754

EP - 1764

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 3

ER -

Matsuura I, Chiang KN, Lai CY, He D, Wang G, Ramkumar R et al. Pin1 promotes transforming growth factor-β-induced migration and invasion. Journal of Biological Chemistry. 2010 Jan 15;285(3):1754-1764. https://doi.org/10.1074/jbc.M109.063826