PDZK1 prevents neointima formation via suppression of breakpoint cluster region kinase in vascular smooth muscle

Wan Ru Lee, Anastasia Sacharidou, Erica Behling-Kelly, Sarah C. Oltmann, Weifei Zhu, Mohamed Ahmed, Robert D. Gerard, David Y. Hui, Jun Ichi Abe, Philip W. Shaul, Chieko Mineo

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Scavenger receptor class B, type I (SR-BI) and its adaptor protein PDZK1 mediate responses to HDL cholesterol in endothelium. Whether the receptor-adaptor protein tandem serves functions in other vascular cell types is unknown. The current work determined the roles of SR-BI and PDZK1 in vascular smooth muscle (VSM). To evaluate possible VSM functions of SR-BI and PDZK1 in vivo, neointima formation was assessed 21 days post-ligation in the carotid arteries of wild-type, SR-BI<sup>-/-</sup> or PDZK1<sup>-/-</sup> mice. Whereas neointima development was negligible in wild-type and SR-BI<sup>-/-</sup>, there was marked neointima formation in PDZK1<sup>-/-</sup> mice. PDZK1 expression was demonstrated in primary mouse VSM cells, and compared to wild-type cells, PDZK1<sup>-/-</sup> VSM displayed exaggerated proliferation and migration in response to platelet derived growth factor (PDGF). Tandem affinity purification-mass spectrometry revealed that PDZK1 interacts with breakpoint cluster region kinase (Bcr), which contains a C-terminal PDZ binding sequence and is known to enhance responses to PDGF in VSM. PDZK1 interaction with Bcr in VSM was demonstrated by pull-down and by coimmunoprecipitation, and the augmented proliferative response to PDGF in PDZK1<sup>-/-</sup>VSM was abrogated by Bcr depletion. Furthermore, compared with wild-type Bcr overexpression, the introduction of a Bcr mutant incapable of PDZK1 binding into VSM cells yielded an exaggerated proliferative response to PDGF. Thus, PDZK1 has novel SR-BIPLOS independent function in VSM that affords protection from neointima formation, and this involves PDZK1 suppression of VSM cell proliferation via an inhibitory interaction with Bcr.

Original languageEnglish (US)
Article numbere0124494
JournalPLoS One
Volume10
Issue number4
DOIs
StatePublished - Apr 17 2015

Fingerprint

Neointima
Vascular Smooth Muscle
blood vessels
smooth muscle
Muscle
phosphotransferases (kinases)
Phosphotransferases
CD36 Antigens
platelet-derived growth factor
Platelet-Derived Growth Factor
receptors
Smooth Muscle Myocytes
myocytes
mice
Cell proliferation
carotid arteries
Carotid Arteries
HDL Cholesterol
endothelium
Endothelium

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

PDZK1 prevents neointima formation via suppression of breakpoint cluster region kinase in vascular smooth muscle. / Lee, Wan Ru; Sacharidou, Anastasia; Behling-Kelly, Erica; Oltmann, Sarah C.; Zhu, Weifei; Ahmed, Mohamed; Gerard, Robert D.; Hui, David Y.; Abe, Jun Ichi; Shaul, Philip W.; Mineo, Chieko.

In: PLoS One, Vol. 10, No. 4, e0124494, 17.04.2015.

Research output: Contribution to journalArticle

Lee, Wan Ru ; Sacharidou, Anastasia ; Behling-Kelly, Erica ; Oltmann, Sarah C. ; Zhu, Weifei ; Ahmed, Mohamed ; Gerard, Robert D. ; Hui, David Y. ; Abe, Jun Ichi ; Shaul, Philip W. ; Mineo, Chieko. / PDZK1 prevents neointima formation via suppression of breakpoint cluster region kinase in vascular smooth muscle. In: PLoS One. 2015 ; Vol. 10, No. 4.
@article{2c63afb931f24b54a3ffab9ebc812bb2,
title = "PDZK1 prevents neointima formation via suppression of breakpoint cluster region kinase in vascular smooth muscle",
abstract = "Scavenger receptor class B, type I (SR-BI) and its adaptor protein PDZK1 mediate responses to HDL cholesterol in endothelium. Whether the receptor-adaptor protein tandem serves functions in other vascular cell types is unknown. The current work determined the roles of SR-BI and PDZK1 in vascular smooth muscle (VSM). To evaluate possible VSM functions of SR-BI and PDZK1 in vivo, neointima formation was assessed 21 days post-ligation in the carotid arteries of wild-type, SR-BI-/- or PDZK1-/- mice. Whereas neointima development was negligible in wild-type and SR-BI-/-, there was marked neointima formation in PDZK1-/- mice. PDZK1 expression was demonstrated in primary mouse VSM cells, and compared to wild-type cells, PDZK1-/- VSM displayed exaggerated proliferation and migration in response to platelet derived growth factor (PDGF). Tandem affinity purification-mass spectrometry revealed that PDZK1 interacts with breakpoint cluster region kinase (Bcr), which contains a C-terminal PDZ binding sequence and is known to enhance responses to PDGF in VSM. PDZK1 interaction with Bcr in VSM was demonstrated by pull-down and by coimmunoprecipitation, and the augmented proliferative response to PDGF in PDZK1-/-VSM was abrogated by Bcr depletion. Furthermore, compared with wild-type Bcr overexpression, the introduction of a Bcr mutant incapable of PDZK1 binding into VSM cells yielded an exaggerated proliferative response to PDGF. Thus, PDZK1 has novel SR-BIPLOS independent function in VSM that affords protection from neointima formation, and this involves PDZK1 suppression of VSM cell proliferation via an inhibitory interaction with Bcr.",
author = "Lee, {Wan Ru} and Anastasia Sacharidou and Erica Behling-Kelly and Oltmann, {Sarah C.} and Weifei Zhu and Mohamed Ahmed and Gerard, {Robert D.} and Hui, {David Y.} and Abe, {Jun Ichi} and Shaul, {Philip W.} and Chieko Mineo",
year = "2015",
month = "4",
day = "17",
doi = "10.1371/journal.pone.0124494",
language = "English (US)",
volume = "10",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "4",

}

TY - JOUR

T1 - PDZK1 prevents neointima formation via suppression of breakpoint cluster region kinase in vascular smooth muscle

AU - Lee, Wan Ru

AU - Sacharidou, Anastasia

AU - Behling-Kelly, Erica

AU - Oltmann, Sarah C.

AU - Zhu, Weifei

AU - Ahmed, Mohamed

AU - Gerard, Robert D.

AU - Hui, David Y.

AU - Abe, Jun Ichi

AU - Shaul, Philip W.

AU - Mineo, Chieko

PY - 2015/4/17

Y1 - 2015/4/17

N2 - Scavenger receptor class B, type I (SR-BI) and its adaptor protein PDZK1 mediate responses to HDL cholesterol in endothelium. Whether the receptor-adaptor protein tandem serves functions in other vascular cell types is unknown. The current work determined the roles of SR-BI and PDZK1 in vascular smooth muscle (VSM). To evaluate possible VSM functions of SR-BI and PDZK1 in vivo, neointima formation was assessed 21 days post-ligation in the carotid arteries of wild-type, SR-BI-/- or PDZK1-/- mice. Whereas neointima development was negligible in wild-type and SR-BI-/-, there was marked neointima formation in PDZK1-/- mice. PDZK1 expression was demonstrated in primary mouse VSM cells, and compared to wild-type cells, PDZK1-/- VSM displayed exaggerated proliferation and migration in response to platelet derived growth factor (PDGF). Tandem affinity purification-mass spectrometry revealed that PDZK1 interacts with breakpoint cluster region kinase (Bcr), which contains a C-terminal PDZ binding sequence and is known to enhance responses to PDGF in VSM. PDZK1 interaction with Bcr in VSM was demonstrated by pull-down and by coimmunoprecipitation, and the augmented proliferative response to PDGF in PDZK1-/-VSM was abrogated by Bcr depletion. Furthermore, compared with wild-type Bcr overexpression, the introduction of a Bcr mutant incapable of PDZK1 binding into VSM cells yielded an exaggerated proliferative response to PDGF. Thus, PDZK1 has novel SR-BIPLOS independent function in VSM that affords protection from neointima formation, and this involves PDZK1 suppression of VSM cell proliferation via an inhibitory interaction with Bcr.

AB - Scavenger receptor class B, type I (SR-BI) and its adaptor protein PDZK1 mediate responses to HDL cholesterol in endothelium. Whether the receptor-adaptor protein tandem serves functions in other vascular cell types is unknown. The current work determined the roles of SR-BI and PDZK1 in vascular smooth muscle (VSM). To evaluate possible VSM functions of SR-BI and PDZK1 in vivo, neointima formation was assessed 21 days post-ligation in the carotid arteries of wild-type, SR-BI-/- or PDZK1-/- mice. Whereas neointima development was negligible in wild-type and SR-BI-/-, there was marked neointima formation in PDZK1-/- mice. PDZK1 expression was demonstrated in primary mouse VSM cells, and compared to wild-type cells, PDZK1-/- VSM displayed exaggerated proliferation and migration in response to platelet derived growth factor (PDGF). Tandem affinity purification-mass spectrometry revealed that PDZK1 interacts with breakpoint cluster region kinase (Bcr), which contains a C-terminal PDZ binding sequence and is known to enhance responses to PDGF in VSM. PDZK1 interaction with Bcr in VSM was demonstrated by pull-down and by coimmunoprecipitation, and the augmented proliferative response to PDGF in PDZK1-/-VSM was abrogated by Bcr depletion. Furthermore, compared with wild-type Bcr overexpression, the introduction of a Bcr mutant incapable of PDZK1 binding into VSM cells yielded an exaggerated proliferative response to PDGF. Thus, PDZK1 has novel SR-BIPLOS independent function in VSM that affords protection from neointima formation, and this involves PDZK1 suppression of VSM cell proliferation via an inhibitory interaction with Bcr.

UR - http://www.scopus.com/inward/record.url?scp=84930004624&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84930004624&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0124494

DO - 10.1371/journal.pone.0124494

M3 - Article

C2 - 25886360

AN - SCOPUS:84930004624

VL - 10

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 4

M1 - e0124494

ER -