A Bafico

A Caricasole

B Bartling

B Chen

B He

BJ Cox

C Banziger

CJ Jeffery

David M. Virshup

DH Huberts

G Froyen

GS Coombs

H Komekado

J Fu

J Witheiler

JJ Barrott

K Bartscherer

K Benhaj

K Tanaka

K Willert

KH Grzeschik

Kyle D. Proffitt

L Doubravska

L Zhai

LM Galli

M Srivastava

Masaru Katoh

MW McCulloch

P Herr

P Polakis

Patrick Tan

R Takada

S Biechele

S Rajagopalan

Simran Kaur

T Kadowaki

Tina Tan Ong

Tracy M. Covey

W Ching

W Yang

X Wang

Y Matsuda

Yonghui Wu

Z Chen

PLoS ONE

PubMed

Crossref

PORCN Moonlights in a Wnt-Independent Pathway That Regulates Cancer Cell Proliferation

Porcupine (PORCN) is a membrane-bound O-acyl transferase that is required for the palmitoylation of Wnt proteins, and that is essential in diverse Wnt pathways for Wnt-Wntless (WLS) binding, Wnt secretion, and Wnt signaling activity. We tested if PORCN was required for the proliferation of transformed cells. Knockdown of PORCN by multiple independent siRNAs results in a cell growth defect in a subset of epithelial cancer cell lines. The growth defect is transformation-dependent in human mammary epithelial (HMEC) cells. Additionally, inducible PORCN knockdown by two independent shRNAs markedly reduces the growth of established MDA-MB-231 cancers in orthotopic xenografts in immunodeficient mice. Unexpectedly, the proliferation defect resulting from loss of PORCN occurs in a Wnt-independent manner, as it is rescued by re-expression of catalytically inactive PORCN, and is not seen after RNAi-mediated knockdown of the Wnt carrier protein WLS, nor after treatment with the PORCN inhibitor IWP. Consistent with a role in a Wnt-independent pathway, knockdown of PORCN regulates a distinct set of genes that are not altered by other inhibitors of Wnt signaling. PORCN protein thus appears to moonlight in a novel signaling pathway that is rate-limiting for cancer cell growth and tumorigenesis independent of its enzymatic function in Wnt biosynthesis and secretion

Tracy M Covey

Kyle D Proffitt

David M Virshup

Directory of Open Access Journals

PORCN moonlights in a Wnt-independent pathway that regulates cancer cell proliferation.

<div><p>Porcupine (PORCN) is a membrane-bound O-acyl transferase that is required for the palmitoylation of Wnt proteins, and that is essential in diverse Wnt pathways for Wnt-Wntless (WLS) binding, Wnt secretion, and Wnt signaling activity. We tested if PORCN was required for the proliferation of transformed cells. Knockdown of PORCN by multiple independent siRNAs results in a cell growth defect in a subset of epithelial cancer cell lines. The growth defect is transformation-dependent in human mammary epithelial (HMEC) cells. Additionally, inducible PORCN knockdown by two independent shRNAs markedly reduces the growth of established MDA-MB-231 cancers in orthotopic xenografts in immunodeficient mice. Unexpectedly, the proliferation defect resulting from loss of PORCN occurs in a Wnt-independent manner, as it is rescued by re-expression of catalytically inactive PORCN, and is not seen after RNAi-mediated knockdown of the Wnt carrier protein WLS, nor after treatment with the PORCN inhibitor IWP. Consistent with a role in a Wnt-independent pathway, knockdown of PORCN regulates a distinct set of genes that are not altered by other inhibitors of Wnt signaling. PORCN protein thus appears to moonlight in a novel signaling pathway that is rate-limiting for cancer cell growth and tumorigenesis independent of its enzymatic function in Wnt biosynthesis and secretion.</p> </div

Tracy M. Covey (171796)

Simran Kaur (171806)

Tina Tan Ong (171812)

Kyle D. Proffitt (171819)

Yonghui Wu (171826)

Patrick Tan (18147)

David M. Virshup (171835)

The Francis Crick Institute

Covey Tracy M.

Kaur Simran

Tan Ong Tina

Proffitt Kyle D.

Wu Yonghui

Tan Patrick

Virshup David M.

Public Library of Science (PLOS)

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Fatty acid modification of Wnt1 and Wnt3a at serine is prerequisite for lipidation at cysteine and is essential for Wnt signalling.

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The segment polarity gene porcupine encodes a putative multitransmembrane protein involved in Wingless processing.

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http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3324524

PORCN moonlights in a wnt-independent pathway that regulates cancer cell proliferation

PORCN moonlights in a wnt-independent pathway that regulates cancer cell proliferation

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Directory of Open Access Journals

The Francis Crick Institute

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