Ect2 links the PKC-Par6α complex to Rac1 activation and cellular transformation

V. Justilien; A. P. Fields

doi:10.1038/onc.2009.217

Ect2 links the PKC-Par6α complex to Rac1 activation and cellular transformation

V. Justilien, A. P. Fields

Cancer Biology

Research output: Contribution to journal › Article › peer-review

101 Scopus citations

Abstract

Protein kinase C (PKC) promotes non-small cell lung cancer (NSCLC) by binding to Par6α and activating a Rac1-Pak-Mek1,2-Erk1,2 signaling cascade. The mechanism by which the PKC-Par6α complex regulates Rac1 is unknown. Here we show that epithelial cell transforming sequence 2 (Ect2), a guanine nucleotide exchange factor for Rho family GTPases, is coordinately amplified and overexpressed with PKC in NSCLC tumors. RNA interference-mediated knockdown of Ect2 inhibits Rac1 activity and blocks transformed growth, invasion and tumorigenicity of NSCLC cells. Expression of constitutively active Rac1 (RacV12) restores transformation to Ect2-deficient cells. Interestingly, the role of Ect2 in transformation is distinct from its well-established role in cytokinesis. In NSCLC cells, Ect2 is mislocalized to the cytoplasm where it binds the PKC-Par6α complex. RNA interference-mediated knockdown of either PKC or Par6α causes Ect2 to redistribute to the nucleus, indicating that the PKC-Par6α complex regulates the cytoplasmic localization of Ect2. Our data indicate that Ect2 and PKC are genetically and functionally linked in NSCLC, acting to coordinately drive tumor cell proliferation and invasion through formation of an oncogenic PKC-Par6α-Ect2 complex.

Original language	English (US)
Pages (from-to)	3597-3607
Number of pages	11
Journal	Oncogene
Volume	28
Issue number	41
DOIs	https://doi.org/10.1038/onc.2009.217
State	Published - Oct 15 2009

Keywords

Anchorage-independent growth
Cytokinesis
Gene amplification
Invasion
Mek-Erk signaling
Rac1

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

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10.1038/onc.2009.217

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title = "Ect2 links the PKC-Par6α complex to Rac1 activation and cellular transformation",

abstract = "Protein kinase C (PKC) promotes non-small cell lung cancer (NSCLC) by binding to Par6α and activating a Rac1-Pak-Mek1,2-Erk1,2 signaling cascade. The mechanism by which the PKC-Par6α complex regulates Rac1 is unknown. Here we show that epithelial cell transforming sequence 2 (Ect2), a guanine nucleotide exchange factor for Rho family GTPases, is coordinately amplified and overexpressed with PKC in NSCLC tumors. RNA interference-mediated knockdown of Ect2 inhibits Rac1 activity and blocks transformed growth, invasion and tumorigenicity of NSCLC cells. Expression of constitutively active Rac1 (RacV12) restores transformation to Ect2-deficient cells. Interestingly, the role of Ect2 in transformation is distinct from its well-established role in cytokinesis. In NSCLC cells, Ect2 is mislocalized to the cytoplasm where it binds the PKC-Par6α complex. RNA interference-mediated knockdown of either PKC or Par6α causes Ect2 to redistribute to the nucleus, indicating that the PKC-Par6α complex regulates the cytoplasmic localization of Ect2. Our data indicate that Ect2 and PKC are genetically and functionally linked in NSCLC, acting to coordinately drive tumor cell proliferation and invasion through formation of an oncogenic PKC-Par6α-Ect2 complex.",

keywords = "Anchorage-independent growth, Cytokinesis, Gene amplification, Invasion, Mek-Erk signaling, Rac1",

author = "V. Justilien and Fields, {A. P.}",

note = "Funding Information: We acknowledge Dr Roderick P Regala for assistance with the ectopic tumor studies, Dr Andras Khoor and Capella Weems for analysis of primary NSCLC tumors, Pam Kreinest and Brandy Edenfield for immunohistochemistry, Dr Lee Jamieson and Alyssa Kunz for technical assistance, and Drs E Aubrey Thompson and Nicole R Murray for critical review of the paper. This work was supported in part by grants from the National Institutes of Health (CA081436), The V Foundation for Cancer Research and The Mayo Foundation to APF.",

year = "2009",

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doi = "10.1038/onc.2009.217",

language = "English (US)",

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AU - Justilien, V.

AU - Fields, A. P.

N1 - Funding Information: We acknowledge Dr Roderick P Regala for assistance with the ectopic tumor studies, Dr Andras Khoor and Capella Weems for analysis of primary NSCLC tumors, Pam Kreinest and Brandy Edenfield for immunohistochemistry, Dr Lee Jamieson and Alyssa Kunz for technical assistance, and Drs E Aubrey Thompson and Nicole R Murray for critical review of the paper. This work was supported in part by grants from the National Institutes of Health (CA081436), The V Foundation for Cancer Research and The Mayo Foundation to APF.

PY - 2009/10/15

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N2 - Protein kinase C (PKC) promotes non-small cell lung cancer (NSCLC) by binding to Par6α and activating a Rac1-Pak-Mek1,2-Erk1,2 signaling cascade. The mechanism by which the PKC-Par6α complex regulates Rac1 is unknown. Here we show that epithelial cell transforming sequence 2 (Ect2), a guanine nucleotide exchange factor for Rho family GTPases, is coordinately amplified and overexpressed with PKC in NSCLC tumors. RNA interference-mediated knockdown of Ect2 inhibits Rac1 activity and blocks transformed growth, invasion and tumorigenicity of NSCLC cells. Expression of constitutively active Rac1 (RacV12) restores transformation to Ect2-deficient cells. Interestingly, the role of Ect2 in transformation is distinct from its well-established role in cytokinesis. In NSCLC cells, Ect2 is mislocalized to the cytoplasm where it binds the PKC-Par6α complex. RNA interference-mediated knockdown of either PKC or Par6α causes Ect2 to redistribute to the nucleus, indicating that the PKC-Par6α complex regulates the cytoplasmic localization of Ect2. Our data indicate that Ect2 and PKC are genetically and functionally linked in NSCLC, acting to coordinately drive tumor cell proliferation and invasion through formation of an oncogenic PKC-Par6α-Ect2 complex.

AB - Protein kinase C (PKC) promotes non-small cell lung cancer (NSCLC) by binding to Par6α and activating a Rac1-Pak-Mek1,2-Erk1,2 signaling cascade. The mechanism by which the PKC-Par6α complex regulates Rac1 is unknown. Here we show that epithelial cell transforming sequence 2 (Ect2), a guanine nucleotide exchange factor for Rho family GTPases, is coordinately amplified and overexpressed with PKC in NSCLC tumors. RNA interference-mediated knockdown of Ect2 inhibits Rac1 activity and blocks transformed growth, invasion and tumorigenicity of NSCLC cells. Expression of constitutively active Rac1 (RacV12) restores transformation to Ect2-deficient cells. Interestingly, the role of Ect2 in transformation is distinct from its well-established role in cytokinesis. In NSCLC cells, Ect2 is mislocalized to the cytoplasm where it binds the PKC-Par6α complex. RNA interference-mediated knockdown of either PKC or Par6α causes Ect2 to redistribute to the nucleus, indicating that the PKC-Par6α complex regulates the cytoplasmic localization of Ect2. Our data indicate that Ect2 and PKC are genetically and functionally linked in NSCLC, acting to coordinately drive tumor cell proliferation and invasion through formation of an oncogenic PKC-Par6α-Ect2 complex.

KW - Anchorage-independent growth

KW - Cytokinesis

KW - Gene amplification

KW - Invasion

KW - Mek-Erk signaling

KW - Rac1

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JO - Oncogene

JF - Oncogene

IS - 41

ER -

Ect2 links the PKC-Par6α complex to Rac1 activation and cellular transformation

Abstract

Keywords

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