Protein kinase c (PKC) βII induces cell invasion through a Ras/Mek-, PKCι/Rac 1-dependent signaling pathway

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Abstract

Protein kinase C βII (PKCβII) promotes colon carcinogenesis. Expression of PKCβII in the colon of transgenic mice induces hyperproliferation and increased susceptibility to colon cancer. To determine molecular mechanisms by which PKCβII promotes colon cancer, we established rat intestinal epithelial (RIE) cells stably expressing PKCβII. Here we show that RIE/PKCβII cells acquire an invasive phenotype that is blocked by the PKCβ inhibitor LY379196. Invasion is not observed in RIE cells expressing a kinase-deficient PKCβII, indicating that PKCβII activity is required for the invasive phenotype. PKCβII induces activation of K-Ras and the Ras effector, Rac1, in RIE/PKCβII cells. PKCβII-mediated invasion is blocked by the Mek inhibitor, U0126, and by expression of either dominant negative Rac1 or kinase-deficient atypical PKCι. Expression of constitutively active Rac1 induces Mek activation and invasion in RIE cells, indicating that Rac1 is the critical down-stream effector of PKCβII-mediated invasion. Taken together, our results define a novel PKCβII → Ras → PKCι/Rac1 → Mek signaling pathway that induces invasion in intestinal epithelial cells. This pathway provides a plausible mechanism by which PKCβII promotes colon carcinogenesis.

Original languageEnglish (US)
Pages (from-to)22118-22123
Number of pages6
JournalJournal of Biological Chemistry
Volume279
Issue number21
DOIs
StatePublished - May 21 2004

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ras Proteins
Protein Kinases
Protein Kinase C
Rats
Epithelial Cells
Colon
5,21 - 12,17-dimetheneo-18H-dibenzo(i,o)pyrrolo(3,4-1)(1,8)diazacyclohexandecine-18,10(19H)dione,8((dimethylamino)methyl)-6,7,8,9,10,11-hexahydro,monomethanesulfonate
Colonic Neoplasms
Carcinogenesis
Phosphotransferases
Chemical activation
Phenotype
Protein Kinase Inhibitors
Transgenic Mice

ASJC Scopus subject areas

  • Biochemistry

Cite this

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title = "Protein kinase c (PKC) βII induces cell invasion through a Ras/Mek-, PKCι/Rac 1-dependent signaling pathway",
abstract = "Protein kinase C βII (PKCβII) promotes colon carcinogenesis. Expression of PKCβII in the colon of transgenic mice induces hyperproliferation and increased susceptibility to colon cancer. To determine molecular mechanisms by which PKCβII promotes colon cancer, we established rat intestinal epithelial (RIE) cells stably expressing PKCβII. Here we show that RIE/PKCβII cells acquire an invasive phenotype that is blocked by the PKCβ inhibitor LY379196. Invasion is not observed in RIE cells expressing a kinase-deficient PKCβII, indicating that PKCβII activity is required for the invasive phenotype. PKCβII induces activation of K-Ras and the Ras effector, Rac1, in RIE/PKCβII cells. PKCβII-mediated invasion is blocked by the Mek inhibitor, U0126, and by expression of either dominant negative Rac1 or kinase-deficient atypical PKCι. Expression of constitutively active Rac1 induces Mek activation and invasion in RIE cells, indicating that Rac1 is the critical down-stream effector of PKCβII-mediated invasion. Taken together, our results define a novel PKCβII → Ras → PKCι/Rac1 → Mek signaling pathway that induces invasion in intestinal epithelial cells. This pathway provides a plausible mechanism by which PKCβII promotes colon carcinogenesis.",
author = "Jie Zhang and Anastasiadis, {Panagiotis Z} and Yan Liu and Thompson, {E Aubrey} and Fields, {Alan P}",
year = "2004",
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T1 - Protein kinase c (PKC) βII induces cell invasion through a Ras/Mek-, PKCι/Rac 1-dependent signaling pathway

AU - Zhang, Jie

AU - Anastasiadis, Panagiotis Z

AU - Liu, Yan

AU - Thompson, E Aubrey

AU - Fields, Alan P

PY - 2004/5/21

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N2 - Protein kinase C βII (PKCβII) promotes colon carcinogenesis. Expression of PKCβII in the colon of transgenic mice induces hyperproliferation and increased susceptibility to colon cancer. To determine molecular mechanisms by which PKCβII promotes colon cancer, we established rat intestinal epithelial (RIE) cells stably expressing PKCβII. Here we show that RIE/PKCβII cells acquire an invasive phenotype that is blocked by the PKCβ inhibitor LY379196. Invasion is not observed in RIE cells expressing a kinase-deficient PKCβII, indicating that PKCβII activity is required for the invasive phenotype. PKCβII induces activation of K-Ras and the Ras effector, Rac1, in RIE/PKCβII cells. PKCβII-mediated invasion is blocked by the Mek inhibitor, U0126, and by expression of either dominant negative Rac1 or kinase-deficient atypical PKCι. Expression of constitutively active Rac1 induces Mek activation and invasion in RIE cells, indicating that Rac1 is the critical down-stream effector of PKCβII-mediated invasion. Taken together, our results define a novel PKCβII → Ras → PKCι/Rac1 → Mek signaling pathway that induces invasion in intestinal epithelial cells. This pathway provides a plausible mechanism by which PKCβII promotes colon carcinogenesis.

AB - Protein kinase C βII (PKCβII) promotes colon carcinogenesis. Expression of PKCβII in the colon of transgenic mice induces hyperproliferation and increased susceptibility to colon cancer. To determine molecular mechanisms by which PKCβII promotes colon cancer, we established rat intestinal epithelial (RIE) cells stably expressing PKCβII. Here we show that RIE/PKCβII cells acquire an invasive phenotype that is blocked by the PKCβ inhibitor LY379196. Invasion is not observed in RIE cells expressing a kinase-deficient PKCβII, indicating that PKCβII activity is required for the invasive phenotype. PKCβII induces activation of K-Ras and the Ras effector, Rac1, in RIE/PKCβII cells. PKCβII-mediated invasion is blocked by the Mek inhibitor, U0126, and by expression of either dominant negative Rac1 or kinase-deficient atypical PKCι. Expression of constitutively active Rac1 induces Mek activation and invasion in RIE cells, indicating that Rac1 is the critical down-stream effector of PKCβII-mediated invasion. Taken together, our results define a novel PKCβII → Ras → PKCι/Rac1 → Mek signaling pathway that induces invasion in intestinal epithelial cells. This pathway provides a plausible mechanism by which PKCβII promotes colon carcinogenesis.

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