Protein Kinase C (PKC) βII Induces Cell Invasion through a Ras/Mek-, PKCι/Rac 1-dependent Signaling Pathway

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