In vitro study reveals human EGFR-1 confers rapid aldosterone sensitivity in ovarian cells, indicating steroid-peptide receptor transactivation via c-Src.
The epidermal growth factor (EGF) regulates cell proliferation, differentiation, and ion transport using ERK1/2 as a downstream effector. Furthermore, the EGF receptor (EGFR) is involved in signaling by G-protein-coupled receptors, growth hormone, and cytokines via transactivation. It has been suggested that steroids interact with peptide hormones. Previously, we have shown that aldosterone modulates EGF responses in Madin-Darby canine kidney cells (Gekle, M., Freudinger, R., Mildenberger, S., and Silbernagl, S. (2002) Am. J. Physiol. 282, F669–F679). Here, we tested the hypothesis that human EGFR-1 can confer alternative aldosterone responsiveness with respect to ERK1/2 phosphorylation to Chinese hamster ovary cells, which do not express EGFR. Wild-type Chinese hamster ovary cells did not respond to EGF or aldosterone. After transfection of human EGFR-1, the cells responded to EGF, but not to aldosterone. However, when submaximal concentrations of EGF were used, nanomolar concentrations of aldosterone potentiated the action of EGF within minutes, resulting in a leftward shift of the EGF dose-response curve. This was not the case in mock-transfected cells. The EGFR kinase inhibitor tyrphostin AG1478 or the MEK1/2 inhibitor U0126 completely prevented the effect. Furthermore, aldosterone enhanced Tyr phosphorylation of c-Src and EGFR, and an inhibitor of cytosolic tyrosine kinases (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyriociaine) prevented the action of aldosterone. Our data show that aldosterone uses the EGF-EGFR-MEK1/2-ERK1/2 signaling cascade to elicit its alternative effects. In the presence of EGF, aldosterone leads to EGFR transactivation via cytosolic tyrosine kinases of the Src family. The epidermal growth factor (EGF) regulates cell proliferation, differentiation, and ion transport using ERK1/2 as a downstream effector. Furthermore, the EGF receptor (EGFR) is involved in signaling by G-protein-coupled receptors, growth hormone, and cytokines via transactivation. It has been suggested that steroids interact with peptide hormones. Previously, we have shown that aldosterone modulates EGF responses in Madin-Darby canine kidney cells (Gekle, M., Freudinger, R., Mildenberger, S., and Silbernagl, S. (2002) Am. J. Physiol. 282, F669–F679). Here, we tested the hypothesis that human EGFR-1 can confer alternative aldosterone responsiveness with respect to ERK1/2 phosphorylation to Chinese hamster ovary cells, which do not express EGFR. Wild-type Chinese hamster ovary cells did not respond to EGF or aldosterone. After transfection of human EGFR-1, the cells responded to EGF, but not to aldosterone. However, when submaximal concentrations of EGF were used, nanomolar concentrations of aldosterone potentiated the action of EGF within minutes, resulting in a leftward shift of the EGF dose-response curve. This was not the case in mock-transfected cells. The EGFR kinase inhibitor tyrphostin AG1478 or the MEK1/2 inhibitor U0126 completely prevented the effect. Furthermore, aldosterone enhanced Tyr phosphorylation of c-Src and EGFR, and an inhibitor of cytosolic tyrosine kinases (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyriociaine) prevented the action of aldosterone. Our data show that aldosterone uses the EGF-EGFR-MEK1/2-ERK1/2 signaling cascade to elicit its alternative effects. In the presence of EGF, aldosterone leads to EGFR transactivation via cytosolic tyrosine kinases of the Src family. The classical genomic mechanism of steroid hormone action involves binding to intracellular receptors and stimulation of transcription and protein synthesis. Yet, aldosterone can also induce rapid responses by interfering with, for example, regulation of intracellular pH or calcium (1Winter D.C. Schneider M.F. O'Sullivan G.C. J. J. S. S. J. Physiol. J. Physiol. J. S. S. intracellular of J. J. and protein kinase protein kinase EGF, epidermal growth EGFR, epidermal growth factor Madin-Darby canine human epidermal growth factor Chinese hamster protein kinase protein kinase EGF, epidermal growth EGFR, epidermal growth factor Madin-Darby canine human epidermal growth factor Chinese hamster protein kinase and ERK1/2 phosphorylation J. D.C. J. S. J. Physiol. also that aldosterone within of cells S. S. J. J. Physiol. alternative of aldosterone have been suggested to by a receptor Am. J. Physiol. receptor has not been has been shown that steroid of with peptide hormone signaling Physiol. and of example, the of with signaling has been as as the of with growth factor and signaling J. J. Am. J. Physiol. In the case of an with and has been suggested and of of with steroids the epidermal growth factor EGF regulates cell proliferation, differentiation, and and in protein kinases as downstream In enhanced EGF signaling has been in cells Furthermore, has been shown that EGF transport in a to enhanced or J. Am. J. Physiol. S. Am. J. Physiol. S. J. The EGF receptor (EGFR) has been shown to involved in signaling for example, G-protein-coupled receptors, growth hormone, and cytokines via a mechanism transactivation This mechanism of transactivation involves EGFR by intracellular signaling and J. EGFR can as a of signaling of or with EGFR has been J. we that aldosterone also with EGF signaling S. S. Am. J. Physiol. In Madin-Darby canine kidney cells, aldosterone the of EGF ERK1/2 phosphorylation and of signaling Furthermore, aldosterone the of EGF and cell and the or of not completely The of steroids with peptide hormone signaling mechanism for alternative steroid action and the an for the of of peptide hormone we the of aldosterone with human EGFR-1 in a using Chinese hamster ovary cells. cells do not express EGFR J. and an to the of in the alternative aldosterone cells and to transfection to elicit alternative aldosterone the presence of signaling for the aldosterone and show that aldosterone the signaling cascade to in its alternative effects. This is by cytosolic tyrosine kinases the hypothesis that alternative of aldosterone EGFR, we cells, which do not express EGFR, with the receptor to a cell for the of the of EGFR in alternative aldosterone that cells did not respond to EGF or aldosterone with ERK1/2 which was with In that EGFR was not by in cells. cells and the of in of the After transfection with the cells responded with enhanced ERK1/2 phosphorylation EGF that the signaling cascade to ERK1/2 was the and of ERK1/2 tested the of aldosterone ERK1/2 the of the ERK1/2 phosphorylation were by an by J. and and for S. S. Am. J. Physiol. This was we to aldosterone and The and in show that cells did not respond to aldosterone However, in the presence of submaximal EGF, aldosterone enhanced ERK1/2 shown in the responsiveness of cells to EGF by the Furthermore, the of aldosterone EGF action was in we that the action of aldosterone is to the of In the presence of aldosterone and EGF, ERK1/2 phosphorylation was by a factor of with EGF The in ERK1/2 phosphorylation was enhanced by a factor of by aldosterone data show that aldosterone EGF signaling via ERK1/2 phosphorylation was not by aldosterone of the effect. Furthermore, did not signaling In the we the of EGF and aldosterone. in cells, aldosterone potentiated the of EGF ERK1/2 was However, the cells did not respond to aldosterone data for the of aldosterone and EGF was tested in In aldosterone a effect. In mock-transfected cells, was The the as of the of aldosterone with respect to ERK1/2 phosphorylation prevented by of c-Src but not by of the to a EGFR signaling the of EGF was enhanced by This hypothesis is by the that stimulation of with the of of MEK1/2 with U0126 or of EGFR kinase with tyrphostin AG1478 the of EGF and aldosterone did not EGF did not ERK1/2 a of the was aldosterone enhanced EGFR Tyr were as EGF and aldosterone. of the the was EGFR. aldosterone enhanced c-Src Tyr was in the presence of the of aldosterone EGFR phosphorylation was was the of ERK1/2 phosphorylation in the presence of EGF or EGF aldosterone. The steroid the the of ERK1/2 the of EGF to a leftward shift in the EGF dose-response with in the effect. aldosterone the cells to EGF, to the in cells S. S. Am. J. Physiol. This is also the data in the of by aldosterone is the of EGF we tested concentrations of aldosterone and a with data show that the in cells S. S. Am. J. Physiol. can by transfection of in an Furthermore, the data show that aldosterone modulates the of the cell to EGF and the of the EGF of have the to the cell of the EGF as shown by in cells for and of in a S. S. Am. J. Physiol. of the of EGF and aldosterone with respect to ERK1/2 data shown were with of the of the that the of aldosterone was in the were as EGF, aldosterone to a leftward shift of the EGF dose-response the of EGF was the of aldosterone with ERK1/2 to the leftward shift of the dose-response shown was the of aldosterone was with a was EGF was the we a to signaling involved in of EGF signaling of the kinase by tyrphostin AG1478 or of the MEK1/2 kinases by U0126 completely prevented ERK1/2 phosphorylation by EGF or aldosterone data show that the were by the transactivation of EGFR has been shown to the cytosolic tyrosine kinase c-Src in J. we tested the c-Src inhibitor In the presence of EGF ERK1/2 However, aldosterone was to the of data that aldosterone via we to the of of by a of ERK1/2 data that a via with respect to signaling which is This hypothesis is by the action of ERK1/2 phosphorylation that as of by did not the action of aldosterone with respect to ERK1/2 the we the hypothesis of the by and The data in show that aldosterone Tyr Furthermore, aldosterone to Tyr phosphorylation of c-Src and EGFR prevented by data the that aldosterone EGF signaling by stimulation of the have shown that steroid as aldosterone can elicit The for the rapid of aldosterone not hypothesis is the of steroid with peptide hormone example, the of with signaling has been as as the of or with growth factor and signaling J. J. Am. J. Physiol. In the case of an with and has been suggested and of have shown that aldosterone EGF signaling with respect to ERK1/2 phosphorylation and in cells S. S. Am. J. Physiol. S. S. of EGFR is involved in the of by as via EGFR is a of is that EGFR also a in alternative aldosterone The in were as transfection to elicit alternative aldosterone the presence of signaling for the aldosterone and data show that of the of EGF were to the alternative signaling in cells. The that the of EGF was for the aldosterone is in with its action in cells, aldosterone an EGF S. S. Am. J. Physiol. S. S. that EGF EGFR to the rapid of ERK1/2 by aldosterone. The steroid hormone leads to a of the cells to EGF shift of the dose-response the effect. signaling and EGFR can receptor by and of the receptor kinase J. In the rapid of and of growth factor of in the presence of receptor kinase has been as a mechanism for transactivation J. to is the that the of EGF not to for transactivation. This is in to the action of aldosterone the for the action of aldosterone not aldosterone for a in which is but of EGF However, in cells with an EGF as cells S. S. Am. J. Physiol. the of aldosterone has the with for aldosterone and EGF in and the of The the has been in cells, the transactivation of the EGFR signaling to enhanced and cell S. S. Am. J. Physiol. S. S. the in has to in for example, EGFR kinase It is that EGFR signaling modulates ion transport and in cell J. Am. J. Physiol. Furthermore, is that EGFR signaling with respect to the and of aldosterone and is that the of aldosterone with EGFR signaling and responses to that is to the mechanism by which aldosterone with the EGFR signaling It has been shown that aldosterone can J. can to of is a for the of aldosterone and the can also EGFR Our data that the is also in was the of EGF ERK1/2 phosphorylation was In when was by the of EGF was of did not the action of aldosterone. not to the signaling that aldosterone to signaling to involved in EGFR transactivation is the cytosolic tyrosine kinase c-Src J. c-Src EGFR, its we the of aldosterone was that the steroid via This hypothesis is by the that aldosterone c-Src phosphorylation and its we can the aldosterone which EGFR when EGF is the cascade is can elicit of to and S. S. Am. J. Physiol. signaling can a of EGFR and of ERK1/2 we have shown the cell of the in cells S. S. Am. J. Physiol. alternative aldosterone and cell proliferation, in to the cell in cells with mock-transfected of the leads to phosphorylation and stimulation of which EGFR when EGF is the cascade is can elicit the of to and signaling can a of EGFR and of ERK1/2 data to the of alternative aldosterone that have to in is not the aldosterone leads to the of Furthermore, we have to the of EGF is a for the alternative action of aldosterone. It also to the receptor can interact with the signaling It has been that the classical receptor to alternative of aldosterone the of the signaling for the classical action of aldosterone the This is of the of EGFR, cell to express the receptor as and cells. we of cells with and the receptor to alternative and classical aldosterone In data show that aldosterone the EGF-EGFR-MEK1/2-ERK1/2 signaling cascade to elicit its alternative and that the is to in cells with EGFR The classical genomic mechanism of steroid hormone action involves binding to intracellular receptors and stimulation of transcription and protein synthesis. Yet, aldosterone can also induce rapid responses by interfering with, for example, regulation of intracellular pH or calcium (1Winter D.C. Schneider M.F. O'Sullivan G.C. J. J. S. S. J. Physiol. J. Physiol. J. S. S. intracellular of J. J. and protein kinase protein kinase EGF, epidermal growth EGFR, epidermal growth factor Madin-Darby canine human epidermal growth factor Chinese hamster protein kinase protein kinase EGF, epidermal growth EGFR, epidermal growth factor Madin-Darby canine human epidermal growth factor Chinese hamster protein kinase and ERK1/2 phosphorylation J. D.C. J. S. J. Physiol. also that aldosterone within of cells S. S. J. J. Physiol. alternative of aldosterone have been suggested to by a receptor Am. J. Physiol. receptor has not been has been shown that steroid of with peptide hormone signaling Physiol. and of example, the of with signaling has been as as the of with growth factor and signaling J. J. Am. J. Physiol. In the case of an with and has been suggested and of of with steroids the epidermal growth factor EGF regulates cell proliferation, differentiation, and and in protein kinases as downstream In enhanced EGF signaling has been in cells Furthermore, has been shown that EGF transport in a to enhanced or J. Am. J. Physiol. S. Am. J. Physiol. S. J. The EGF receptor (EGFR) has been shown to involved in signaling for example, G-protein-coupled receptors, growth hormone, and cytokines via a mechanism transactivation This mechanism of transactivation involves EGFR by intracellular signaling and J. EGFR can as a of signaling of or with EGFR has been J. we that aldosterone also with EGF signaling S. S. Am. J. Physiol. In Madin-Darby canine kidney cells, aldosterone the of EGF ERK1/2 phosphorylation and of signaling Furthermore, aldosterone the of EGF and cell The and the or of not completely The of steroids with peptide hormone signaling mechanism for alternative steroid action and the an for the of of peptide hormone In we the of aldosterone with human EGFR-1 in a using Chinese hamster ovary cells. cells do not express EGFR J. and an to the of in the alternative aldosterone cells and to transfection to elicit alternative aldosterone the presence of signaling for the aldosterone and Our show that aldosterone the signaling cascade to in its alternative effects. This is by cytosolic tyrosine kinases the hypothesis that alternative of aldosterone EGFR, we cells, which do not express EGFR, with the receptor to a cell for the of the of EGFR in alternative aldosterone that cells did not respond to EGF or aldosterone with ERK1/2 which was with In that EGFR was not by in cells. cells and the of in of the After transfection with the cells responded with enhanced ERK1/2 phosphorylation EGF that the signaling cascade to ERK1/2 was the and of ERK1/2 tested the of aldosterone ERK1/2 the of the ERK1/2 phosphorylation were by an by J. and and for S. S. Am. J. Physiol. This was we to aldosterone and The and in show that cells did not respond to aldosterone However, in the presence of submaximal EGF, aldosterone enhanced ERK1/2 shown in the responsiveness of cells to EGF by the Furthermore, the of aldosterone EGF action was in we that the action of aldosterone is to the of In the presence of aldosterone and EGF, ERK1/2 phosphorylation was by a factor of with EGF The in ERK1/2 phosphorylation was enhanced by a factor of by aldosterone data show that aldosterone EGF signaling via ERK1/2 phosphorylation was not by aldosterone of the effect. Furthermore, did not signaling In the we the of the of aldosterone with respect to ERK1/2 phosphorylation prevented by of c-Src but not by of the to a EGFR signaling the of EGF was enhanced by This hypothesis is by the that stimulation of with the of of MEK1/2 with U0126 or of EGFR kinase with tyrphostin AG1478 the of EGF and aldosterone did not EGF did not ERK1/2 a of the was aldosterone enhanced EGFR Tyr were as EGF and aldosterone. of the the was EGFR. aldosterone enhanced c-Src Tyr was in the presence of the of aldosterone EGFR phosphorylation was was the of ERK1/2 phosphorylation in the presence of EGF or EGF aldosterone. The steroid the the of ERK1/2 the of EGF to a leftward shift in the EGF dose-response with in the effect. aldosterone the cells to EGF, to the in cells S. S. Am. J. Physiol. This is also the data in the of by aldosterone is the of EGF we tested concentrations of aldosterone and a with data show that the in cells S. S. Am. J. Physiol. can by transfection of in an Furthermore, the data show that aldosterone modulates the of the cell to EGF and the of the EGF of have the to the cell of the EGF as shown by in cells for and of in a S. S. Am. J. Physiol. of the of EGF and aldosterone with respect to ERK1/2 data shown were with of the of the that the of aldosterone was in the were as EGF, aldosterone to a leftward shift of the EGF dose-response the of EGF was the of aldosterone with ERK1/2 to the leftward shift of the dose-response shown was the of aldosterone was with a was EGF was the we a to signaling involved in of EGF signaling of the kinase by tyrphostin AG1478 or of the MEK1/2 kinases by U0126 completely prevented ERK1/2 phosphorylation by EGF or aldosterone data show that the were by the transactivation of EGFR has been shown to the cytosolic tyrosine kinase c-Src in J. we tested the c-Src inhibitor In the presence of EGF ERK1/2 However, aldosterone was to the of data that aldosterone via we to the of of by a of ERK1/2 data that a via with respect to signaling which is This hypothesis is by the action of ERK1/2 phosphorylation that as of by did not the action of aldosterone with respect to ERK1/2 the we the hypothesis of the by and The data in show that aldosterone Tyr Furthermore, aldosterone to Tyr phosphorylation of c-Src and EGFR prevented by data the that aldosterone EGF signaling by stimulation of the hypothesis that alternative of aldosterone EGFR, we cells, which do not express EGFR, with the receptor to a cell for the of the of EGFR in alternative aldosterone that cells did not respond to EGF or aldosterone with ERK1/2 which was with In that EGFR was not by in cells. cells and the of in of the After transfection with the cells responded with enhanced ERK1/2 phosphorylation EGF that the signaling cascade to ERK1/2 was the and of ERK1/2 tested the of aldosterone ERK1/2 the of the ERK1/2 phosphorylation were by an by J. and and for S. S. Am. J. Physiol. This was we to aldosterone and The and in show that cells did not respond to aldosterone However, in the presence of submaximal EGF, aldosterone enhanced ERK1/2 shown in the responsiveness of cells to EGF by the Furthermore, the of aldosterone EGF action was in we that the action of aldosterone is to the of In the presence of aldosterone and EGF, ERK1/2 phosphorylation was by a factor of with EGF The in ERK1/2 phosphorylation was enhanced by a factor of by aldosterone data show that aldosterone EGF signaling via ERK1/2 phosphorylation was not by aldosterone of the effect. Furthermore, did not signaling In the we the the of ERK1/2 phosphorylation in the presence of EGF or EGF aldosterone. The steroid the the of ERK1/2 the of EGF to a leftward shift in the EGF dose-response with in the effect. aldosterone the cells to EGF, to the in cells S. S. Am. J. Physiol. This is also the data in the of by aldosterone is the of EGF we tested concentrations of aldosterone and a with data show that the in cells S. S. Am. J. Physiol. can by transfection of in an Furthermore, the data show that aldosterone modulates the of the cell to EGF and the of the EGF of have the to the cell of the EGF as shown by in cells for and of in a S. S. Am. J. Physiol. In the we a to signaling involved in of EGF signaling of the kinase by tyrphostin AG1478 or of the MEK1/2 kinases by U0126 completely prevented ERK1/2 phosphorylation by EGF or aldosterone data show that the were by the transactivation of EGFR has been shown to the cytosolic tyrosine kinase c-Src in J. we tested the c-Src inhibitor In the presence of EGF ERK1/2 However, aldosterone was to the of data that aldosterone via we to the of of by a of ERK1/2 data that a via with respect to signaling which is This hypothesis is by the action of ERK1/2 phosphorylation that as of by did not the action of aldosterone with respect to ERK1/2 In the we the hypothesis of the by and The data in show that aldosterone Tyr Furthermore, aldosterone to Tyr phosphorylation of c-Src and EGFR prevented by data the that aldosterone EGF signaling by stimulation of the have shown that steroid as aldosterone can elicit The for the rapid of aldosterone not hypothesis is the of steroid with peptide hormone example, the of with signaling has been as as the of or with growth factor and signaling J. J. Am. J. Physiol. In the case of an with and has been suggested and of have shown that aldosterone EGF signaling with respect to ERK1/2 phosphorylation and in cells S. S. Am. J. Physiol. S. S. of EGFR is involved in the of by as via EGFR is a of is that EGFR also a in alternative aldosterone The in were as transfection to elicit alternative aldosterone the presence of signaling for the aldosterone and data show that of the of EGF were to the alternative signaling in cells. The that the of EGF was for the aldosterone is in with its action in cells, aldosterone an EGF S. S. Am. J. Physiol. S. S. that EGF EGFR to the rapid of ERK1/2 by aldosterone. The steroid hormone leads to a of the cells to EGF shift of the dose-response the effect. signaling and EGFR can receptor by and of the receptor kinase J. In the rapid of and of growth factor of in the presence of receptor kinase has been as a mechanism for transactivation J. to is the that the of EGF not to for transactivation. This is in to the action of aldosterone the for the action of aldosterone not aldosterone for a in which is but of EGF However, in cells with an EGF as cells S. S. Am. J. Physiol. the of aldosterone has the with for aldosterone and EGF in and the of The the has been in cells, the transactivation of the EGFR signaling to enhanced and cell S. S. Am. J. Physiol. S. S. the in has to in for example, EGFR kinase It is that EGFR signaling modulates ion transport and in cell J. Am. J. Physiol. Furthermore, is that EGFR signaling with respect to the and of aldosterone and is that the of aldosterone with EGFR signaling and responses to that is to the mechanism by which aldosterone with the EGFR signaling It has been shown that aldosterone can J. can to of is a for the of aldosterone and the can also EGFR Our data that the is also in was the of EGF ERK1/2 phosphorylation was In when was by the of EGF was of did not the action of aldosterone. not to the signaling that aldosterone to signaling to involved in EGFR transactivation is the cytosolic tyrosine kinase c-Src J. c-Src EGFR, its we the of aldosterone was that the steroid via This hypothesis is by the that aldosterone c-Src phosphorylation and its we can the aldosterone which EGFR when EGF is the cascade is can elicit of to and S. S. Am. J. Physiol. signaling can a of EGFR and of ERK1/2 we have shown the cell of the in cells S. S. Am. J. Physiol. alternative aldosterone and cell proliferation, in to the cell in cells with mock-transfected data to the of alternative aldosterone that have to in is not the aldosterone leads to the of Furthermore, we have to the of EGF is a for the alternative action of aldosterone. It also to the receptor can interact with the signaling It has been that the classical receptor to alternative of aldosterone the of the signaling for the classical action of aldosterone the This is of the of EGFR, cell to express the receptor as and cells. we of cells with and the receptor to alternative and classical aldosterone In data show that aldosterone the EGF-EGFR-MEK1/2-ERK1/2 signaling cascade to elicit its alternative and that the is to in cells with EGFR the have shown that steroid as aldosterone can elicit The for the rapid of aldosterone not hypothesis is the of steroid with peptide hormone example, the of with signaling has been as as the of or with growth factor and signaling J. J. Am. J. Physiol. In the case of an with and has been suggested and of have shown that aldosterone EGF signaling with respect to ERK1/2 phosphorylation and in cells S. S. Am. J. Physiol. S. S. of EGFR is involved in the of by as via EGFR is a of is that EGFR also a in alternative aldosterone The in were as transfection to elicit alternative aldosterone the presence of signaling for the aldosterone and Our data show that of the of EGF were to the alternative signaling in cells. The that the of EGF was for the aldosterone is in with its action in cells, aldosterone an EGF S. S. Am. J. Physiol. S. S. that EGF EGFR to the rapid of ERK1/2 by aldosterone. The steroid hormone leads to a of the cells to EGF shift of the dose-response the effect. signaling and EGFR can receptor by and of the receptor kinase J. In the rapid of and of growth factor of in the presence of receptor kinase has been as a mechanism for transactivation J. to is the that the of EGF not to for transactivation. This is in to the action of aldosterone the for the action of aldosterone not aldosterone for a in which is but of EGF However, in cells with an EGF as cells S. S. Am. J. Physiol. the of aldosterone has the with The for aldosterone and EGF in and the of The the has been in cells, the transactivation of the EGFR signaling to enhanced and cell S. S. Am. J. Physiol. S. S. the in has to in for example, EGFR kinase It is that EGFR signaling modulates ion transport and in cell J. Am. J. Physiol. Furthermore, is that EGFR signaling with respect to the and of aldosterone and is that the of aldosterone with EGFR signaling and responses to aldosterone. The that is to the mechanism by which aldosterone with the EGFR signaling It has been shown that aldosterone can J. can to of is a for the of aldosterone and the can also EGFR Our data that the is also in was the of EGF ERK1/2 phosphorylation was In when was by the of EGF was of did not the action of aldosterone. not to the signaling that aldosterone to signaling to involved in EGFR transactivation is the cytosolic tyrosine kinase c-Src J. c-Src EGFR, its we the of aldosterone was that the steroid via This hypothesis is by the that aldosterone c-Src phosphorylation and its we can the aldosterone which EGFR when EGF is the cascade is can elicit of to and S. S. Am. J. Physiol. signaling can a of EGFR and of ERK1/2 we have shown the cell of the in cells S. S. Am. J. Physiol. alternative aldosterone and cell proliferation, in to the cell in cells with mock-transfected cells. Our data to the of alternative aldosterone that have to in is not the aldosterone leads to the of Furthermore, we have to the of EGF is a for the alternative action of aldosterone. It also to the receptor can interact with the signaling It has been that the classical receptor to alternative of aldosterone the of the signaling for the classical action of aldosterone the This is of the of EGFR, cell to express the receptor as and cells. we of cells with and the receptor to alternative and classical aldosterone In data show that aldosterone the EGF-EGFR-MEK1/2-ERK1/2 signaling cascade to elicit its alternative and that the is to in cells with EGFR
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