Abstract
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Journal of Biological Chemistry |
| Vol/bind | 280 |
| Udgave nummer | 12 |
| Sider (fra-til) | 11961-72 |
| Antal sider | 11 |
| ISSN | 0021-9258 |
| DOI | |
| Status | Udgivet - 2005 |
| Udgivet eksternt | Ja |
Bibliografisk note
Keywords: Actins; Animals; Antigens, CD44; Cell Line, Tumor; Cell Movement; DNA-Binding Proteins; Disease Progression; Estrogen Receptor alpha; Female; Humans; Hyaluronic Acid; Mice; Mitogen-Activated Protein Kinase 1; Ovarian Neoplasms; Phosphorylation; Proto-Oncogene Proteins; RNA, Small Interfering; Rats; Signal Transduction; Trans-Activation (Genetics); Transcription Factors; cdc42 GTP-Binding Protein; ets-Domain Protein Elk-1; ras GTPase-Activating ProteinsAdgang til dokumentet
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I: Journal of Biological Chemistry, Bind 280, Nr. 12, 2005, s. 11961-72.
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review
}
TY - JOUR
T1 - Hyaluronan-CD44 interaction with IQGAP1 promotes Cdc42 and ERK signaling, leading to actin binding, Elk-1/estrogen receptor transcriptional activation, and ovarian cancer progression.
AU - Bourguignon, Lilly Y W
AU - Gilad, Eli
AU - Rothman, Kori
AU - Peyrollier, Karine
N1 - Keywords: Actins; Animals; Antigens, CD44; Cell Line, Tumor; Cell Movement; DNA-Binding Proteins; Disease Progression; Estrogen Receptor alpha; Female; Humans; Hyaluronic Acid; Mice; Mitogen-Activated Protein Kinase 1; Ovarian Neoplasms; Phosphorylation; Proto-Oncogene Proteins; RNA, Small Interfering; Rats; Signal Transduction; Trans-Activation (Genetics); Transcription Factors; cdc42 GTP-Binding Protein; ets-Domain Protein Elk-1; ras GTPase-Activating Proteins
PY - 2005
Y1 - 2005
N2 - In this study, we have examined the interaction of hyaluronan (HA)-CD44 with IQGAP1 (one of the binding partners for the Rho GTPase Cdc42) in SK-OV-3.ipl human ovarian tumor cells. Immunological and biochemical analyses indicated that IQGAP1 (molecular mass of approximately 190 kDa) is expressed in SK-OV-3.ipl cells and that IQGAP1 interacts directly with Cdc42 in a GTP-dependent manner. Both IQGAP1 and Cdc42 were physically linked to CD44 in SK-OV-3.ipl cells following HA stimulation. Furthermore, the HA-CD44-induced Cdc42-IQGAP1 complex regulated cytoskeletal function via a close association with F-actin that led to ovarian tumor cell migration. In addition, the binding of HA to CD44 promoted the association of ERK2 with the IQGAP1 molecule, which stimulated both ERK2 phosphorylation and kinase activity. The activated ERK2 then increased the phosphorylation of both Elk-1 and estrogen receptor-alpha (ER alpha), resulting in Elk-1- and estrogen-responsive element-mediated transcriptional up-regulation. Down-regulation of IQGAP1 (by treating cells with IQGAP1-specific small interfering RNAs) not only blocked IQGAP1 association with CD44, Cdc42, F-actin, and ERK2 but also abrogated HA-CD44-induced cytoskeletal function, ERK2 signaling (e.g. ERK2 phosphorylation/activity, ERK2-mediated Elk-1/ER alpha phosphorylation, and Elk-1/ER alpha-specific transcriptional activation), and tumor cell migration. Taken together, these findings indicate that HA-CD44 interaction with IQGAP1 serves as a signal integrator by modulating Cdc42 cytoskeletal function, mediating Elk-1-specific transcriptional activation, and coordinating "cross-talk" between a membrane receptor (CD44) and a nuclear hormone receptor (ER alpha) signaling pathway during ovarian cancer progression.
AB - In this study, we have examined the interaction of hyaluronan (HA)-CD44 with IQGAP1 (one of the binding partners for the Rho GTPase Cdc42) in SK-OV-3.ipl human ovarian tumor cells. Immunological and biochemical analyses indicated that IQGAP1 (molecular mass of approximately 190 kDa) is expressed in SK-OV-3.ipl cells and that IQGAP1 interacts directly with Cdc42 in a GTP-dependent manner. Both IQGAP1 and Cdc42 were physically linked to CD44 in SK-OV-3.ipl cells following HA stimulation. Furthermore, the HA-CD44-induced Cdc42-IQGAP1 complex regulated cytoskeletal function via a close association with F-actin that led to ovarian tumor cell migration. In addition, the binding of HA to CD44 promoted the association of ERK2 with the IQGAP1 molecule, which stimulated both ERK2 phosphorylation and kinase activity. The activated ERK2 then increased the phosphorylation of both Elk-1 and estrogen receptor-alpha (ER alpha), resulting in Elk-1- and estrogen-responsive element-mediated transcriptional up-regulation. Down-regulation of IQGAP1 (by treating cells with IQGAP1-specific small interfering RNAs) not only blocked IQGAP1 association with CD44, Cdc42, F-actin, and ERK2 but also abrogated HA-CD44-induced cytoskeletal function, ERK2 signaling (e.g. ERK2 phosphorylation/activity, ERK2-mediated Elk-1/ER alpha phosphorylation, and Elk-1/ER alpha-specific transcriptional activation), and tumor cell migration. Taken together, these findings indicate that HA-CD44 interaction with IQGAP1 serves as a signal integrator by modulating Cdc42 cytoskeletal function, mediating Elk-1-specific transcriptional activation, and coordinating "cross-talk" between a membrane receptor (CD44) and a nuclear hormone receptor (ER alpha) signaling pathway during ovarian cancer progression.
U2 - 10.1074/jbc.M411985200
DO - 10.1074/jbc.M411985200
M3 - Journal article
C2 - 15655247
SN - 0021-9258
VL - 280
SP - 11961
EP - 11972
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 12
ER -