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PMID: 16428439 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

Essential role for Rac in heregulin beta1 mitogenic signaling: a mechanism that involves epidermal growth factor receptor and is independent of ErbB4.

Molecular and cellular biology ·Vol. 26 ·No. 3 ·2006-02-00 ·Pages 831-42

Yang C, Liu Y, Lemmon MA, Kazanietz MG

Abstract

Heregulins are a family of ligands for the ErbB3/ErbB4 receptors that play important roles in breast cancer cell proliferation and tumorigenesis. Limited information is available on the contribution of Rho GTPases to heregulin-mediated signaling. In breast cancer cells, heregulin beta1 (HRG) causes a strong activation of Rac; however, it does so with striking differences in kinetics compared to epidermal growth factor, which signals through ErbB1 (epidermal growth factor receptor [EGFR]). Using specific ErbB receptor inhibitors and depletion of receptors by RNA interference (RNAi), we established that, surprisingly, activation of Rac by HRG is mediated not only by ErbB3 and ErbB2 but also by transactivation of EGFR, and it is independent of ErbB4. Similar receptor requirements are observed for HRG-induced actin cytoskeleton reorganization and mitogenic activity via extracellular signal-regulated kinase (ERK). HRG-induced Rac activation was phosphatidylinositol 3-kinase dependent and Src independent. Furthermore, inactivation of Rac by expression of the Rac GTPase-activating protein beta2-chimerin inhibited HRG-induced ERK activation, mitogenicity, and migration in breast cancer cells. HRG mitogenic activity was also impaired by depletion of Rac1 using RNAi. Our studies established that Rac is a critical mediator of HRG mitogenic signaling in breast cancer cells and highlight additional levels of complexity for ErbB receptor coupling to downstream effectors that control aberrant proliferation and transformation.

MeSH Terms
Antibodies, Blocking/pharmacology Breast Neoplasms/enzymology Cell Movement Cell Proliferation Enzyme Activation ErbB Receptors/antagonists & inhibitors,genetics,metabolism Female Humans Neoplasm Proteins/metabolism Neuregulin-1/metabolism Phosphatidylinositol 3-Kinases/metabolism Phosphoinositide-3 Kinase Inhibitors Protein Kinase Inhibitors/pharmacology Proto-Oncogene Proteins c-akt/antagonists & inhibitors,metabolism RNA Interference Receptor, ErbB-2/antagonists & inhibitors,genetics,metabolism Receptor, ErbB-3/antagonists & inhibitors,genetics,metabolism Receptor, ErbB-4 Tumor Cells, Cultured src-Family Kinases/antagonists & inhibitors,metabolism
Chemicals
Antibodies, Blocking Neoplasm Proteins Neuregulin-1 Phosphoinositide-3 Kinase Inhibitors Protein Kinase Inhibitors beta-chimaerin heregulin beta1 ERBB4 protein, human ErbB Receptors Receptor, ErbB-2 Receptor, ErbB-3 Receptor, ErbB-4 src-Family Kinases Proto-Oncogene Proteins c-akt
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Yang Chengfeng
Department of Pharmacology, University of Pennsylvania School of Medicine, 816 Biomedical Research Building II/III, 421 Curie Blvd., Philadelphia, PA 19104-6160, USA.
Liu Ying
Lemmon Mark A
Kazanietz Marcelo G
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.26.3.831-842.2006
Published
2006-02-00
Pages
831-42
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC1347034
Subset
IM
Grants
NCI NIH HHS · R01 CA079992-09 · United States
NCI NIH HHS · R01 CA079992 · United States
NCI NIH HHS · R01 CA074197 · United States
NCI NIH HHS · R01-CA74197 · United States
NCI NIH HHS · R01 CA096768 · United States
External Links
PubMed source DOI: 10.1128/MCB.26.3.831-842.2006 PMC Full Text View journal details
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