HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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

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.
AuthorsChengfeng Yang, Ying Liu, Mark A Lemmon, Marcelo G Kazanietz
JournalMolecular and cellular biology (Mol Cell Biol) Vol. 26 Issue 3 Pg. 831-42 (Feb 2006) ISSN: 0270-7306 [Print] United States
PMID16428439 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • 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
Topics
  • 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)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: