Abstract
Rac GTPases, small G-proteins widely implicated in tumorigenesis and metastasis, transduce signals from tyrosine-kinase, G-protein-coupled receptors (GPCRs), and integrins, and control a number of essential cellular functions including motility, adhesion, and proliferation. Deregulation of Rac signaling in cancer is generally a consequence of enhanced upstream inputs from tyrosine-kinase receptors, PI3K or Guanine nucleotide Exchange Factors (GEFs), or reduced Rac inactivation by GTPase Activating Proteins (GAPs). In breast cancer cells Rac1 is a downstream effector of ErbB receptors and mediates migratory responses by ErbB1/EGFR ligands such as EGF or TGFα and ErbB3 ligands such as heregulins. Recent advances in the field led to the identification of the Rac-GEF P-Rex1 as an essential mediator of Rac1 responses in breast cancer cells. P-Rex1 is activated by the PI3K product PIP3 and Gβγ subunits, and integrates signals from ErbB receptors and GPCRs. Most notably, P-Rex1 is highly overexpressed in human luminal breast tumors, particularly those expressing ErbB2 and estrogen receptor (ER). The P-Rex1/Rac signaling pathway may represent an attractive target for breast cancer therapy.
Copyright © 2011. Published by Elsevier Inc.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Review
MeSH terms
-
Animals
-
Breast Neoplasms / genetics
-
Breast Neoplasms / metabolism*
-
Breast Neoplasms / pathology
-
Cell Adhesion
-
Cell Communication
-
Cell Movement
-
Cell Proliferation
-
Cell Transformation, Neoplastic / genetics
-
Cell Transformation, Neoplastic / metabolism*
-
Cell Transformation, Neoplastic / pathology
-
Epidermal Growth Factor / metabolism
-
ErbB Receptors / genetics
-
ErbB Receptors / metabolism
-
Female
-
GTPase-Activating Proteins / genetics
-
GTPase-Activating Proteins / metabolism*
-
Guanine Nucleotide Exchange Factors / genetics
-
Guanine Nucleotide Exchange Factors / metabolism*
-
Humans
-
Mice
-
Neuregulins / genetics
-
Neuregulins / metabolism
-
Phosphatidylinositol 3-Kinases / genetics
-
Phosphatidylinositol 3-Kinases / metabolism
-
Receptors, G-Protein-Coupled / genetics
-
Receptors, G-Protein-Coupled / metabolism
-
Signal Transduction*
-
Transforming Growth Factor alpha / metabolism
-
rac GTP-Binding Proteins / genetics
-
rac GTP-Binding Proteins / metabolism
Substances
-
GTPase-Activating Proteins
-
Guanine Nucleotide Exchange Factors
-
Neuregulins
-
Receptors, G-Protein-Coupled
-
Transforming Growth Factor alpha
-
Epidermal Growth Factor
-
Phosphatidylinositol 3-Kinases
-
ErbB Receptors
-
rac GTP-Binding Proteins