p38MAPK induces cell surface alpha4 integrin downregulation to facilitate erbB-2-mediated invasion.
We have previously shown that human breast cancer cells that overexpress erbB-2 are growth factor-independent. In order to test the contribution of erbB-2 to this and other transformed phenotypes without the genetic instability of cancer cells, erbB-2 was overexpressed in human mammary epithelial (HME) cells. ErbB-2-overexpressing HME cells exhibit several transformed phenotypes including cell surface alpha(4) integrin downregulation and invasiveness. We formulated a model for invasiveness that depends on a cell's ability to downregulate alpha(4) integrin. As small G-proteins play a role in cytoskeleton remodeling and as this is a likely route for alpha(4) integrin trafficking, we investigated the role of small G-proteins and their downstream signals in mediating alpha(4) integrin downregulation and invasiveness using Rac 1. Dominant-negative Rac 1 blocked erbB-2-mediated invasion and reversed erbB-2-mediated alpha(4) integrin downregulation. In addition, constitutively active Rac 1 induced alpha(4) integrin downregulation and invasiveness. In erbB-2-overexpressing and in constitutively active Rac 1-expressing cells, a p38MAP kinase (p38MAPK) inhibitor blocked invasiveness and reversed alpha(4) integrin downregulation. These data suggest a model in which erbB-2 signaling activates Rac 1, which, in turn, activates p38MAPK, leading to the downregulation of alpha(4) integrin. These data strengthen the model where loss of alpha(4) integrin at the cell surface, leading to reduced alpha(4) integrin binding to plasma fibronectin, plays a role in erbB-2-mediated invasiveness.
Woods Ignatoski
Kathleen M
KM
Department of Radiation Oncology and the Comprehensive Cancer Center, University of Michigan Health Systems, Ann Arbor, MI 48109-0948, USA.
Grewal
Navdeep K
NK
Markwart
Sonja
S
Livant
Donna L
DL
Ethier
Stephen P
SP
D000199:Actins / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002469:Cell Separation; D002471:Cell Transformation, Neoplastic; D003599:Cytoskeleton / Q000378:metabolism; D015536:Down-Regulation; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005353:Fibronectins / Q000097:blood; D005434:Flow Cytometry; D005799:Genes, Dominant; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D039441:Integrin alpha4 / Q000096:biosynthesis*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D010641:Phenotype; D021381:Protein Transport; D011725:Pyridines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases
D000199:Actins; D004791:Enzyme Inhibitors; D005353:Fibronectins; D007093:Imidazoles; D039441:Integrin alpha4; D020928:Mitogen-Activated Protein Kinases; D011725:Pyridines; D018719:Erb-b2 Receptor Tyrosine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole