ERK5 promotes Src-induced podosome formation by limiting Rho activation.
Increased Src activity, often associated with tumorigenesis, leads to the formation of invasive adhesions termed podosomes. Podosome formation requires the function of Rho family guanosine triphosphatases and reorganization of the actin cytoskeleton. In addition, Src induces changes in gene expression required for transformation, in part by activating mitogen-activated protein kinase (MAPK) signaling pathways. We sought to determine whether MAPK signaling regulates podosome formation. Unlike extracellular signal-regulated kinase 1/2 (ERK1/2), ERK5 is constitutively activated in Src-transformed fibroblasts. ERK5-deficient cells expressing v-Src exhibited increased RhoA activation and signaling, which lead to cellular retraction and an inability to form podosomes or induce invasion. Addition of the Rho-kinase inhibitor Y27632 to ERK5-deficient cells expressing v-Src led to cellular extension and restored podosome formation. In Src-transformed cells, ERK5 induced the expression of a Rho GTPase-activating protein (RhoGAP), RhoGAP7/DLC-1, via activation of the transcription factor myocyte enhancing factor 2C, and RhoGAP7 expression restored podosome formation in ERK5-deficient cells. We conclude that ERK5 promotes Src-induced podosome formation by inducing RhoGAP7 and thereby limiting Rho activation.
Schramp
Mark
M
Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA.
Ying
Olivia
O
Kim
Tai Young
TY
Martin
G Steven
GS
D000199:Actins / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D000818:Animals; D002461:Cell Line, Transformed; D021961:Cell Membrane Structures / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D064326:MEF2 Transcription Factors; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D048054:Mitogen-Activated Protein Kinase 7 / Q000172:deficiency / Q000378:metabolism*; D050505:Mutant Proteins / Q000378:metabolism; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D018994:Myosin Light Chains / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D013696:Temperature; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
D000199:Actins; D000577:Amides; C430864:DLC-1 (deleted in liver cancer) protein, mouse; D020690:GTPase-Activating Proteins; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D050505:Mutant Proteins; D018006:Myogenic Regulatory Factors; D018994:Myosin Light Chains; D011725:Pyridines; D025521:Tumor Suppressor Proteins; C108830:Y 27632; D016392:Proto-Oncogene Proteins pp60(c-src); D054460:rho-Associated Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048054:Mitogen-Activated Protein Kinase 7; D020741:rho GTP-Binding Proteins