TGFbeta1 activates c-Jun and Erk1 via alphaVbeta6 integrin.
Transforming growth factor beta (TGFbeta) plays an important role in animal development and many cellular processes. A variety of cellular functions that are required for tumor metastasis are controlled by integrins, a family of cell adhesion receptors. Overexpression of alphaVbeta6 integrin is associated with lymph node metastasis of gastric carcinomas. It has been demonstrated that a full TGFbeta1 signal requires both alphaVbeta6 integrin and SMAD pathway. TGFbeta1 binds to alphaVbeta6 via the DLXXL motif, a freely accessible amino acid sequence in the mature form of TGFbeta1. Binding of mature TGFbeta1 to alphaVbeta6 leads to immobilization and tyrosine phosphorylation of proteins, which are associated with focal adhesions, a hallmark of integrin-mediated signal transduction. Here, we show that binding of mature TGFbeta1 recruits the mitogen-activated protein kinase kinase kinase 1 (MEKK1), a mediator of c-Jun activation, and the extracellular signaling-regulated kinase-1 (Erk1) to focal adhesions. In addition, the p21-activated kinase 1 (PAK1) is associated with focal adhesions and differentially phosphorylated upon TGFbeta1 stimulation. We conclude that TGFbeta1 activates c-Jun via the MEKK1/p38 MAP kinase pathway and influences cytoskeletal organization. These finding may provide a link between TGFbeta1 and the metastatic behavior of cancers.
Luettich
Karsta
K
1Department of Dermatology, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York, 10021, USA. karsta.luettich@molecular-cancer.org
Schmidt
Christian
C
D000818:Animals; D000951:Antigens, Neoplasm / Q000032:analysis / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000032:analysis; D003599:Cytoskeleton / Q000737:chemistry; D004789:Enzyme Activation; D022001:Focal Adhesions / Q000737:chemistry / Q000201:enzymology; D016023:Integrins / Q000032:analysis / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000032:analysis; D020935:MAP Kinase Signaling System; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis / Q000378:metabolism*; D051419:Paxillin; D010750:Phosphoproteins / Q000032:analysis; D017346:Protein Serine-Threonine Kinases / Q000032:analysis; D016755:Proto-Oncogene Proteins c-jun / Q000032:analysis / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D054462:p21-Activated Kinases
D000951:Antigens, Neoplasm; D003598:Cytoskeletal Proteins; D016023:Integrins; D051419:Paxillin; D010750:Phosphoproteins; D016755:Proto-Oncogene Proteins c-jun; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C073878:integrin alphavbeta6; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases