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TGFbeta1 activates c-Jun and Erk1 via alphaVbeta6 integrin.

Luettich K, Schmidt C - Mol. Cancer (2003)

Bottom Line: Overexpression of alphaVbeta6 integrin is associated with lymph node metastasis of gastric carcinomas.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: 1Department of Dermatology, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York, 10021, USA. karsta.luettich@molecular-cancer.org

ABSTRACT
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.

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Erk1 is associated with focal adhesions. BxPC-3 cells were stimulated with 10 nM of mature TGFβ1 for ten minutes followed by preparation of the Triton-X100 nonsoluble fraction and precipitation with αVβ6 integrin antibodies. The precipitate was then re-precipitated with anti-FAK antibodies (sc-1688) and analyzed with an Erk1 antibody (sc-93). In part, the cells were preincubated with a TGFβ1 antibody [10].
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Figure 5: Erk1 is associated with focal adhesions. BxPC-3 cells were stimulated with 10 nM of mature TGFβ1 for ten minutes followed by preparation of the Triton-X100 nonsoluble fraction and precipitation with αVβ6 integrin antibodies. The precipitate was then re-precipitated with anti-FAK antibodies (sc-1688) and analyzed with an Erk1 antibody (sc-93). In part, the cells were preincubated with a TGFβ1 antibody [10].

Mentions: MEKK1 is absolutely required for cellular responses, which alter the integrity of the microtubule cytoskeleton and cell shape; MEKK1 is the MAPK kinase kinase regulating the JNK pathway [24,25]. The significance for a cytoskeletal immobilization of c-Jun is not known. We also detected Erk1 associated with focal adhesions in BxPC-3 cells, stimulated with 10 nM of mature TGFβ1 (Figure 5). Most strikingly, we observed two bands for the phosphorylated form of Erk1. These bands are not visible after incubation with phosphatases (data not shown).


TGFbeta1 activates c-Jun and Erk1 via alphaVbeta6 integrin.

Luettich K, Schmidt C - Mol. Cancer (2003)

Erk1 is associated with focal adhesions. BxPC-3 cells were stimulated with 10 nM of mature TGFβ1 for ten minutes followed by preparation of the Triton-X100 nonsoluble fraction and precipitation with αVβ6 integrin antibodies. The precipitate was then re-precipitated with anti-FAK antibodies (sc-1688) and analyzed with an Erk1 antibody (sc-93). In part, the cells were preincubated with a TGFβ1 antibody [10].
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC222989&req=5

Figure 5: Erk1 is associated with focal adhesions. BxPC-3 cells were stimulated with 10 nM of mature TGFβ1 for ten minutes followed by preparation of the Triton-X100 nonsoluble fraction and precipitation with αVβ6 integrin antibodies. The precipitate was then re-precipitated with anti-FAK antibodies (sc-1688) and analyzed with an Erk1 antibody (sc-93). In part, the cells were preincubated with a TGFβ1 antibody [10].
Mentions: MEKK1 is absolutely required for cellular responses, which alter the integrity of the microtubule cytoskeleton and cell shape; MEKK1 is the MAPK kinase kinase regulating the JNK pathway [24,25]. The significance for a cytoskeletal immobilization of c-Jun is not known. We also detected Erk1 associated with focal adhesions in BxPC-3 cells, stimulated with 10 nM of mature TGFβ1 (Figure 5). Most strikingly, we observed two bands for the phosphorylated form of Erk1. These bands are not visible after incubation with phosphatases (data not shown).

Bottom Line: Overexpression of alphaVbeta6 integrin is associated with lymph node metastasis of gastric carcinomas.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: 1Department of Dermatology, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York, 10021, USA. karsta.luettich@molecular-cancer.org

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus