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TGFbeta1 signaling via alphaVbeta6 integrin.

Kracklauer MP, Schmidt C, Sclabas GM - Mol. Cancer (2003)

Bottom Line: Our data provide support for the existence of an alternate TGFbeta1 signaling pathway that is independent of the known SMAD pathway.This alternate pathway involves alphaVbeta6 integrin and the Ras/MAP kinase pathway and does not employ an RGD motif in TGFbeta1-sensitive tumor cells.The combined action of these two pathways seems to be necessary to elicit a complete TGFbeta1 signal.

View Article: PubMed Central - HTML - PubMed

Affiliation: Section of Molecular Cell and Developmental Biology, Institute for Cellular and Molecular Biology, The University of Texas at Austin, 1 University Station, A4800, 78712, Austin, TX, USA. mordechai30@hotmail.com

ABSTRACT

Background: Transforming growth factor beta1 (TGFbeta1) is a potent inhibitor of epithelial cell growth, thus playing an important role in tissue homeostasis. Most carcinoma cells exhibit a reduced sensitivity for TGFbeta1 mediated growth inhibition, suggesting TGFbeta1 participation in the development of these cancers. The tumor suppressor gene DPC4/SMAD4, which is frequently inactivated in carcinoma cells, has been described as a key player in TGFbeta1 mediated growth inhibition. However, some carcinoma cells lacking functional SMAD4 are sensitive to TGFbeta1 induced growth inhibition, thus requiring a SMAD4 independent TGFbeta1 pathway.

Results: Here we report that mature TGFbeta1 is a ligand for the integrin alphaVbeta6, independent of the common integrin binding sequence motif RGD. After TGFbeta1 binds to alphaVbeta6 integrin, different signaling proteins are activated in TGFbeta1-sensitive carcinoma cells, but not in cells that are insensitive to TGFbeta1. Among others, interaction of TGFbeta1 with the alphaVbeta6 integrin resulted in an upregulation of the cell cycle inhibitors p21/WAF1 and p27 leading to growth inhibition in SMAD4 deleted as well as in SMAD4 wildtype carcinoma cells.

Conclusions: Our data provide support for the existence of an alternate TGFbeta1 signaling pathway that is independent of the known SMAD pathway. This alternate pathway involves alphaVbeta6 integrin and the Ras/MAP kinase pathway and does not employ an RGD motif in TGFbeta1-sensitive tumor cells. The combined action of these two pathways seems to be necessary to elicit a complete TGFbeta1 signal.

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Hypothesis about an alternate TGFβ1 signaling pathway via αVβ6 integrin, independent of RGD. This pathway may be required for full TGFβ1 induced transcriptional activation, which explains the TGFβ1 sensitivity of those cells lacking DPC4/SMAD4 function that still react with growth inhibition.
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Figure 10: Hypothesis about an alternate TGFβ1 signaling pathway via αVβ6 integrin, independent of RGD. This pathway may be required for full TGFβ1 induced transcriptional activation, which explains the TGFβ1 sensitivity of those cells lacking DPC4/SMAD4 function that still react with growth inhibition.

Mentions: It has been reported that activated integrins are associated with the cytoskeleton. Here, we show that binding of mature TGFβ1 to αVβ6 integrin resulted in an association of the cytoskeleton (Figure 10). In a variety of integrin-mediated signaling pathways, tyrosinephosphorylation of proteins immobilized to the cytoskeleton is enhanced [66,67]. The same was true in our experimental settings only for the TGFβ1-sensitive cells. This upregulation of tyrosine phosphorylation was inhibited by preincubation with a TGFβ1 neutralizing antibody or by blocking of αVβ6 integrin, thus again proving mature TGFβ1 as an initial signaling ligand for αVβ6.


TGFbeta1 signaling via alphaVbeta6 integrin.

Kracklauer MP, Schmidt C, Sclabas GM - Mol. Cancer (2003)

Hypothesis about an alternate TGFβ1 signaling pathway via αVβ6 integrin, independent of RGD. This pathway may be required for full TGFβ1 induced transcriptional activation, which explains the TGFβ1 sensitivity of those cells lacking DPC4/SMAD4 function that still react with growth inhibition.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC184456&req=5

Figure 10: Hypothesis about an alternate TGFβ1 signaling pathway via αVβ6 integrin, independent of RGD. This pathway may be required for full TGFβ1 induced transcriptional activation, which explains the TGFβ1 sensitivity of those cells lacking DPC4/SMAD4 function that still react with growth inhibition.
Mentions: It has been reported that activated integrins are associated with the cytoskeleton. Here, we show that binding of mature TGFβ1 to αVβ6 integrin resulted in an association of the cytoskeleton (Figure 10). In a variety of integrin-mediated signaling pathways, tyrosinephosphorylation of proteins immobilized to the cytoskeleton is enhanced [66,67]. The same was true in our experimental settings only for the TGFβ1-sensitive cells. This upregulation of tyrosine phosphorylation was inhibited by preincubation with a TGFβ1 neutralizing antibody or by blocking of αVβ6 integrin, thus again proving mature TGFβ1 as an initial signaling ligand for αVβ6.

Bottom Line: Our data provide support for the existence of an alternate TGFbeta1 signaling pathway that is independent of the known SMAD pathway.This alternate pathway involves alphaVbeta6 integrin and the Ras/MAP kinase pathway and does not employ an RGD motif in TGFbeta1-sensitive tumor cells.The combined action of these two pathways seems to be necessary to elicit a complete TGFbeta1 signal.

View Article: PubMed Central - HTML - PubMed

Affiliation: Section of Molecular Cell and Developmental Biology, Institute for Cellular and Molecular Biology, The University of Texas at Austin, 1 University Station, A4800, 78712, Austin, TX, USA. mordechai30@hotmail.com

ABSTRACT

Background: Transforming growth factor beta1 (TGFbeta1) is a potent inhibitor of epithelial cell growth, thus playing an important role in tissue homeostasis. Most carcinoma cells exhibit a reduced sensitivity for TGFbeta1 mediated growth inhibition, suggesting TGFbeta1 participation in the development of these cancers. The tumor suppressor gene DPC4/SMAD4, which is frequently inactivated in carcinoma cells, has been described as a key player in TGFbeta1 mediated growth inhibition. However, some carcinoma cells lacking functional SMAD4 are sensitive to TGFbeta1 induced growth inhibition, thus requiring a SMAD4 independent TGFbeta1 pathway.

Results: Here we report that mature TGFbeta1 is a ligand for the integrin alphaVbeta6, independent of the common integrin binding sequence motif RGD. After TGFbeta1 binds to alphaVbeta6 integrin, different signaling proteins are activated in TGFbeta1-sensitive carcinoma cells, but not in cells that are insensitive to TGFbeta1. Among others, interaction of TGFbeta1 with the alphaVbeta6 integrin resulted in an upregulation of the cell cycle inhibitors p21/WAF1 and p27 leading to growth inhibition in SMAD4 deleted as well as in SMAD4 wildtype carcinoma cells.

Conclusions: Our data provide support for the existence of an alternate TGFbeta1 signaling pathway that is independent of the known SMAD pathway. This alternate pathway involves alphaVbeta6 integrin and the Ras/MAP kinase pathway and does not employ an RGD motif in TGFbeta1-sensitive tumor cells. The combined action of these two pathways seems to be necessary to elicit a complete TGFbeta1 signal.

Show MeSH
Related in: MedlinePlus