Abstract
alpha6beta4 integrin and the Met receptor for HGF have been shown independently to promote invasive growth. We demonstrate here that Met selectively associates with alpha6beta4. In carcinoma cells expressing Met alone, HGF does not exert significant biological effects. Ectopic expression of alpha6beta4 restores HGF-regulated processes. Following Met activation, alpha6beta4 is tyrosine phosphorylated and combines with Shc and PI3K, generating an additional signaling platform that potentiates HGF-triggered activation of Ras- and PI3K-dependent pathways. In the presence of an alpha6beta4 mutant defective for Shc recruitment, Met cannot sustain HGF-mediated responses. Surprisingly, a truncated beta4 unable to bind laminins retains the activity of wild-type alpha6beta4. Such findings invoke an unexpected role for alpha6beta4 in cancer invasion as a functional amplifier of biochemical outputs rather than a mechanical adhesive device.
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Adaptor Proteins, Vesicular Transport*
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Animals
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Antigens, Surface / genetics
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Antigens, Surface / metabolism*
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Cell Adhesion
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Cell Line
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Female
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Hepatocyte Growth Factor / metabolism*
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Humans
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Integrin alpha6beta4
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Integrins / genetics
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Integrins / metabolism*
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Lung Neoplasms / pathology
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Lung Neoplasms / secondary
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Mice
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Mice, Nude
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Microscopy, Fluorescence
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Mitogen-Activated Protein Kinases / metabolism
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Neoplasm Invasiveness
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Neoplasms, Experimental / metabolism
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Neoplasms, Experimental / pathology*
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation
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Phosphotyrosine / metabolism
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Precipitin Tests
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Protein Serine-Threonine Kinases*
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Protein Subunits
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Proteins / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-met / metabolism*
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Shc Signaling Adaptor Proteins
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Signal Transduction*
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Src Homology 2 Domain-Containing, Transforming Protein 1
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Stomach Neoplasms / metabolism
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Stomach Neoplasms / pathology
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Transfection
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Tumor Cells, Cultured
Substances
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport
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Antigens, Surface
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Integrin alpha6beta4
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Integrins
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Protein Subunits
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Proteins
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Proto-Oncogene Proteins
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SHC1 protein, human
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Shc Signaling Adaptor Proteins
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Shc1 protein, mouse
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Src Homology 2 Domain-Containing, Transforming Protein 1
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Phosphotyrosine
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Hepatocyte Growth Factor
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Proto-Oncogene Proteins c-met
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinases