Abstract
To understand the mechanism of Axl signaling, we have initiated studies to delineate downstream components in interleukin-3-dependent 32D cells by using a chimeric receptor containing the recombinant epidermal growth factor (EGF) receptor extracellular and transmembrane domains and the Axl kinase domain (EAK [for EGF receptor-Axl kinase]). We have previously shown that upon exogenous EGF stimulation, 32D-EAK cells are capable of proliferation in the absence of interleukin-3. With this system, we determined that EAK-induced cell survival and mitogenesis are dependent upon the Ras/extracellular-signal-regulated protein kinase (ERK) cascade. Although the phosphatidylinositol-3 kinase pathway is activated upon EAK signaling, it appears to be dispensable for the biological actions of the Axl kinase. Furthermore, we demonstrated that different threshold levels of Ras/ERK activation are needed to induce a block to apoptosis or proliferation in 32D cells. Recently, we have identified an Axl ligand, GAS6. Surprisingly, GAS6-stimulated 32D-Axl cells exhibited no blockage to apoptosis or mitogenic response which is correlated with the absence of Ras/ERK activation. Taken together, these data suggest that different extracellular domains dramatically alter the intracellular response of the Axl kinase. Furthermore, our data suggest that the GAS6-Axl interaction does not induce mitogenesis and that its exact role remains to be determined.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
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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Axl Receptor Tyrosine Kinase
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Base Sequence
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Cell Division
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Cell Line
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DNA Primers / genetics
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Enzyme Activation
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ErbB Receptors / genetics
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ErbB Receptors / metabolism
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GRB2 Adaptor Protein
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Intercellular Signaling Peptides and Proteins*
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Mice
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases*
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Molecular Sequence Data
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Oncogene Proteins / genetics
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Oncogene Proteins / metabolism*
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Phosphatidylinositol 3-Kinases
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Phosphotransferases (Alcohol Group Acceptor) / metabolism
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Proteins / metabolism
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Proto-Oncogene Proteins
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / metabolism*
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / 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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ras Proteins / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport
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DNA Primers
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GRB2 Adaptor Protein
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Grb2 protein, mouse
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Intercellular Signaling Peptides and Proteins
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Oncogene Proteins
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Proteins
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Proto-Oncogene Proteins
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Recombinant Fusion Proteins
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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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growth arrest-specific protein 6
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Phosphatidylinositol 3-Kinases
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Phosphotransferases (Alcohol Group Acceptor)
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ErbB Receptors
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Receptor Protein-Tyrosine Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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ras Proteins
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Axl Receptor Tyrosine Kinase
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AXL receptor tyrosine kinase, mouse