Abstract
We demonstrate here that growth hormone (GH) stimulates the activation of Rap1 and Rap2 in NIH-3T3 cells. Full activation of Rap1 and Rap2 by GH necessitated the combined activity of both JAK2 and c-Src kinases, although c-Src was predominantly required. GH-stimulated Rap1 and Rap2 activity was also demonstrated to be CrkII-C3G-dependent. GH stimulated the tyrosine phosphorylation of C3G, which again required the combined activity of JAK2 and c-Src. C3G tyrosine residue 504 was required for GH-stimulated Rap activation. Activated Rap1 inhibited GH-stimulated activation of RalA and subsequent GH-stimulated p44/42 MAP kinase activity and Elk-1-mediated transcription. In addition, we demonstrated that C3G-Rap1 mediated CrkII enhancement of GH-stimulated JNK/SAPK activity. We have therefore identified a linear JAK2-independent pathway switching GH-stimulated p44/42 MAP kinase and JNK/SAPK activities.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3 Cells
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Animals
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CSK Tyrosine-Protein Kinase
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Guanine Nucleotide-Releasing Factor 2 / chemistry
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Guanine Nucleotide-Releasing Factor 2 / metabolism*
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Human Growth Hormone / pharmacology*
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Humans
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Janus Kinase 2
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MAP Kinase Signaling System / drug effects*
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Mice
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / metabolism
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Phosphorylation
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-crk
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Recombinant Proteins / pharmacology
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Tyrosine / chemistry
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rap GTP-Binding Proteins / metabolism
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rap1 GTP-Binding Proteins / metabolism*
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src-Family Kinases
Substances
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Guanine Nucleotide-Releasing Factor 2
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-crk
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Recombinant Proteins
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Human Growth Hormone
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Tyrosine
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Protein-Tyrosine Kinases
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CSK Tyrosine-Protein Kinase
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JAK2 protein, human
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Jak2 protein, mouse
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Janus Kinase 2
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src-Family Kinases
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CSK protein, human
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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RAP2A protein, human
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Rap2a protein, mouse
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rap GTP-Binding Proteins
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rap1 GTP-Binding Proteins