Abstract
Synergism between the RAS and Hedgehog (HH) pathways has been suggested for carcinogenesis in the pancreas, lung and colon. We investigated the molecular cross-talk between RAS and HH signaling and found that, although mutant RAS induces or enhances SHH expression and favors paracrine HH signaling, it antagonizes autocrine HH signal transduction. Activated RAS can be found in primary cilia, the central organelle of HH signal transduction, but functions in a cilium-independent manner and interferes with Gli2 function and Gli3 processing. In addition, the cell-autonomous negative regulation of HH signal transduction involves the RAS effector molecule dual specificity tyrosine phosphorylated and regulated kinase 1B (DYRK1B). In line with a redirection of autocrine toward paracrine HH signaling by a KRAS-DYRK1B network, we find high levels of GLI1 expression restricted to the stromal compartment and not to SHH-expressing tumor cells in human pancreatic adenocarcinoma.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / genetics
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Adenocarcinoma / metabolism
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Animals
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Autocrine Communication* / genetics
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Base Sequence
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Cilia / metabolism
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Disease Models, Animal
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Dyrk Kinases
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Genes, ras
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Hedgehog Proteins / genetics
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Hedgehog Proteins / metabolism*
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Humans
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Kruppel-Like Transcription Factors / genetics
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Kruppel-Like Transcription Factors / metabolism
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Mice
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Models, Biological
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Mutation*
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NIH 3T3 Cells
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Pancreatic Neoplasms / genetics
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Pancreatic Neoplasms / metabolism
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Paracrine Communication* / genetics
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism*
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins p21(ras)
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Neoplasm / genetics
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RNA, Neoplasm / metabolism
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RNA, Small Interfering / genetics
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Zinc Finger Protein GLI1
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Zinc Finger Protein Gli2
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Zinc Finger Protein Gli3
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ras Proteins / antagonists & inhibitors
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ras Proteins / genetics*
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ras Proteins / metabolism*
Substances
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GLI1 protein, human
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GLI2 protein, human
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GLI3 protein, human
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Hedgehog Proteins
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KRAS protein, human
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Kruppel-Like Transcription Factors
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Nerve Tissue Proteins
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Nuclear Proteins
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Proto-Oncogene Proteins
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RNA, Messenger
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RNA, Neoplasm
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RNA, Small Interfering
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SHH protein, human
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Transcription Factors
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Zinc Finger Protein GLI1
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Zinc Finger Protein Gli2
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Zinc Finger Protein Gli3
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins p21(ras)
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ras Proteins