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DYRK1B-dependent autocrine-to-paracrine shift of Hedgehog signaling by mutant RAS

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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.

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Figure 1: KRAS-induced paracrine HH signaling.
Figure 2: Oncogenic KRAS is an inhibitor of HH signaling.
Figure 3: Molecular interaction of RAS(12V) with the HH pathway.
Figure 4: Mechanism of HH pathway inhibition by RAS(12V).
Figure 5: DYRK1B mediates the HH-suppressive aspects of mutant RAS.
Figure 6: Effects of KRAS-DYRK1B in human cancer cells.
Figure 7: Cilia-independent HH pathway effects of KRAS and TGFβ.
Figure 8: Schematic summary of the KRAS effects on HH signaling.

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Acknowledgements

We are indebted to R. Marais (ICR, London), K. Okazaki (Kurume Univ.), M. Muenke (US National Institutes of Health), C. Counter (Duke Univ.), J. Bos (Univ. Utrecht), P. Beachy (Stanford), F. Aberger (Univ. Salzburg), J. Taipale (Karolinska Institutet), M. Löhr (Karolinska Institutet) and J. Bergman (Karolinska Institutet) for kind provision of reagents, plasmids and cell lines, F. de Sauvage and S. Scales at Genentech for the provision of the anti-HH antibody, S. Teglund and V. Jaks for critical comments on the manuscript and E. Tuksammel for technical help and animal caretaking. We are grateful for grant support from the Swedish Cancer Society, the Wenner-Gren-Foundation, the Lars Hiertas Minne Foundation and the Karolinska Institutet to M.L. and from the Swedish Cancer Society, the Swedish Research Council, the US National Institutes of Health National Cancer Institute (Mouse Models of Human Cancers Consortium Grant UO1 CA105491) and Swiss Bridge to R.T. T.S. is a Marie Curie International Incoming Fellow.

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M.L., C.G., M.B. and R.T. designed experiments; M.L., Å.B., T.S., U.T., Q.J., V.F. and C.G. performed experiments; M.L. and R.T. interpreted data and wrote the manuscript.

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Correspondence to Rune Toftgård.

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Lauth, M., Bergström, Å., Shimokawa, T. et al. DYRK1B-dependent autocrine-to-paracrine shift of Hedgehog signaling by mutant RAS. Nat Struct Mol Biol 17, 718–725 (2010). https://doi.org/10.1038/nsmb.1833

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