DYRK1B-dependent autocrine-to-paracrine shift of Hedgehog signaling by mutant RAS.
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.
Karolinska Institutet, Center for Biosciences, Department of Biosciences and Nutrition, Huddinge, Sweden.
Matthias
M
Lauth
Asa
A
Bergström
Takashi
T
Shimokawa
Ulrica
U
Tostar
Qianren
Q
Jin
Volker
V
Fendrich
Carmen
C
Guerra
Mariano
M
Barbacid
Rune
R
Toftgård
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019898:Autocrine Communication / Q000235:genetics; D001483:Base Sequence; D002923:Cilia / Q000378:metabolism; D004195:Disease Models, Animal; D011905:Genes, ras; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism; D019899:Paracrine Communication / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D000097603:Dyrk Kinases
D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3; D018631:ras Proteins; D000097603:Dyrk Kinases; C400551:GLI1 protein, human; C082593:GLI2 protein, human; C065683:GLI3 protein, human; C117307:KRAS protein, human; C509239:SHH protein, human