PMID- 20512148
OWN - NLM
STAT- MEDLINE
DCOM- 20100623
LR  - 20231213
IS  - 1545-9985 (Electronic)
IS  - 1545-9985 (Linking)
VI  - 17
IP  - 6
DP  - 2010 Jun
TI  - DYRK1B-dependent autocrine-to-paracrine shift of Hedgehog signaling by mutant 
      RAS.
PG  - 718-25
LID - 10.1038/nsmb.1833 [doi]
AB  - 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.
FAU - Lauth, Matthias
AU  - Lauth M
AD  - Karolinska Institutet, Center for Biosciences, Department of Biosciences and 
      Nutrition, Huddinge, Sweden.
FAU - Bergstrom, Asa
AU  - Bergstrom A
FAU - Shimokawa, Takashi
AU  - Shimokawa T
FAU - Tostar, Ulrica
AU  - Tostar U
FAU - Jin, Qianren
AU  - Jin Q
FAU - Fendrich, Volker
AU  - Fendrich V
FAU - Guerra, Carmen
AU  - Guerra C
FAU - Barbacid, Mariano
AU  - Barbacid M
FAU - Toftgard, Rune
AU  - Toftgard R
LA  - eng
GR  - UO1 CA105491/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100530
PL  - United States
TA  - Nat Struct Mol Biol
JT  - Nature structural & molecular biology
JID - 101186374
RN  - 0 (GLI1 protein, human)
RN  - 0 (GLI2 protein, human)
RN  - 0 (GLI3 protein, human)
RN  - 0 (Hedgehog Proteins)
RN  - 0 (KRAS protein, human)
RN  - 0 (Kruppel-Like Transcription Factors)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA, Neoplasm)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (SHH protein, human)
RN  - 0 (Transcription Factors)
RN  - 0 (Zinc Finger Protein GLI1)
RN  - 0 (Zinc Finger Protein Gli2)
RN  - 0 (Zinc Finger Protein Gli3)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
RN  - EC 3.6.5.2 (ras Proteins)
SB  - IM
MH  - Adenocarcinoma/genetics/metabolism
MH  - Animals
MH  - *Autocrine Communication/genetics
MH  - Base Sequence
MH  - Cilia/metabolism
MH  - Disease Models, Animal
MH  - Genes, ras
MH  - Hedgehog Proteins/genetics/*metabolism
MH  - Humans
MH  - Kruppel-Like Transcription Factors/genetics/metabolism
MH  - Mice
MH  - Models, Biological
MH  - *Mutation
MH  - NIH 3T3 Cells
MH  - Nerve Tissue Proteins/genetics/metabolism
MH  - Nuclear Proteins/genetics/metabolism
MH  - Pancreatic Neoplasms/genetics/metabolism
MH  - *Paracrine Communication/genetics
MH  - Protein Serine-Threonine Kinases/genetics/*metabolism
MH  - Protein-Tyrosine Kinases/genetics/*metabolism
MH  - Proto-Oncogene Proteins/antagonists & inhibitors/*genetics/*metabolism
MH  - Proto-Oncogene Proteins p21(ras)
MH  - RNA, Messenger/genetics/metabolism
MH  - RNA, Neoplasm/genetics/metabolism
MH  - RNA, Small Interfering/genetics
MH  - Transcription Factors/genetics/metabolism
MH  - Zinc Finger Protein GLI1
MH  - Zinc Finger Protein Gli2
MH  - Zinc Finger Protein Gli3
MH  - ras Proteins/antagonists & inhibitors/*genetics/*metabolism
MH  - Dyrk Kinases
EDAT- 2010/06/01 06:00
MHDA- 2010/06/24 06:00
CRDT- 2010/06/01 06:00
PHST- 2009/05/07 00:00 [received]
PHST- 2010/03/16 00:00 [accepted]
PHST- 2010/06/01 06:00 [entrez]
PHST- 2010/06/01 06:00 [pubmed]
PHST- 2010/06/24 06:00 [medline]
AID - nsmb.1833 [pii]
AID - 10.1038/nsmb.1833 [doi]
PST - ppublish
SO  - Nat Struct Mol Biol. 2010 Jun;17(6):718-25. doi: 10.1038/nsmb.1833. Epub 2010 May 
      30.