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Crosstalk Between MAP Kinase And Hedgehog Pathways by Direct Phosphorylation of Gli Transcription Factors
Author(s) -
Bardwell Lee,
Bardwell A Jane,
Wu Beibei,
Waterman Marian
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1112.1
Subject(s) - gli1 , hedgehog , crosstalk , hedgehog signaling pathway , mapk/erk pathway , cancer research , phosphorylation , smoothened , kinase , gli2 , microbiology and biotechnology , biology , signal transduction , transcription factor , chemistry , genetics , gene , physics , optics
MAP kinase pathways are hyperactivated in many of the same tumor types in which Hedgehog signaling is deregulated. Indeed, crosstalk between the Hedgehog/Gli pathway and Ras/mitogen‐activated protein kinase (MAPK) signaling pathways occurs in many types of cancer, including pancreatic cancer, melanoma, colorectal cancer, and medulloblastoma, and may contribute to the emergence of clinical resistance to Hedgehog pathway inhibitors (reviewed in [1, 2]). However, the molecular mechanism(s) of this crosstalk are unclear. We have shown that the transcription factors Gli1 and Gli3, which are downstream targets of the Hedgehog pathway, are also efficient substrates of ERK and JNK‐family MAPKs [3]. Here we show that MAPKs phosphorylate Gli1, Gli2 and Gli3 on residues located near the binding site for Sufu, a key negative regulator of Gli function. Furthermore, we show that MAPK‐mediated phosphorylation weakens the binding of Sufu to Gli1‐3. We have mapped the MAPK phosphorylation sites in Gli1, and show that three sites are collectively necessary and sufficient for Sufu release. Cells expressing Gli1 alleles mutated in these residues exhibit perturbed Hedgehog signaling. Hence, we identify a functional mechanism of MAPK‐Hedgehog crosstalk that could contribute to developmental signaling, tumorigenesis and clinical resistance. Support or Funding Information This work was supported by NIH‐NIGMS grant P50‐GM76516 and by a grant from the University of California Cancer Research Coordinating Committee