Formation of an active Ci/Gli-Sufu-Fu/Ulk3 transcriptional complexes can prevent premature loss of CiA/GliA function because unbound Ci/Gli is more accessible to HIB/speckle-type POZ protein (SPOP) mediated degradation in the nucleus (37, 48, 77, 78), which could explain why ectopic Hh pathway activation in Sufu mutants or Sufu Ptch1 double mutants was less dramatic than that in Ptch1 mutants (37, 71, 75), and why increasing Sufu gene dosage could promote medulloblastoma tumorigenesis caused by Ptch1 ablation (79). The gene discussed is SPOP; the disease is medulloblastoma.