STK36

STK36, the mammalian ortholog of Drosophila Fused, is a serine-threonine kinase with dual roles spanning Hedgehog signal transduction and motile cilia assembly (PMID:8861096, PMID:23907739). In Drosophila, fused acts genetically downstream of Hedgehog and Patched to transmit the Hh signal controlling dpp and engrailed expression, operating within the same pathway as Costal-2, Cubitus interruptus, and PKA without being epistatic to them (PMID:8861096). In mammals, STK36 enhances GLI-induced transcription, with the long human isoform selectively potentiating GLI2 activity, and its loss impairs Hedgehog signaling output (PMID:15268766). Its transcriptional contribution is controlled by the E3 ubiquitin ligase MID1, which ubiquitinates and proteasomally cleaves Fu to couple the MID1-PP2A complex to GLI3 regulation (PMID:25278022). Independently of its signaling role, STK36 is required for assembly of the central pair apparatus and orientation of motile cilia, localizing to motile cilia where it physically associates with the kinesin Kif27 at the cilium base and with central pair components Spag16 and Pcdp1 (PMID:23907739). Homozygous loss-of-function mutations in STK36 cause primary ciliary dyskinesia with a central pair defect, with the protein localizing between the radial spokes and central pair of the axoneme (PMID:28543983).

1. 1996 High

   Established that Fused operates within the Hedgehog pathway to transmit the signal, fixing its genetic position downstream of Hh and Patched and clarifying its relationship to Costal-2, Ci, and PKA.

   Evidence Genetic epistasis using Drosophila imaginal disc mutations and ectopic Hh expression

   PMID:8861096

   Open questions at the time

   • Does not identify direct biochemical substrates of the kinase
   • Pathway position relative to Ci/Cos-2 left unresolved (same pathway but not epistatic)
   • No mammalian generalization addressed
2. 2004 Medium

   Showed the human ortholog STK36 retains a transcriptional function, with isoform-specific potentiation of GLI2 but not GLI1, indicating the Drosophila signaling role extends to mammals at the level of GLI effectors.

   Evidence Splice isoform characterization by RT-PCR and luciferase reporter assays for GLI1/GLI2 in transient overexpression

   PMID:15268766

   Open questions at the time

   • Overexpression reporter assay only, no endogenous validation
   • Mechanism of GLI2-selective enhancement unknown
   • Did not reverse SUFU-mediated GLI inhibition, leaving the regulatory node undefined
3. 2007 Low

   Extended GLI-enhancing activity to mouse Fu and provided loss-of-function support for a Hedgehog role in a cellular context.

   Evidence Mouse Fu cDNA cloning, Gli reporter overexpression, and RNAi knockdown in one cell line

   PMID:18600476

   Open questions at the time

   • Single RNAi experiment in one cell line without rescue or mutagenesis
   • Context-dependence of the Hedgehog requirement not delineated
   • No biochemical mechanism established
4. 2013 High

   Revealed a Hedgehog-independent function for Fu in motile cilia, identifying it as essential for central pair assembly and cilia orientation and naming its direct structural partners.

   Evidence Conditional knockout mouse oviduct analysis, TEM of ciliary ultrastructure, immunofluorescence, and reciprocal Co-IP with Kif27, Spag16, and Pcdp1

   PMID:23907739

   Open questions at the time

   • Whether kinase catalytic activity is required for central pair assembly not tested
   • Order of recruitment of Kif27/Spag16/Pcdp1 unresolved
   • Relationship between ciliary and Hedgehog roles not reconciled
5. 2014 High

   Defined how Fu protein levels are controlled, showing MID1 ubiquitinates and cleaves Fu to link the MID1-PP2A complex to GLI3 transcriptional output.

   Evidence Biochemical ubiquitination and proteasomal cleavage assays and MID1-Fu interaction studies in SHH-active cancer cells

   PMID:25278022

   Open questions at the time

   • Functional consequence of Fu cleavage products not characterized
   • Whether this regulation operates in cilia as well as signaling unknown
   • In vivo relevance of MID1-Fu axis not established
6. 2017 Medium

   Connected STK36 loss directly to human disease, demonstrating that loss-of-function mutations cause primary ciliary dyskinesia with a central pair defect.

   Evidence Gene sequencing identifying homozygous STK36 mutations and TEM of respiratory epithelial cilia in an affected individual

   PMID:28543983

   Open questions at the time

   • Single patient/family with no functional rescue experiment
   • Precise axonemal position inferred, not directly mapped
   • Genotype-phenotype spectrum across patients undefined

• The catalytic substrates of STK36 kinase activity in both Hedgehog signaling and central pair assembly remain unidentified, leaving the mechanistic link between its enzymatic function and its two cellular roles open.
• No phosphorylation substrate identified
• Whether kinase activity is required for ciliary versus signaling functions untested
• Structural basis of partner binding unknown