CEP43

CEP43 (FGFR1OP/FOP) is a centrosomal protein that anchors a recruitment hierarchy at the mother centriole governing intraflagellar transport and ciliogenesis (PMID:28625565, PMID:28428259). Its N-terminal segment, which embeds a LisH domain and folds into an antiparallel five-helix bundle, mediates dimerization and centrosomal targeting (PMID:16690081). At the ciliary base CEP43 recruits CEP19, which in turn captures GTP-bound RABL2; RABL2-GTP engages the IFT-B complex through the IFT74-IFT81 heterodimer to initiate transport into the cilium (PMID:28625565, PMID:28428259). Loss of function in mouse perturbs ciliogenesis, alters centriolar satellite movements and pericentriolar material composition, and disrupts Hedgehog signaling, producing a short rib-polydactyly ciliopathy phenotype that models a human skeletal dysplasia (PMID:29982567). Beyond its centrosomal role, CEP43 is required in intestinal epithelial cells for non-muscle myosin II activity, maintaining actomyosin cytoskeleton integrity, crypt cell adhesion, and epithelial resilience (PMID:38942017). A FGFR1OP-RET translocation fusion confers constitutive tyrosine kinase activity that transforms cells and drives myeloproliferative disease, a property of the chimeric kinase rather than wild-type CEP43 (PMID:24315414).

1. 2006 High

   Establishing the structural basis for CEP43 self-association answered how the protein achieves centrosomal targeting at the molecular level.

   Evidence X-ray crystallography of the N-terminal domain at 1.6 Å with truncation-mutant localization assays

   PMID:16690081

   Open questions at the time

   • N-terminal domain is necessary but not sufficient for localization, leaving additional targeting determinants undefined
   • no structure of the full-length protein or of any partner complex
2. 2017 High

   Identifying CEP43 as the centriolar anchor for CEP19 placed it at the top of a recruitment hierarchy that initiates IFT entry into cilia.

   Evidence AP-MS, reciprocal Co-IP, gene disruption, and localization assays across two independent labs, including Chlamydomonas and human cell systems

   PMID:28428259 PMID:28625565

   Open questions at the time

   • binding interface between CEP43 and CEP19 not structurally mapped
   • regulation/timing of the CEP43–CEP19–RABL2 recruitment cascade unresolved
3. 2018 Medium

   An in vivo loss-of-function model linked CEP43 to ciliogenesis, centriolar satellite dynamics, and Hedgehog-dependent skeletal development.

   Evidence Mouse Fop mutant with ciliogenesis, Hedgehog readouts, and centriolar satellite immunofluorescence

   PMID:29982567

   Open questions at the time

   • mechanistic link between CEP43 and centriolar satellite movement not defined
   • whether the skeletal phenotype is solely IFT-dependent is unresolved
4. 2024 High

   A tissue-specific knockout revealed a cilium-independent role for CEP43 in sustaining actomyosin integrity through non-muscle myosin II.

   Evidence Conditional knockout in mouse intestinal epithelium with colitis challenge and direct myosin II activity measurement

   PMID:38942017

   Open questions at the time

   • molecular link between CEP43 and myosin II activation not defined
   • relationship of this role to the centrosomal function unknown
5. 2013 Medium

   Characterization of the FGFR1OP-RET fusion showed how CEP43 sequences contribute to oncogenic kinase activation when fused to RET.

   Evidence Cloning, NIH3T3 transformation, Ba/F3 cytokine-independence, signaling analysis, and murine bone marrow transplantation

   PMID:24315414

   Open questions at the time

   • contribution of CEP43 dimerization domain to fusion kinase activation not isolated
   • phenotype reflects the chimera, not endogenous CEP43
6. 2025 Low

   Network prioritization nominated CEP43 as a candidate human ciliopathy gene, extending its developmental relevance to patients.

   Evidence Protein interaction network propagation plus variant identification in unsolved ciliopathy cases

   PMID:41715205

   Open questions at the time

   • computational prioritization with no functional validation of the variants
   • causality in patients not established

• How CEP43 mechanistically couples its centrosomal/ciliary anchoring role to non-muscle myosin II regulation in epithelial cells remains unresolved.
• no molecular bridge between CEP43 and myosin II identified
• no structural model of CEP43 partner complexes
• tissue-specificity of its two functional roles unexplained