CKAP2L

CKAP2L (Radmis) is a cell cycle-regulated microtubule-associated protein that governs the fidelity of mitotic spindle assembly and the homeostasis of microtubule-based organelles (PMID:24260314, PMID:41370039). Its protein levels peak at G2/M, and it relocalizes from the interphase nucleus to the centrosome, mitotic spindle, and ciliary basal body during division (PMID:39073037, PMID:41370039); its destruction after mitosis depends on APC/C-mediated degradation through a KEN box (PMID:24260314). At the spindle, CKAP2L stabilizes and bundles microtubules and is required for bipolar spindle formation, correct chromosome segregation, and cytokinesis, such that its loss produces multipolar spindles, chromosome bridges, shortened spindles, and multinucleation (PMID:24260314, PMID:41370039). Loss-of-function mutations in CKAP2L cause Filippi syndrome, with patient cells showing absence of CKAP2L from spindle poles together with multipolar spindles and segregation defects (PMID:25439729). Beyond mitosis, CKAP2L acts as a negative regulator of primary cilium length, and its knockout in mice produces abnormally elongated flagella and reduced male fertility (PMID:41370039). Its transcription is repressed by FOXP3 and activated by FOXM1 and RFX5 (PMID:35065924, PMID:40646610, PMID:39851233). A separate body of work places CKAP2L in transcriptional and oncogenic signaling roles: it interacts with RNA Polymerase II to regulate transcription elongation of cell-cycle and spindle genes (PMID:33472893), and modulates PI3K/AKT/mTOR signaling, in part by binding AKT and reducing its ubiquitin-mediated degradation (PMID:42245708).

1. 2013 High

   Established CKAP2L/Radmis as a microtubule-associated protein required for normal mitotic spindle architecture in neural progenitors, defining its core cellular role.

   Evidence Subtractive screening, shRNA knockdown, overexpression in vitro and in vivo, immunofluorescence in NSPCs

   PMID:24260314

   Open questions at the time

   • Molecular basis of microtubule stabilization not defined
   • KEN-box/APC/C degradation inferred but direct ubiquitination not shown
2. 2014 High

   Connected CKAP2L loss-of-function to a human Mendelian disease, demonstrating its spindle-pole function is essential for faithful mitosis in patient cells.

   Evidence Homozygosity mapping, whole-exome sequencing, immunofluorescence of patient lymphoblastoid lines

   PMID:25439729

   Open questions at the time

   • Does not resolve how spindle defects translate to the developmental phenotypes of Filippi syndrome
3. 2021 Medium

   Proposed a non-spindle function in which CKAP2L binds RNA Pol II to regulate transcription elongation of cell-cycle and checkpoint genes.

   Evidence Reciprocal Co-IP, RNAi screen, proliferation assays in NSCLC cells

   PMID:33472893

   Open questions at the time

   • Single-lab Co-IP not independently replicated
   • Direct vs indirect effect on elongation machinery unresolved
4. 2022 Medium

   Identified FOXP3 as a transcriptional repressor of CKAP2L and linked CKAP2L to AKT/mTOR pathway activation in cancer cells.

   Evidence ChIP/promoter binding, Western blot of pathway phosphorylation, overexpression/silencing in breast cancer lines

   PMID:35065924

   Open questions at the time

   • Mechanism connecting a spindle MAP to AKT/mTOR activation not defined
   • Not independently replicated
5. 2024 Medium

   Defined the cell-cycle and subcellular dynamics of human CKAP2L, showing G2/M-peaking levels and an interphase-nuclear to mitotic-spindle relocalization with a microtubule-bundling phenotype.

   Evidence Cell cycle synchronization, immunofluorescence, ectopic overexpression in cancer cells

   PMID:39073037

   Open questions at the time

   • Function of interphase nuclear pool unclear
   • Mechanism of relocalization unknown
6. 2025 High

   Extended CKAP2L function beyond the spindle to microtubule-based organelles, establishing it as a negative regulator of cilium/flagellum length with an in vivo fertility phenotype.

   Evidence Ckap2l knockout mouse, immunofluorescence to centrosome/spindle/basal body, ciliary length measurements, sperm analysis

   PMID:41370039

   Open questions at the time

   • Molecular mechanism limiting cilium length unknown
   • Relationship between ciliary and spindle roles not resolved
7. 2025 Medium

   Identified FOXM1 and RFX5 as transcriptional activators of CKAP2L, embedding it in proliferative transcriptional programs in cancer.

   Evidence ChIP-qPCR, dual-luciferase reporter, knockdown, rescue experiments in bladder and colorectal cancer cells

   PMID:39851233 PMID:40646610

   Open questions at the time

   • Conflicting reports on whether CKAP2L activates or inactivates AKT/mTOR downstream
   • Single-lab studies not independently replicated
8. 2026 Medium

   Proposed a direct biochemical mechanism for oncogenic signaling, in which CKAP2L binds AKT and suppresses its ubiquitin-proteasome degradation to sustain PI3K/AKT signaling, and engages a STAT3/AREG/EGFR axis.

   Evidence Co-IP, ubiquitination assays, cycloheximide chase, MG132 treatment, RNA-seq, ChIP in endometrial and colorectal cancer cells

   PMID:41823522 PMID:42245708

   Open questions at the time

   • No structural basis for CKAP2L-AKT interaction
   • How a microtubule MAP physically protects AKT from ubiquitination unexplained
   • Single-lab studies

• How CKAP2L's spindle/ciliary structural role mechanistically integrates with its reported transcriptional (RNA Pol II) and signaling (AKT/mTOR, STAT3) functions remains unresolved.
• No unifying model linking microtubule and signaling functions
• Direction of AKT/mTOR regulation conflicts across studies
• Signaling mechanisms rely on single-lab evidence