Affinage

ARL13B

ADP-ribosylation factor-like protein 13B · UniProt Q3SXY8

Length
428 aa
Mass
48.6 kDa
Annotated
2026-04-28
65 papers in source corpus 37 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ARL13B is a palmitoylated, atypical small GTPase that serves as the master organizer of primary cilium composition, structure, and signaling. It localizes to the ciliary membrane via palmitoylation and a C-terminal RVEP-containing ciliary targeting sequence transported by TULP3/IFT-A and Rab8-GDP/TNPO1, where it functions as a guanine nucleotide exchange factor (GEF) for ARL3, spatially restricting ARL3·GTP-dependent release of lipidated cargo within cilia; this GEF activity is separable from ARL13B's roles in ciliary length regulation, Sonic hedgehog (Shh) signal transduction, and tubulin binding that anchors membrane proteins uniformly along the axoneme (PMID:26551564, PMID:29255182, PMID:29592971, PMID:32129762). ARL13B regulates retrograde IFT-A-mediated trafficking through its interaction with INPP5E, controls axoneme polyglutamylation via RAB11-FIP5-dependent import of glutamylases TTLL5/6, and modulates Smoothened ciliary entry to govern Hedgehog pathway output including Gli activator/repressor balance (PMID:27927754, PMID:30120249, PMID:21976698, PMID:29378965). Outside cilia, ARL13B participates in endocytic recycling, actin-dependent cell migration through interaction with Myh9, and Shh-mediated axon guidance via a cilia-independent mechanism (PMID:23223633, PMID:24777479, PMID:31825820). Mutations in ARL13B cause Joubert syndrome, with disease-causing variants disrupting GEF activity, ciliary targeting, or protein interactions critical for ciliary cargo trafficking and signaling (PMID:18674751, PMID:29255182).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2008 High

    Establishing ARL13B as a ciliary protein whose loss-of-function causes a human ciliopathy resolved the question of whether this small GTPase had ciliary relevance and linked it directly to Joubert syndrome pathogenesis.

    Evidence Immunolocalization in murine neurons, zebrafish scorpion mutant rescue with wild-type but not patient-mutant ARL13B, human mutation identification

    PMID:18674751

    Open questions at the time
    • Mechanism by which ARL13B supports cilia formation unknown
    • No biochemical activity defined
    • No ciliary targeting determinants mapped
  2. 2009 High

    Systematic domain analysis revealed that multiple regions of ARL13B are required for ciliary localization, and that ciliary residence is essential for in vivo function, framing ARL13B as a compartment-restricted effector.

    Evidence Zebrafish deletion/point mutant series with functional rescue readout

    PMID:19906870

    Open questions at the time
    • Specific targeting motifs not yet defined at residue level
    • No biochemical or structural understanding of GTPase activity
  3. 2010 High

    Identifying palmitoylation as necessary for ciliary membrane association and showing ARL13B regulates IFT stability and transmembrane protein localization established it as a membrane-anchored regulator of ciliary protein composition.

    Evidence C. elegans genetics and palmitoylation mutant analysis combined with mammalian cell culture

    PMID:20231383

    Open questions at the time
    • Identity of direct effectors/interactors unknown
    • Mechanism of IFT regulation unclear
  4. 2011 High

    Demonstrating that Arl13b-null cilia constitutively accumulate Smoothened regardless of pathway status established ARL13B as a gatekeeper of Hedgehog signaling component ciliary dynamics, and linked dorsal neural tube BMP patterning defects to disrupted Shh signaling.

    Evidence Mouse Arl13b-null cells with immunofluorescence of Shh pathway components; Arl13b(hnn) mutant epistasis for BMP/Wnt pathways

    PMID:21539826 PMID:21976698

    Open questions at the time
    • Whether ARL13B directly interacts with Smoothened unknown
    • Molecular mechanism of Smo entry/exit control unresolved
  5. 2012 High

    Multiple discoveries converged to define ARL13B's functional network: interaction with INPP5E for ciliary targeting, regulation of interneuronal migration via ciliary guidance receptors, control of endocytic recycling outside cilia, and a role in left-right axis specification.

    Evidence Co-IP/interaction mapping with INPP5E and patient mutations (PMID:23150559); live imaging of interneuronal cilia in conditional KO mice (PMID:23153492); shRNA screen with endocytic recycling assays (PMID:23223633); Arl13b(hnn) mutant Nodal/Cerl2 analysis (PMID:22554696)

    PMID:22554696 PMID:23150559 PMID:23153492 PMID:23223633

    Open questions at the time
    • No direct enzymatic activity assigned
    • Relationship between ciliary and extraciliary pools unclear
    • How endocytic recycling role relates to ciliary function unknown
  6. 2013 High

    Systematic C. elegans genetics and quantitative imaging revealed ARL13B is restricted to a subciliary membrane compartment via a C-terminal RVVP motif, undergoes IFT-like motility, and associates with IFT-B complexes via IFT46/IFT74, defining the machinery confining ARL13B within cilia.

    Evidence C. elegans mutant panel (>20 strains), in vivo FRAP, mass spectrometry interactomics, motif mutagenesis

    PMID:24339792

    Open questions at the time
    • Whether IFT-B interaction is required for function or just transport unclear
    • Mammalian subciliary compartmentalization not verified
  7. 2014 High

    The crystal structure of Arl13B revealed an incomplete GTPase active site explaining its negligible intrinsic hydrolysis, and Joubert syndrome mutations Arg79Q and R200C disrupted structural elements required for conformational switching, providing the first structural framework for disease mutations.

    Evidence X-ray crystallography of Chlamydomonas Arl13B, biochemical GTPase assays, structural analysis of patient mutations

    PMID:24168557

    Open questions at the time
    • No effector or substrate identified biochemically
    • Mammalian structure not determined
  8. 2015 High

    The central biochemical function of ARL13B was resolved as a guanine nucleotide exchange factor (GEF) for ARL3, spatially restricted to cilia, generating a ciliary ARL3·GTP compartment for lipidated cargo release; Joubert syndrome mutations impaired this GEF activity, directly connecting enzymatic function to disease.

    Evidence In vitro reconstituted GEF assay with purified proteins, structural analysis, cellular ARL3·GTP measurement, patient mutation functional testing

    PMID:26551564

    Open questions at the time
    • Whether all ciliary functions depend on GEF activity unknown
    • ARL3-independent ciliary roles not defined
  9. 2015 High

    Identification of exocyst subunits Sec5 and Sec8 as direct GTP-preferring effectors of ARL13B, with genetic synergy in ciliogenesis, linked ARL13B to vesicular trafficking machinery required for cilium assembly.

    Evidence Direct binding assays, co-IP, zebrafish double morphant and conditional mouse KO genetic interaction

    PMID:26582389

    Open questions at the time
    • Whether exocyst mediates ARL13B's effect on ciliary membrane extension unclear
    • Cargo delivered by exocyst in this context unidentified
  10. 2016 High

    ARL13B was shown to regulate IFT-A-mediated retrograde trafficking through its interaction with INPP5E (not IFT-B), explaining why ARL13B-knockout cells accumulate IFT complexes at tips and fail to remove GPR161 from cilia; the RVEP sequence was confirmed as the mammalian ciliary targeting determinant.

    Evidence ARL13B-KO cell lines, visible IP assay with IFT46/IFT56, mutant rescue with RVEP variants

    PMID:27927754

    Open questions at the time
    • How INPP5E-ARL13B interaction mechanistically regulates IFT-A remains unclear
    • Whether phosphoinositide remodeling by INPP5E is the operative mechanism unresolved
  11. 2017 High

    Biochemical confirmation that mammalian ARL13B has very low intrinsic GTPase activity and serves as an ARL3-GEF, together with identification of palmitoylation as essential for both ciliary trafficking and protein stability (but not merely membrane attachment), refined the post-translational and enzymatic framework for ARL13B function.

    Evidence Purified recombinant protein nucleotide assays (PMID:28487361); palmitoylation assays in mouse kidneys with lipid variant comparisons (PMID:28848045)

    PMID:28487361 PMID:28848045

    Open questions at the time
    • GAP identity for ARL13B unknown
    • Whether casein kinase 2 phosphorylation regulates GEF activity untested
  12. 2017 High

    A separation-of-function Joubert syndrome variant (G75R) that abolishes ARL3-GEF activity while retaining GTPase activity and Shh signaling rescue demonstrated that ARL13B's GEF function is specifically linked to Joubert syndrome and is mechanistically separable from ciliary length and Hedgehog roles.

    Evidence ARL3-GEF assays with G75R, Arl13b hennin null cell rescue, patient variant identification

    PMID:29255182

    Open questions at the time
    • Which GEF-independent functions are relevant to disease unclear
    • How ARL13B regulates Shh independently of GEF activity unresolved
  13. 2018 High

    Multiple mechanistic layers were defined: ARL13B directly binds tubulin via its G-domain to anchor ciliary membrane proteins uniformly along the axoneme; it controls axoneme polyglutamylation via RAB11-FIP5-dependent import of TTLL5/6 glutamylases; and its ciliary role is essential for photoreceptor outer segment morphogenesis.

    Evidence In vitro tubulin binding assay plus domain mutant rescue (PMID:29592971); Co-IP of ARL13B-FIP5 with CCP5 depletion rescue (PMID:30120249); retinal conditional KO with ERG and EM (PMID:30573647)

    PMID:29592971 PMID:30120249 PMID:30573647

    Open questions at the time
    • Whether tubulin binding and polyglutamylation regulation are independent or connected pathways unclear
    • Structural basis of tubulin-G-domain interaction unknown
  14. 2018 High

    Loss of Arl13b reduces maximal Shh signaling while generating low-level constitutive Gli activator, and genetic removal of Arl13b prevents medulloblastoma driven by oncogenic Smo or Ptch1 deletion, positioning ARL13B as required for Hedgehog-driven tumorigenesis.

    Evidence Mouse medulloblastoma models (Ptch1 deletion, SmoA1), Arl13b conditional deletion, human MB cell line knockdown

    PMID:29378965

    Open questions at the time
    • Whether ARL13B inhibition is therapeutically feasible for Hedgehog-driven cancers untested
    • Mechanism of low-level constitutive Gli activation in Arl13b-null cells unresolved
  15. 2019 High

    A cilia-localization-deficient variant (V358A) was shown to fully support Shh-mediated axon guidance both in vitro and in vivo, proving ARL13B has a bona fide cilia-independent role in axon guidance, operating from growth cones.

    Evidence Conditional mouse KO with V358A rescue, commissural axon guidance assays, in vitro growth cone turning assay

    PMID:31825820

    Open questions at the time
    • Extraciliary ARL13B effectors in growth cones not identified
    • Whether GEF activity is required for axon guidance unclear
  16. 2020 High

    The V358A knock-in mouse confirmed in vivo that ARL13B's Shh signaling role is cilia-independent, while ciliary ARL13B is specifically required for generating ciliary ARL3·GTP and INPP5E pools, definitively separating intra-ciliary and extra-ciliary ARL13B functions.

    Evidence V358A knock-in mouse with Shh pathway assays, ciliary ARL3/INPP5E localization

    PMID:32129762

    Open questions at the time
    • How extraciliary ARL13B activates Shh signaling mechanistically remains unknown
    • Whether V358A affects all ciliary cargoes not comprehensively tested
  17. 2023 High

    The ciliary delivery mechanism of ARL13B was resolved: TULP3 transports ARL13B via an N-terminal amphipathic helix interacting with the TULP3 tubby domain, requiring IFT-A binding; independently, Rab8-GDP and TNPO1 simultaneously bind the C-terminal RVEP-containing targeting sequence to promote ciliary entry.

    Evidence TULP3/ARL13B domain interaction mapping with IFT-A mutant rescue (PMID:36652335); purified protein pulldowns with Rab8-GDP and TNPO1, TurboID proximity ligation, knockdown validation (PMID:36907439)

    PMID:36652335 PMID:36907439

    Open questions at the time
    • Whether TULP3 and Rab8/TNPO1 pathways act sequentially or in parallel unclear
    • Stoichiometry and structural basis of the ternary Rab8-TNPO1-CTS complex not determined
  18. 2025 High

    Tissue-specific roles of ciliary ARL13B were delineated: it is essential for cone outer segment morphogenesis independently of GEF activity, required for spermatogenesis, and participates in PKD1-dependent renal cystogenesis through its GEF activity for ARL3.

    Evidence V358A and R79Q knock-in mice with retinal ERG and EM (PMID:40721319); ARL13B-Cerulean null rescue with fertility testing (PMID:40916698); Pkd1-deficient mice combined with V358A/R79Q alleles (preprint)

    PMID:40721319 PMID:40916698

    Open questions at the time
    • Substrates of ARL3·GTP relevant to cystogenesis not identified
    • Mechanism linking ARL13B to spermatogenesis beyond ciliary requirement unknown
    • Whether ARL13B roles in renal cystogenesis translate to therapeutic targets in PKD untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the identity of a GAP for ARL13B, the structural basis of its GEF activity for ARL3 in full-length mammalian protein, the mechanism by which extraciliary ARL13B transduces Shh signaling, and how ARL13B coordinates its multiple distinct biochemical activities (GEF, tubulin binding, polyglutamylation control) within the ciliary compartment.
  • No GAP identified for ARL13B
  • Full-length mammalian ARL13B structure not solved
  • Extraciliary Shh signaling mechanism unknown
  • Integration of tubulin binding, GEF, and polyglutamylation functions not modeled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0003924 GTPase activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005929 cilium 6 GO:0005856 cytoskeleton 2 GO:0005886 plasma membrane 2 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1852241 Organelle biogenesis and maintenance 5 R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-9709957 Sensory Perception 2
Partners
ARL3INPP5EMYH9RAB8ASEC5SEC8TNPO1TULP3

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 ARL13B protein localizes to cilia in primary neurons and is required for ciliogenesis; mutations in ARL13B cause Joubert syndrome, and wild-type but not patient-mutant ARL13B rescued the arl13b scorpion zebrafish mutant, establishing evolutionarily conserved ciliary function. Zebrafish rescue experiments, immunolocalization in murine cerebellum neurons, loss-of-function zebrafish mutant American journal of human genetics High 18674751
2009 Ciliary localization of Arl13b is essential for its in vivo function; multiple regions of Arl13b are required for ciliary targeting, and cilia-excluded variants fail to rescue zebrafish arl13b mutant phenotypes. Zebrafish deletion/point mutant rescue experiments, live imaging, immunolocalization Development (Cambridge, England) High 19906870
2010 Arl13b/ARL-13 associates with ciliary membranes via palmitoylation motifs and is required to stabilize anterograde intraflagellar transport (IFT) and regulate ciliary transmembrane protein localization; loss-of-function in C. elegans causes ciliary morphology/ultrastructure defects and abnormal accumulation of transmembrane proteins including elevated PKD-2 ciliary abundance. C. elegans genetics, palmitoylation mutant analysis, ciliary protein localization assays, IFT analysis, mammalian cell culture The Journal of cell biology High 20231383
2011 Arl13b regulates the dynamic localization of Sonic hedgehog (Shh) signaling components in cilia; in Arl13b-null cilia, Smoothened (Smo) is constitutively enriched regardless of Shh pathway stimulation, indicating Arl13b controls ciliary entry and distribution of Smo. Mouse Arl13b-null mutant cells, immunofluorescence localization of Shh pathway components, live imaging of ciliary dynamics Molecular biology of the cell High 21976698
2011 Arl13b is required non-autonomously for BMP signaling in the dorsal neural tube; the dorsal patterning defects in Arl13b(hnn) mutants result from abnormal BMP signaling caused indirectly by disrupted Shh signaling, while downstream Wnt signaling remains normal despite abnormal Wnt ligand expression. Mouse Arl13b(hnn) mutant epistasis analysis, neural tube patterning assays, BMP and Wnt pathway readouts Developmental biology Medium 21539826
2012 Arl13b in primary cilia is required for the migration and placement of cortical interneurons; guidance cue receptors essential for interneuronal migration localize to interneuronal primary cilia but their concentration and dynamics are altered in the absence of Arl13b; Joubert syndrome-causing ARL13B variants induce defective interneuronal migration. Live imaging of interneuronal cilia, conditional mouse knockout, receptor localization assays Developmental cell High 23153492
2012 ARL13B interacts with INPP5E and facilitates its ciliary targeting through a functional network; ARL13B missense mutations causing Joubert syndrome disrupt the ARL13B-INPP5E interaction; ARL13B, INPP5E, PDE6D, and CEP164 form a distinct functional network for ciliary targeting of INPP5E. Co-immunoprecipitation, protein-protein interaction assays, ciliary targeting assays, patient mutation functional analysis Proceedings of the National Academy of Sciences of the United States of America High 23150559
2012 Arl13b regulates endocytic recycling traffic; silencing Arl13b causes clustering of early endosomes, accumulation of endocytic cargo, and delayed CD1a recycling; Arl13b colocalizes with Arf6 and Rab22a (endocytic recycling markers) and interacts with the actin cytoskeleton. shRNA screen, CD1a surface expression/recycling assays, colocalization with endocytic markers, actin interaction studies Proceedings of the National Academy of Sciences of the United States of America Medium 23223633
2012 Arl13b is required for left-right axis specification; loss of Arl13b results in failure to downregulate Cerl2 and failure to maintain asymmetric Nodal expression in the node, leading to symmetric expression of both genes and subsequent heterotaxia. Mouse Arl13b(hnn) mutant analysis, in situ hybridization for Nodal/Cerl2 expression Developmental biology Medium 22554696
2013 ARL13B/ARL-13 is restricted to an Inv-like subciliary membrane compartment; compartmentalization requires a C-terminal RVVP motif and membrane anchoring; IFT-A/B, IFT-dynein, and BBS genes prevent ARL-13 accumulation at periciliary membranes; MKS/NPHP modules comprise a transition zone barrier to ARL-13 diffusion; ARL-13 undergoes IFT-like motility; human ARL13B forms functional associations with IFT-B complexes via IFT46 and IFT74. C. elegans genetics (>20 mutants), quantitative imaging, in vivo FRAP, quantitative protein complex analysis (MS), C-terminal motif mutagenesis PLoS genetics High 24339792
2014 Crystal structure of Chlamydomonas Arl13B (G-domain plus C-terminal region) reveals an incomplete active site accounting for the absence of intrinsic GTP hydrolysis; patient mutations R79Q and R200C disrupt intramolecular stabilizing interactions, with Arg79 being critical for the GDP/GTP conformational change. X-ray crystallography, biochemical GTPase assays, structural analysis of patient mutations The Biochemical journal High 24168557
2014 Arl13b is required for ciliary membrane extension and ciliary length regulation; overexpression increases ciliary length as a function of protein amount; the GTPase activity is essential for ciliary membrane protrusion; Arl13b functions downstream of the ciliogenic transcription factors FoxJ1 and Rfx to promote ciliary length. Zebrafish overexpression, mammalian cell overexpression, GTPase-dead mutant analysis, FoxJ1-deficient zebrafish rescue experiments Developmental biology Medium 25448689
2014 Arl13b interacts with non-muscle myosin heavy chain IIA (Myh9); both proteins localize to circular dorsal ruffles (CDRs) induced by PDGF stimulation; Arl13b and Myh9 are required for CDR formation and cell migration, establishing Arl13b as a regulator of actin cytoskeleton remodeling through Myh9. Co-immunoprecipitation, immunofluorescence colocalization, siRNA knockdown, CDR formation assay, cell migration assay, zebrafish neural crest migration Journal of cell science Medium 24777479
2015 ARL13B is the guanine nucleotide exchange factor (GEF) for ARL3; GEF activity is mediated by the G-domain plus an additional C-terminal helix; switch regions of ARL13B are involved in the interaction with ARL3; overexpression of ARL13B in mammalian cells increases ARL3·GTP levels; Joubert syndrome patient mutations impair GEF activity and thus ARL3 activation; through ARL13B's exclusive ciliary localization, ARL3 activation is spatially restricted to generate a ciliary ARL3·GTP compartment for release of lipidated cargo. In vitro GEF activity assays, structural analysis, overexpression in mammalian cells with ARL3·GTP measurement, patient mutation functional testing eLife High 26551564
2015 Arl13b binds directly to exocyst subunits Sec8 and Sec5, with preferential binding to the GTP-bound form of Arl13b, establishing the exocyst as an Arl13b effector; Arl13b and exocyst subunit sec10 interact synergistically in ciliogenesis in zebrafish and in mouse kidney. Direct binding assays (Arl13b-Sec8, Arl13b-Sec5), co-immunoprecipitation, zebrafish genetic interaction (double morphants), conditional mouse knockout Molecular biology of the cell High 26582389
2016 ARL13B interacts with the IFT46-IFT56 dimer of the IFT-B complex; in ARL13B-knockout cells, IFT-A and IFT-B complexes accumulate at ciliary tips and GPR161 cannot exit cilia; ARL13B regulates IFT-A-mediated retrograde protein trafficking through its interaction with INPP5E (not IFT-B); ciliary targeting of ARL13B is dependent on the RVEP sequence in its C-terminal region. Visible immunoprecipitation assay, ARL13B-knockout cell lines, ciliary protein localization, mutant rescue experiments Journal of cell science High 27927754
2017 Purified mammalian ARL13B is an atypical GTPase with very low intrinsic GTPase activity; it functions as a GEF for ARL3; three Joubert syndrome missense mutations impair its biochemical activities; murine Arl13b is a substrate for casein kinase 2 phosphorylation. In vitro nucleotide binding assays, intrinsic and GAP-stimulated GTPase assays, ARL3-GEF activity assays with purified recombinant protein, mutagenesis of consensus GTPase motifs The Journal of biological chemistry High 28487361
2017 Palmitoylation of ARL13b is required for its trafficking to cilia and for its function within cilia; palmitoylation dramatically increases ARL13b protein stability; myristoylation can substitute for palmitoylation for ciliary localization but not for ciliary function; depalmitoylation promotes ARL13b degradation during cilia resorption. Biochemical palmitoylation assays in mouse kidneys, cellular and in vivo mutant studies, protein stability assays, depalmitoylation inhibitor experiments The Journal of biological chemistry High 28848045
2017 Arl13b interacts with Smoothened (Smo) and regulates Smo stability, trafficking, and ciliary localization in gastric cancer cells; Arl13b stimulates proliferation, migration, and invasion in vitro and in vivo through Hh pathway activation. Co-immunoprecipitation, cell-based trafficking/stability assays, in vitro proliferation/migration assays, in vivo xenograft models Cancer research Medium 28611043
2017 A novel ARL13B variant (G75R) abolishes ARL3 GEF activity while retaining GTPase activity and ability to rescue cilia length and Shh signaling defects, demonstrating that ARL13B's GEF activity for ARL3 is separable from its other ciliary functions and is specifically linked to Joubert syndrome pathogenesis. ARL3-GEF activity assays, Arl13b hennin null cell rescue, whole-exome sequencing patient variant analysis European journal of human genetics : EJHG High 29255182
2018 ARL13B controls axoneme polyglutamylation by interacting with RAB11 effector FIP5 to promote cilia import of glutamylases TTLL5 and TTLL6; hypoglutamylation caused by deficient ARL13B-RAB11-FIP5 trafficking promotes cilia disassembly and impairs cilia signaling by disrupting anchoring of sensory receptors and trafficking of signaling molecules; depletion of deglutamylase CCP5 restores hypoglutamylation-induced cilia defects. Co-immunoprecipitation (ARL13B-FIP5 interaction), ciliary import assays, CCP5 depletion rescue, immunofluorescence of signaling receptors Nature communications High 30120249
2018 ARL13B binds tubulin directly via its G-domain, independently of GTPase activity; the G-domain interaction with the axoneme is necessary for uniform distribution of ciliary membrane proteins (Smoothened, SSTR3) along the cilium; GTPase-inactive ARL13B-T35N enables uniform ciliary protein distribution while ΔGD mutant does not. In vitro tubulin binding assay, domain deletion/point mutant analysis, mouse embryonic fibroblast rescue assays, immunofluorescence of ciliary membrane protein distribution Journal of cell science High 29592971
2018 ARL13B is required at multiple stages of retinogenesis including early postnatal retinal progenitor proliferation, photoreceptor cilia development, and outer segment disc morphogenesis; loss of ARL13B causes mislocalization of rhodopsin, prenylated PDE6, and IFT88 in photoreceptors. Conditional knockout (Six3-Cre pan-retina and Pde6g-CreERT2 inducible rod-specific), ERG, immunofluorescence, electron microscopy The Journal of neuroscience : the official journal of the Society for Neuroscience High 30573647
2019 Arl13b functions outside of primary cilia in Shh-mediated axon guidance; Arl13b localizes to axons and growth cones; a cilia-localization-deficient Arl13b variant (V358A) is sufficient to mediate Shh-dependent axon guidance both in vitro and in vivo, demonstrating a cilia-independent role. Conditional mouse KO, commissural axon guidance assays in vivo, in vitro guidance assay, cilia-excluded variant (V358A) rescue Cell reports High 31825820
2018 Loss of Arl13b results in low-level constitutive Gli activator function and reduces maximal Shh signaling; disruption of Arl13b inhibits Shh overactivation downstream of oncogenic SmoA1 and prevents medulloblastoma formation in Ptch1-deleted mouse model. Mouse medulloblastoma model (Ptch1 deletion), Arl13b conditional deletion, ARL13B knockdown in human MB cell lines, Gli activator/repressor assays Proceedings of the National Academy of Sciences of the United States of America High 29378965
2019 Loss of the transition zone protein Ahi1 reduces ciliary localization of Arl13b and decreases non-membrane-associated Arl13b stability via the proteasome pathway; Ahi1 promotes Arl13b ciliary recruitment and stabilizes Arl13b protein, with these changes linked to defective cell migration. Ahi1 knockout MEFs, immunofluorescence of Arl13b ciliary levels, proteasome inhibitor rescue of Arl13b stability, cell motility assays Journal of cell science Medium 31391239
2020 A cilia-excluded ARL13B variant (V358A) retains all known biochemical activities (GEF, GTPase) but cannot enter cilia; mice expressing Arl13b(V358A) are viable with normal Shh transduction but display short cilia and lack ciliary ARL3 and INPP5E; these data show ARL13B's role in Shh signaling can be uncoupled from its function within cilia. Knock-in mouse model (V358A), immunofluorescence, Shh pathway assays, ciliary protein localization eLife High 32129762
2018 TULP3 is required for ciliary localization of membrane-associated proteins ARL13B and INPP5E; this requires TULP3 binding to IFT-A, as a TULP3 mutant lacking IFT-A binding cannot rescue ARL13B ciliary localization in TULP3-KO cells. TULP3 knockout RPE-1 cells, immunofluorescence of ciliary ARL13B, TULP3 mutant rescue experiments Biochemical and biophysical research communications Medium 30583862
2023 TULP3 transports ARL13B to cilia through an N-terminal amphipathic helix of ARL13B that interacts with the TULP3 tubby domain; this transport requires TULP3 binding to IFT-A but not to phosphoinositides; TULP3-mediated trafficking of ARL13B also regulates ciliary enrichment of farnesylated and myristoylated downstream effectors (ARL3, INPP5E). TULP3/ARL13B interaction mapping, domain mutagenesis, ciliary localization rescue assays, IFT-A binding mutant analysis Molecular biology of the cell High 36652335
2023 Rab8-GDP (not GTP) and TNPO1 simultaneously and directly bind to the C-terminal 17-amino-acid ciliary targeting sequence (CTS) of Arl13b containing the RVEP motif; Rab8-GDP enhances TNPO1-CTS interaction; knockdown of Rab8 or TNPO1 decreases ciliary localization of endogenous Arl13b. Pulldown assays with purified recombinant proteins and cell lysates, TurboID-based proximity ligation, CTS truncation/point mutant analysis, Rab8/TNPO1 knockdown The Journal of biological chemistry High 36907439
2023 ARL13B interacts with VEGFR2 and regulates its membrane and ciliary localization, consequently activating VEGFR2 downstream signaling in endothelial cells; ARL13B also enhances VEGFA expression by activating Hedgehog signaling in glioma cells. GST-fusion protein pulldown, co-immunoprecipitation, VEGFR2 localization assays, genetically engineered mouse models, intracranially transplanted tumor model Neuro-oncology Medium 36322624
2025 Ciliary ARL13B is essential for body weight regulation in adult mice; cilia-excluded ARL13B (V358A) causes hyperphagia, obesity, and insulin resistance; ARL13B's GEF activity for ARL3 is not required for body weight regulation; inducible restoration of wild-type ciliary ARL13B in 4-week-old V358A mice rescues obesity and metabolic impairments. Knock-in mouse models (V358A cilia-excluded, R79Q GEF-dead), inducible ARL13B expression rescue, metabolic phenotyping bioRxiv : the preprint server for biologypreprint High 37577625
2025 Ciliary ARL13B and its GEF activity for ARL3 are required for PKD1-dependent renal cystogenesis; loss of ciliary ARL13B (V358A) or mutation of the GEF-critical residue (R79Q) suppresses Pkd1-dependent cysts, kidney enlargement, renal fibrosis, and β-catenin/cyclin D1 elevation. Pkd1-deficient adult mouse model combined with V358A and R79Q Arl13b knock-in alleles, renal histology, cystic index, BUN measurements, fibrosis staining, western blots bioRxivpreprint Medium
2025 PRPF8-dependent splicing of ARL13B controls cilia formation; an alternative ARL13B transcript lacking exon 9 (promoted by Prpf8 loss) encodes a shorter protein that lacks interactions with intraflagellar transport proteins, perturbs cilium formation, and causes laterality defects. Mouse and zebrafish Prpf8 mutants, RT-PCR of ARL13B splice variants, overexpression of exon-9-lacking transcript, co-immunoprecipitation with IFT proteins bioRxivpreprint Medium 40501629
2022 PAK2 acts upstream of ARL13B in a ciliogenesis signaling pathway in brain endothelial cells; overexpression of ARL13B-GFP rescues cilia numbers and cerebral hemorrhage in pak2a zebrafish mutants; PDGF-BB and VEGF-A trigger PAK2-ARL13B ciliogenesis signaling through VEGFR-2. Zebrafish pak2a mutant rescue with ARL13B-GFP, primary human brain microvascular EC experiments, ligand stimulation assays Biochemical pharmacology Medium 35700757
2025 Ciliary ARL13B is essential for cone outer segment morphogenesis and vision; cilia-excluded ARL13B (V358A) causes early loss of cone-mediated vision, shortened cone axonemes, structural abnormalities in cone outer segments, and mislocalization of IFT88 and TULP1 in photoreceptors; GEF-impaired ARL13B (R79Q) does not cause this phenotype. Knock-in mouse model (V358A), ERG, immunohistochemistry, transmission electron microscopy, comparison with R79Q GEF-dead model The Journal of neuroscience : the official journal of the Society for Neuroscience High 40721319
2025 ARL13B knockout completely abolishes primary ciliogenesis (rather than merely shortening cilia); multiple regions of ARL13B are necessary for rescue; ARL13B-knockout cells also lose response to SMO-mediated hedgehog stimulation. CRISPR/Cas9 knockout cell lines, immunofluorescence for cilia, SMO-agonist hedgehog response assay, domain deletion rescue Scientific reports Medium 40707593
2025 Ciliary ARL13B is required for spermatogenesis; mice rescued from embryonic lethality by ARL13B-Cerulean expression develop normally but males fail to sire offspring, revealing a role for ARL13B in male fertility. Arl13b null mouse rescue with ARL13B-Cerulean knock-in, fertility testing Journal of cell science Medium 40916698

Source papers

Stage 0 corpus · 65 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Mutations in the cilia gene ARL13B lead to the classical form of Joubert syndrome. American journal of human genetics 317 18674751
2011 Arl13b regulates ciliogenesis and the dynamic localization of Shh signaling proteins. Molecular biology of the cell 241 21976698
2012 Arl13b in primary cilia regulates the migration and placement of interneurons in the developing cerebral cortex. Developmental cell 197 23153492
2012 ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting. Proceedings of the National Academy of Sciences of the United States of America 196 23150559
2010 Joubert syndrome Arl13b functions at ciliary membranes and stabilizes protein transport in Caenorhabditis elegans. The Journal of cell biology 161 20231383
2015 A G-protein activation cascade from Arl13B to Arl3 and implications for ciliary targeting of lipidated proteins. eLife 125 26551564
2009 Cilia localization is essential for in vivo functions of the Joubert syndrome protein Arl13b/Scorpion. Development (Cambridge, England) 124 19906870
2013 Active transport and diffusion barriers restrict Joubert Syndrome-associated ARL13B/ARL-13 to an Inv-like ciliary membrane subdomain. PLoS genetics 88 24339792
2016 Regulation of ciliary retrograde protein trafficking by the Joubert syndrome proteins ARL13B and INPP5E. Journal of cell science 80 27927754
2015 Arl13b and the exocyst interact synergistically in ciliogenesis. Molecular biology of the cell 70 26582389
2014 A function for the Joubert syndrome protein Arl13b in ciliary membrane extension and ciliary length regulation. Developmental biology 70 25448689
2020 ARL13B regulates Sonic hedgehog signaling from outside primary cilia. eLife 69 32129762
2018 Axoneme polyglutamylation regulated by Joubert syndrome protein ARL13B controls ciliary targeting of signaling molecules. Nature communications 66 30120249
2018 TULP3 is required for localization of membrane-associated proteins ARL13B and INPP5E to primary cilia. Biochemical and biophysical research communications 51 30583862
2017 Palmitoylation of the ciliary GTPase ARL13b is necessary for its stability and its role in cilia formation. The Journal of biological chemistry 51 28848045
2014 Identification of a novel ARL13B variant in a Joubert syndrome-affected patient with retinal impairment and obesity. European journal of human genetics : EJHG 51 25138100
2012 Arl13b regulates endocytic recycling traffic. Proceedings of the National Academy of Sciences of the United States of America 51 23223633
2017 Biochemical characterization of purified mammalian ARL13B protein indicates that it is an atypical GTPase and ARL3 guanine nucleotide exchange factor (GEF). The Journal of biological chemistry 48 28487361
2019 The Ciliary Protein Arl13b Functions Outside of the Primary Cilium in Shh-Mediated Axon Guidance. Cell reports 47 31825820
2018 Disruption of the ciliary GTPase Arl13b suppresses Sonic hedgehog overactivation and inhibits medulloblastoma formation. Proceedings of the National Academy of Sciences of the United States of America 44 29378965
2018 ARL13B, a Joubert Syndrome-Associated Protein, Is Critical for Retinogenesis and Elaboration of Mouse Photoreceptor Outer Segments. The Journal of neuroscience : the official journal of the Society for Neuroscience 42 30573647
2011 Disrupted dorsal neural tube BMP signaling in the cilia mutant Arl13b hnn stems from abnormal Shh signaling. Developmental biology 39 21539826
2012 Temporal deletion of Arl13b reveals that a mispatterned neural tube corrects cell fate over time. Development (Cambridge, England) 38 23014696
2023 ARL13B promotes angiogenesis and glioma growth by activating VEGFA-VEGFR2 signaling. Neuro-oncology 37 36322624
2014 Arl13b and the non-muscle myosin heavy chain IIA are required for circular dorsal ruffle formation and cell migration. Journal of cell science 37 24777479
2014 Visualization of astrocytic primary cilia in the mouse brain by immunofluorescent analysis using the cilia marker Arl13b. Acta medica Okayama 37 25519025
2017 Arl13b Promotes Gastric Tumorigenesis by Regulating Smo Trafficking and Activation of the Hedgehog Signaling Pathway. Cancer research 35 28611043
2014 Structural insights into the small G-protein Arl13B and implications for Joubert syndrome. The Biochemical journal 34 24168557
2023 Interactions between TULP3 tubby domain and ARL13B amphipathic helix promote lipidated protein transport to cilia. Molecular biology of the cell 32 36652335
2019 Ciliary genes arl13b, ahi1 and cc2d2a differentially modify expression of visual acuity phenotypes but do not enhance retinal degeneration due to mutation of cep290 in zebrafish. PloS one 32 30970040
2018 The Joubert syndrome protein ARL13B binds tubulin to maintain uniform distribution of proteins along the ciliary membrane. Journal of cell science 30 29592971
2017 Reduced primary cilia length and altered Arl13b expression are associated with deregulated chondrocyte Hedgehog signaling in alkaptonuria. Journal of cellular physiology 26 28158906
2016 Arl13b Interacts With Vangl2 to Regulate Cilia and Photoreceptor Outer Segment Length in Zebrafish. Investigative ophthalmology & visual science 26 27571019
2016 The ciliary GTPase Arl13b regulates cell migration and cell cycle progression. Cell adhesion & migration 17 26963749
2021 Smoothened and ARL13B are critical in mouse for superior cerebellar peduncle targeting. Genetics 16 34132778
2022 Arl13b controls basal cell stemness properties and Hedgehog signaling in the mouse epididymis. Cellular and molecular life sciences : CMLS 14 36261680
2019 Ahi1 promotes Arl13b ciliary recruitment, regulates Arl13b stability and is required for normal cell migration. Journal of cell science 14 31391239
2020 The Joubert Syndrome Gene arl13b is Critical for Early Cerebellar Development in Zebrafish. Neuroscience bulletin 13 32812127
2019 Arl13b Regulates Breast Cancer Cell Migration and Invasion by Controlling Integrin-Mediated Signaling. Cancers 13 31569511
2012 Defective Nodal and Cerl2 expression in the Arl13b(hnn) mutant node underlie its heterotaxia. Developmental biology 12 22554696
2024 Postnatal Dynamic Ciliary ARL13B and ADCY3 Localization in the Mouse Brain. Cells 11 38334651
2022 Ciliogenesis mechanisms mediated by PAK2-ARL13B signaling in brain endothelial cells is responsible for vascular stability. Biochemical pharmacology 11 35700757
2022 TMEM67 is required for the gating function of the transition zone that controls entry of membrane-associated proteins ARL13B and INPP5E into primary cilia. Biochemical and biophysical research communications 11 36334440
2017 A novel Cre-inducible knock-in ARL13B-tRFP fusion cilium reporter. Genesis (New York, N.Y. : 2000) 10 28948682
2017 A novel homozygous ARL13B variant in patients with Joubert syndrome impairs its guanine nucleotide-exchange factor activity. European journal of human genetics : EJHG 10 29255182
2023 Rab8 and TNPO1 are ciliary transport adaptors for GTPase Arl13b by interacting with its RVEP motif containing ciliary targeting sequence. The Journal of biological chemistry 8 36907439
2023 Increasing Ciliary ARL13B Expression Drives Active and Inhibitor-Resistant Smoothened and GLI into Glioma Primary Cilia. Cells 7 37830570
2018 Developmental expression of the zebrafish Arf-like small GTPase paralogs arl13a and arl13b. Gene expression patterns : GEP 7 30009987
2018 The unusual flagellar-targeting mechanism and functions of the trypanosome ortholog of the ciliary GTPase Arl13b. Journal of cell science 6 30097558
2025 Ciliary ARL13B is essential for body weight regulation in adult mice. bioRxiv : the preprint server for biology 5 37577625
2024 Novel compound heterozygous variants in ARL13B lead to Joubert syndrome. Journal of cellular physiology 5 38219074
2019 The Dynamic and Complex Role of the Joubert Syndrome-Associated Ciliary Protein, ADP-Ribosylation Factor-Like GTPase 13B (ARL13B) in Photoreceptor Development and Maintenance. Advances in experimental medicine and biology 5 31884661
2025 Knocking out ARL13B completely abolishes primary ciliogenesis in cell lines. Scientific reports 3 40707593
2025 ARL13B-Cerulean rescues Arl13b-null mouse from embryonic lethality and reveals a role for ARL13B in spermatogenesis. Journal of cell science 2 40916698
2024 ARL13B promotes cell cycle through the sonic hedgehog signaling pathway to alleviate nerve damage during cerebral ischemia/reperfusion in rats. Biochemical pharmacology 2 39038552
2023 Arl13b promotes the proliferation, migration, osteogenesis, and mechanosensation of osteoblasts. Tissue & cell 2 37058812
2025 ARL13B regulates juxtaposed cilia-cilia elongation in BBSome dependent manner in Caenorhabditis elegans. iScience 1 39925426
2025 ARL13B-Cerulean rescues Arl13b-null mouse from embryonic lethality and reveals a role for ARL13B in spermatogenesis. bioRxiv : the preprint server for biology 1 40196635
2025 Volumetric Imaging and Analysis of Primary Cilia in Musculoskeletal Tissue using the ARL13B-CENTRIN-2 Mouse Model. Journal of visualized experiments : JoVE 0 40228007
2025 The RNA splicing factor PRPF8 is required for left-right organiser cilia differentiation and determination of cardiac left-right asymmetry via regulation of Arl13b splicing. bioRxiv : the preprint server for biology 0 40501629
2025 Ciliary ARL13B Is Essential for Vision and Morphogenesis of Cone Outer Segments. The Journal of neuroscience : the official journal of the Society for Neuroscience 0 40721319
2025 The Role of ARL13B in Mitochondrial Homeostasis in Cultured Human Corneal Endothelial Cells. Investigative ophthalmology & visual science 0 41091001
2025 Unraveling the Genetic Links Between Polycystic Kidney Disease and Hypertension Through ARL13B. International journal of nephrology and renovascular disease 0 41158202
2025 Loss of a primary cilia protein ARL13B promotes TGFβ-1 induced EMT of RPE in proliferative vitreoretinopathy via increasing Smad3 expression. Frontiers in cell and developmental biology 0 41425088
2024 Induction of IMPDH-Based Cytoophidia by a Probable IMP-Dependent ARL13B-IMPDH Interaction. Biochemistry. Biokhimiia 0 39865040