STK38L

STK38L (NDR2) is a cytoplasmic serine/threonine kinase of the NDR/LATS family that integrates phosphorylation, ubiquitination, SUMOylation, and acetylation inputs to regulate membrane trafficking, ciliogenesis, autophagy, integrin signaling, and innate immunity. Its catalytic activation requires autophosphorylation at Ser-282, upstream phosphorylation at Thr-442, and binding of Mob2 as an activating subunit, with additional regulation by TRIM27-mediated non-degradative ubiquitination, SENP2-mediated de-SUMOylation, and SIRT1/p300-controlled reversible acetylation at K463 (PMID:15037617, PMID:15067004, PMID:35670107, PMID:38908669, PMID:31427083). STK38L phosphorylates Rabin8 at Ser-272 to drive Rab8 activation and ciliary membrane assembly from peroxisome-associated and Golgi exit sites, phosphorylates β1-integrin at Thr-788/789 to promote integrin trafficking and synaptic plasticity in hippocampal neurons, phosphorylates Filamin A at Ser-2152 to enable LFA-1 activation in T cells, and phosphorylates IRF3 at Ser-303 to stabilize IRF3 for antiviral innate immune responses (PMID:23435566, PMID:39774853, PMID:24719112, PMID:40439020, PMID:30568657, PMID:36417850). STK38L also restrains autophagy amplitude by phosphorylating ULK1 at Ser-495, priming it for TRIM27-mediated degradation, scaffolds the RIG-I/TRIM25 complex to potentiate antiviral signaling, and promotes Smurf1-mediated degradation of MEKK2 to dampen IL-17-driven inflammation (PMID:35670107, PMID:39561008, PMID:30775439, PMID:30504095).

1. 2004 High

   Establishing the activation mechanism of NDR2 resolved how this kinase is switched on: Mob2 binding dramatically stimulates catalytic activity, while Ser-282 autophosphorylation and Thr-442 phosphorylation by an upstream kinase are both required, with S100B additionally stimulating autophosphorylation in vitro.

   Evidence Co-IP from Jurkat T-cells and HeLa cells with in vitro kinase assays, phospho-site mutagenesis, and okadaic acid treatment

   PMID:15037617 PMID:15067004

   Open questions at the time

   • The upstream kinase for Thr-442 was not definitively identified in these studies (PDK1 role was implied later)
   • How Mob2 binding allosterically activates NDR2 structurally is unresolved
   • Relative contributions of S100B vs. Mob2 in physiological contexts remain unclear
2. 2004 High

   Demonstrating that NDR2 is predominantly cytoplasmic and associates with the actin cytoskeleton in neurons established its distinct subcellular context compared to nuclear NDR1 and linked it to neurite morphology.

   Evidence Fluorescence microscopy of tagged proteins in HeLa/COS/PC12 cells and cortical neurons, actin co-precipitation

   PMID:15037617 PMID:15067004 PMID:15308672

   Open questions at the time

   • Whether actin association is direct or scaffolded was not determined
   • Specific actin-binding domain not mapped
3. 2006 High

   Identifying ARK5 Thr-211 as a direct NDR2 substrate downstream of IGF-1 signaling was the first demonstration of NDR2 phosphorylating a defined substrate in a growth factor pathway relevant to cell survival and invasion.

   Evidence In vitro kinase assay with phospho-site mutagenesis, IGF-1 stimulation, cell survival and invasion assays

   PMID:16488889

   Open questions at the time

   • Whether NDR2–ARK5 axis operates in non-cancer physiological contexts was not tested
   • PDK1 involvement at Thr-442 was suggested but not directly demonstrated with reconstituted components
4. 2013 High

   Showing that NDR2 phosphorylates Rabin8 at Ser-272 to switch its binding from phosphatidylserine to the exocyst subunit Sec15, thereby activating Rab8 and driving ciliary membrane assembly, established NDR2 as a central regulator of ciliogenesis.

   Evidence In vitro kinase assay, phospho-mimetic/non-phosphorylatable Rabin8 mutants, lipid binding assay, ciliogenesis assay, Co-IP

   PMID:23435566

   Open questions at the time

   • The upstream signal triggering NDR2 activation specifically for ciliogenesis was not identified
   • Whether other NDR family members can compensate was not addressed
5. 2014 High

   Demonstrating that Ndr2 phosphorylates β1-integrin at Thr-788/789 on endosomes and that Ndr2 knockout mice have reduced dendritic integrin activation and altered hippocampal morphology revealed a neuronal trafficking function for the kinase.

   Evidence In vitro phosphorylation, endosome fractionation, surface biotinylation, constitutive knockout mouse with hippocampal phenotype

   PMID:24719112

   Open questions at the time

   • Which endosomal sorting machinery cooperates with NDR2-phosphorylated integrins was not defined
   • Behavioral consequences of altered dendritic complexity were not reported
6. 2017 High

   Localizing NDR2 to peroxisomes via its C-terminal PTS1-like GKL motif recognized by Pex5p, and showing this peroxisomal localization is required for ciliogenesis, linked peroxisome biology to ciliary membrane biogenesis through a single kinase.

   Evidence Colocalization with peroxisome markers, Pex5p binding assay, ciliogenesis rescue with NDR2-ΔL mutant, PEX gene knockdown

   PMID:28122914

   Open questions at the time

   • How peroxisomal localization facilitates Rabin8 phosphorylation at ciliary precursor membranes is mechanistically unclear
   • Whether NDR2 has peroxisome-intrinsic substrates is unknown
7. 2017 Medium

   Placing STK38L upstream of LATS2 in KRAS-dependent pancreatic cancer cells, where its depletion induces apoptosis and p21 upregulation, identified a survival function in PDAC.

   Evidence RNAi epistasis by double knockdown of STK38L and LATS2, apoptosis and proliferation assays

   PMID:29108249

   Open questions at the time

   • The direct biochemical mechanism linking STK38L to LATS2 regulation was not established
   • Generalizability beyond the ADEX PDAC subtype is untested
8. 2018 High

   Identifying Filamin A Ser-2152 as a direct NDR2 substrate upon TCR stimulation, with phosphorylation releasing FLNa from LFA-1 to permit talin/kindlin-3 binding, revealed how NDR2 controls integrin inside-out activation in T cells.

   Evidence In vitro kinase assay, phospho-mimetic mutants, Co-IP, LFA-1 conformation assay in T cells

   PMID:30568657

   Open questions at the time

   • How TCR signaling activates NDR2 was not defined
   • Whether this mechanism operates for integrins beyond LFA-1 is unknown
9. 2018 Medium

   Demonstrating that NDR2 scaffolds Smurf1-mediated K48-ubiquitination and degradation of MEKK2 to suppress IL-17 inflammatory signaling extended NDR2 function to a kinase-independent scaffolding role in innate inflammation.

   Evidence Co-IP, ubiquitination assay, siRNA knockdown, cytokine expression

   PMID:30504095

   Open questions at the time

   • Whether NDR2 kinase activity is required for the Smurf1 interaction was not tested
   • Independent replication needed
10. 2019 High

    Showing that NDR2 bridges RIG-I and TRIM25 to enhance K63-polyubiquitination of RIG-I, with conditional knockout mice displaying impaired antiviral responses, established a scaffolding function in innate antiviral immunity.

    Evidence Co-IP, kinase-inactive mutants, ubiquitination assay, Lysm-Cre conditional KO mice with viral challenge

    PMID:30775439

    Open questions at the time

    • Whether kinase activity or only scaffolding is needed for RIG-I activation was not fully resolved
    • Contribution relative to NDR1 in the same pathway not addressed
11. 2019 Medium

    Identifying GEF-H1 as a direct NDR2 substrate whose phosphorylation inactivates RhoB, driving a RASSF1A-loss-dependent migration and cytokinesis defect axis, connected NDR2 to Rho GTPase regulation in cancer.

    Evidence Co-IP, phosphorylation assay, siRNA epistasis, xenograft assay

    PMID:30979377

    Open questions at the time

    • The exact phosphorylation site on GEF-H1 was not fully mapped
    • Independent validation in non-bronchial cell types is lacking
12. 2019 Medium

    Mapping reversible acetylation of NDR2 at K463 controlled by SIRT1 (deacetylase) and p300/CBP (acetyltransferases) added a post-translational regulatory layer, with HDAC6 and HDAC1/2 serving as backup deacetylases in SIRT1-deficient cells.

    Evidence Mass spectrometry, Co-IP with acetyltransferases/deacetylases, SIRT1 KO cells

    PMID:31427083

    Open questions at the time

    • Functional consequence of acetylation on kinase activity or substrate selection was not determined
    • Whether K463 acetylation and SUMOylation compete at the same residue was not tested
13. 2022 High

    Demonstrating that TRIM27 non-degradatively ubiquitinates STK38L (K6/K11 chains) to activate it, after which STK38L phosphorylates ULK1 at Ser-495 to prime ULK1 for TRIM27-mediated K48-ubiquitination and degradation, revealed a feedback circuit that restrains autophagy amplitude.

    Evidence In vitro ubiquitination and kinase assays, mutagenesis, Co-IP, Trim27 KO mice

    PMID:35670107

    Open questions at the time

    • Whether TRIM27-mediated ubiquitination of STK38L is stimulus-specific beyond starvation is unknown
    • The deubiquitinase counteracting TRIM27 on STK38L was not identified
14. 2022 High

    Identifying IRF3 Ser-303 as a direct STK38L substrate that prevents IRF3 proteasomal degradation at steady state, with STK38L-KO mice showing compromised antiviral responses, established STK38L as a constitutive guardian of innate immune readiness.

    Evidence In vitro kinase assay, phospho-site mutagenesis, STK38L-KO mice with viral challenge, IRF3 stability assay

    PMID:36417850

    Open questions at the time

    • The proteasomal pathway that degrades unphosphorylated IRF3 was not identified
    • Whether NDR1 can partially compensate for IRF3 stabilization is untested
15. 2024 Medium

    Revealing that SENP2-mediated de-SUMOylation at K463 enhances NDR2 kinase activity, which then destabilizes p21 to accelerate G1/S transition, added SUMOylation as a regulatory switch converging on the same residue as acetylation.

    Evidence SUMO deconjugation assay, kinase activity assay, cell cycle analysis, siRNA in lung cancer cells

    PMID:38908669

    Open questions at the time

    • The SUMO E3 ligase responsible for NDR2 SUMOylation was not identified
    • Interplay between SUMOylation, acetylation, and ubiquitination at K463 needs systematic analysis
    • Independent replication outside lung cancer cells is lacking
16. 2024 Medium

    Conditional myeloid NDR2 knockout mice showing lower bone mass due to enhanced osteoclastogenesis, rescued by ULK1 inhibition, connected the NDR2–ULK1 autophagy axis to bone homeostasis in vivo.

    Evidence Lysm-Cre conditional KO mice, autophagy/mitophagy assays, ULK1 inhibitor rescue

    PMID:39561008

    Open questions at the time

    • Whether NDR2 directly phosphorylates ULK1 in osteoclast precursors or acts through TRIM27 was not tested
    • Single-lab finding awaiting independent replication
17. 2025 High

    Showing NDR2 phosphorylates Rabin8 at S272 at trans-Golgi/Golgi exit sites in vertebrate photoreceptors, interacts with VAMP7, and is required for rhodopsin Golgi-to-cilia trafficking extended the Rabin8 phosphorylation mechanism to specialized sensory cilia in vivo.

    Evidence Transgenic Xenopus expressing GFP-Rabin8 phospho-mutants, Co-IP with VAMP7, fluorescence microscopy of rod photoreceptors

    PMID:39774853

    Open questions at the time

    • Whether NDR2 directly binds VAMP7 or is scaffolded remains unclear
    • Mammalian photoreceptor validation not yet shown
18. 2025 Medium

    Demonstrating that NDR2 deficiency in hippocampal neurons reduces phospho-β1-integrin at synapses, decreases synaptic density, and impairs LTP — rescued by integrin-activating RGD peptide — established NDR2 as essential for synapse formation and plasticity via integrin signaling.

    Evidence Constitutive NDR2 KO mice, phospho-β1-integrin immunostaining, synaptic density quantification, LTP electrophysiology, RGD peptide rescue

    PMID:40439020

    Open questions at the time

    • Behavioral consequences (learning/memory) in NDR2 KO mice not reported
    • Whether NDR2 acts cell-autonomously in postsynaptic neurons vs. presynaptic was not dissected
19. 2025 Medium

    Linking NDR2 to ATG9A-dependent autophagosome formation, lysosomal trafficking, and Golgi repositioning for filopodia-driven migration in lung cancer cells added a migration-autophagy nexus to NDR2 function.

    Evidence siRNA/shRNA knockdown, LC3-II immunoblot, ATG9A functional assay, migration assay, Golgi repositioning microscopy

    PMID:41390758

    Open questions at the time

    • Direct substrate linking NDR2 to ATG9A regulation not identified
    • Relationship to the TRIM27–ULK1 axis not tested
    • Single-lab finding in cancer cell lines

• How the diverse post-translational modifications of STK38L at K463 (acetylation, SUMOylation) and elsewhere (ubiquitination, phosphorylation) are temporally coordinated to direct substrate selection across its multiple functions — ciliogenesis, autophagy, integrin trafficking, and innate immunity — remains an open question.
• No structural model of NDR2 with Mob2 or substrates is available
• Systematic identification of the full substrate repertoire has not been performed
• Relative contributions of NDR1 vs. NDR2 to shared pathways are poorly defined