Affinage

SLK

STE20-like serine/threonine-protein kinase · UniProt Q9H2G2

Length
1235 aa
Mass
142.7 kDa
Annotated
2026-06-10
52 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLK is a Ste20-family serine/threonine kinase that couples upstream adhesion and growth-factor signaling to actin and microtubule remodeling, focal adhesion turnover, mitotic progression, and apoptosis (PMID:18382658, PMID:22203681). Catalytic activation requires phosphorylation of activation-segment residues Thr183 and Ser189; mutation of these sites abolishes kinase activity, downstream JNK/p38 and AP-1 signaling, and apoptotic induction (PMID:22203681, PMID:28475647). Through these activities SLK phosphorylates a defined substrate set to control cytoskeletal architecture: it activates ERM proteins (ezrin/radixin/moesin) to restrict apical microvilli and, at mitotic entry, to polarize LGN/NuMA at the cortex for correct spindle orientation (PMID:23209304, PMID:24958772); it phosphorylates paxillin on Ser250 to drive focal adhesion turnover and migration downstream of FAK/c-Src (PMID:23128389, PMID:18382658); it phosphorylates the dynactin subunit p150(Glued) to target it to the centrosome and maintain the radial microtubule array and Golgi reorientation in polarized cells (PMID:23985322, PMID:18287541); and it phosphorylates RhoA on Ser188 downstream of the angiotensin II type 2 receptor to promote GDI-mediated cytosolic sequestration and vasodilation (PMID:18420945). SLK additionally phosphorylates and strongly activates Plk1 on Thr210 in its activation segment, increasing Plk1 catalytic efficiency, and its activity rises during G2 in a manner required for spindle assembly and cell cycle progression (PMID:18298087, PMID:16236704). In the apoptotic arm, caspase-3 cleaves SLK to liberate an N-terminal pro-apoptotic kinase domain and a C-terminal domain that independently disassembles actin stress fibers, and SLK activates JNK/p38 and ASK1 and promotes p53 phosphorylation to amplify ischemia-reperfusion-induced apoptosis (PMID:10611247, PMID:16316999, PMID:19640899). SLK activity is regulated by binding partners—LMO4 and RNAseT2 activate it while Ldb1/2 and the nucleoporin Tpr restrain it—and by inhibitory CK2 phosphorylation at Ser347/348 induced by v-Src (PMID:25882817, PMID:41980967, PMID:19675209, PMID:26094769, PMID:16837460). A CRISPR kinase-dead knock-in establishes that SLK kinase activity controls Rac1/RhoA balance, stress fiber formation, and focal adhesion turnover, and is essential for development, homozygous loss being embryonic lethal (PMID:38871226).

Mechanistic history

Synthesis pass · year-by-year structured walk · 30 steps
  1. 1999 Medium

    Established SLK as a signaling kinase that engages the stress/apoptotic JNK pathway and localizes to the cell periphery, framing it as more than an orphan kinase.

    Evidence In vitro kinase assay, immunofluorescence, and apoptosis staining in fibroblasts

    PMID:10602516

    Open questions at the time
    • No direct JNK substrate or intermediary identified
    • Overexpression-based, no endogenous loss-of-function
  2. 2000 High

    Resolved how SLK partitions its pro-apoptotic and cytoskeletal functions by showing caspase-3 cleavage liberates a kinase domain and a separate actin-disassembling C-terminal domain.

    Evidence In vitro and in vivo caspase-3 cleavage assays with domain overexpression and apoptosis readouts

    PMID:10611247

    Open questions at the time
    • Mechanism by which C-terminal domain disassembles actin not defined
    • In vivo relevance of cleavage products untested
  3. 2000 Medium

    Linked SLK to cell-cycle control by showing it phosphorylates Plk1 and its activity peaks in G2.

    Evidence In vitro kinase assay and cell-cycle synchronization with activity measurement

    PMID:10886374

    Open questions at the time
    • Phosphosite on Plk1 not yet mapped
    • How SLK activity is timed to G2 unknown
  4. 2002 Medium

    Positioned SLK on the cytoskeleton, associating with microtubules and acting through Rac1 to drive stress fiber disassembly at adhesion sites.

    Evidence Co-IP with alpha-tubulin, dominant-negative Rac1 microinjection, adenoviral overexpression

    PMID:12151406

    Open questions at the time
    • Direct cytoskeletal substrates not identified here
    • Relationship between microtubule binding and kinase activity unresolved
  5. 2005 Medium

    Identified ASK1 as an SLK substrate selectively driving p38, and showed C-terminal homodimerization enhances kinase activity, tying activation mechanism to stress signaling.

    Evidence In vitro kinase assay, co-IP for dimerization, MAPK phosphorylation blots under chemical anoxia

    PMID:16316999

    Open questions at the time
    • ASK1 phosphosite not defined
    • Selectivity for p38 over JNK/ERK mechanism unexplained
  6. 2005 Medium

    Demonstrated SLK is required for mitotic progression and spindle assembly, placing it upstream of H1/cdc2 kinase activation.

    Evidence Kinase-dead/siRNA knockdown with cyclin and phospho-H3 readouts, Xenopus oocyte microinjection

    PMID:16236704

    Open questions at the time
    • Direct mitotic substrate at spindle not identified in this study
    • Mechanism of G2 arrest molecularly incomplete
  7. 2006 Medium

    Defined a negative regulatory input: v-Src induces CK2 to phosphorylate SLK at Ser347/348, suppressing its activity.

    Evidence In vitro kinase assay, deletion analysis, CK2 inhibitor, co-localization

    PMID:16837460

    Open questions at the time
    • Structural basis for inhibition by S347/348 phosphorylation unknown
    • Physiological contexts of CK2 regulation beyond v-Src untested
  8. 2008 High

    Identified RhoA Ser188 as a direct SLK substrate downstream of AT2R, explaining SLK control of vascular tone via RhoA sequestration.

    Evidence In vitro kinase assay, RhoA S188 mutagenesis, signaling inhibitors in vascular smooth muscle

    PMID:18420945

    Open questions at the time
    • Direct SLK activation step downstream of SHP-1/CK2 not fully reconstituted
    • Tissue specificity of the AT2R-SLK-RhoA axis untested
  9. 2008 High

    Quantified the SLK-Plk1 relationship, showing SLK phosphorylates Plk1 Thr210 to increase catalytic efficiency ~202-fold, defining a mitotic activation cascade.

    Evidence Reconstituted kinase assay with purified proteins and kcat/KM measurements

    PMID:18298087

    Open questions at the time
    • In vivo contribution of SLK to Plk1 activation versus other activators unquantified
  10. 2008 Medium

    Established SLK as a centrosomal regulator that phosphorylates p150(Glued) to anchor microtubules and polarize the Golgi for directed migration.

    Evidence Dominant-negative/RNAi with dynactin/centrosome/microtubule immunofluorescence

    PMID:18287541

    Open questions at the time
    • p150(Glued) phosphosite not mapped in this study
    • Microtubule nucleation versus anchoring separation incomplete
  11. 2008 Medium

    Connected SLK to focal adhesion turnover and migration downstream of the FAK/c-Src complex, distinguishing activation (FAK/Src/MAPK) from leading-edge recruitment (Src-dependent, FAK-independent).

    Evidence Knockdown, dominant-negative SLK, scratch-wound activity assay, inhibitor dissection

    PMID:18382658

    Open questions at the time
    • Direct focal-adhesion substrate not yet identified here
    • Recruitment receptor/adaptor at leading edge unknown
  12. 2009 Medium

    Extended migration control to ErbB2/Neu signaling, showing SLK activation requires specific Neu phosphotyrosines and multiple downstream effectors for invasion.

    Evidence Knockdown, kinase-inactive SLK, signaling inhibitors, migration/invasion assays

    PMID:19525980

    Open questions at the time
    • Direct link between Neu phosphosites and SLK activation step unresolved
    • Pathway integration with FAK/Src axis not unified
  13. 2009 Medium

    Implicated SLK in p53-dependent apoptosis, showing it promotes p53 Ser33/Ser315 phosphorylation and transactivation in a JNK-dependent manner during ischemia-reperfusion.

    Evidence p53 reporter, p53 site mutagenesis, JNK and p53 inhibitors, dominant-negative SLK

    PMID:19640899

    Open questions at the time
    • Whether SLK phosphorylates p53 directly or via JNK not separated
    • In vivo p53 dependence beyond cell model untested
  14. 2009 Medium

    Identified Ldb1/2 as direct C-terminal binding partners that hold SLK inactive, defining a transcriptional-cofactor brake on the kinase during migration.

    Evidence In vitro binding, reciprocal Co-IP, co-localization, siRNA migration assays

    PMID:19675209

    Open questions at the time
    • Mechanism of inactivation by Ldb1/2 not structurally defined
    • Both knockdown and overexpression increase motility, leaving dose-response unclear
  15. 2011 Medium

    Showed controlled homodimerization of the catalytic domain is sufficient to enhance activity and drive JNK/p38 activation, Bax expression, and apoptosis, linking dimerization to function.

    Evidence Regulated dimerization system (Fv-SLK + AP20187) with kinase, MAPK, and apoptosis readouts

    PMID:21677149

    Open questions at the time
    • Whether endogenous full-length SLK dimerizes not addressed here
    • Artificial dimerizer may not reflect native activation
  16. 2011 High

    Defined the molecular basis of SLK activation: Thr183/Ser189 activation-segment phosphorylation is required for activity and is enhanced by dimerization.

    Evidence Activation-segment mutagenesis, in vitro kinase assay, MAPK/AP-1 reporters, regulated dimerization

    PMID:22203681

    Open questions at the time
    • Upstream kinase versus autophosphorylation contribution to T183/S189 not fully separated
  17. 2012 High

    Identified SLK (with LOK) as the kinase activating ezrin to restrict microvilli to the apical epithelial domain, defining an ERM substrate relationship in vivo context.

    Evidence Proteomic identification, RNAi, drug-resistant kinase variants, live imaging, fractionation

    PMID:23209304

    Open questions at the time
    • Mechanism of local SLK activation at microvilli not defined
    • Relative contribution of LOK versus SLK unresolved
  18. 2012 High

    Mapped paxillin Ser250 as a direct SLK substrate required for paxillin redistribution and migration, mechanistically linking SLK to focal adhesion dynamics.

    Evidence In vitro kinase assay, S250A mutant migration assay, phospho-FAK Y397 blots

    PMID:23128389

    Open questions at the time
    • How S250 phosphorylation alters paxillin interactions not defined
  19. 2013 High

    Resolved the centrosomal mechanism by showing SLK phosphorylates p150(Glued) isoform 1A specifically to target it to the centrosome, separable from its microtubule-organizing activity.

    Evidence In vitro kinase assay, isoform-specific analysis, artificial centrosomal targeting rescue

    PMID:23985322

    Open questions at the time
    • Exact p150(Glued) phosphosite not specified
    • How phosphorylation drives centrosomal targeting unresolved
  20. 2014 High

    Established SLK as the mitotic ERM activator that polarizes LGN/NuMA for spindle orientation, with in vivo relevance in neocortical progenitors.

    Evidence In vitro kinase assay, micropatterned spindle-orientation assay, cortical LGN/NuMA IF, in vivo mouse cortex

    PMID:24958772

    Open questions at the time
    • How SLK is activated specifically at mitotic entry unresolved
    • Redundancy with LOK in mitosis not addressed
  21. 2015 Medium

    Identified LMO4 as a direct activating partner that recruits SLK to the leading edge in a Src-dependent manner, defining a positive regulatory input for migration.

    Evidence In vitro kinase assay, Co-IP after wounding, conditional LMO4 KO, SYF cell rescue, IF

    PMID:25882817

    Open questions at the time
    • Structural basis of LMO4-mediated activation unknown
    • Relationship between LMO4 activation and Ldb1/2 inhibition unintegrated
  22. 2015 Medium

    Mapped C-terminal coiled-coil interactions with Tpr and alpha-actinin-4, showing Tpr restrains SLK autophosphorylation and apoptosis at the nuclear envelope.

    Evidence Mass spectrometry, protein complementation, Co-IP, autophosphorylation and AP-1/apoptosis assays

    PMID:26094769

    Open questions at the time
    • Mechanism of Tpr inhibition not structurally defined
    • Functional role of alpha-actinin-4 interaction unclear
  23. 2016 Medium

    Showed SLK directs cell motility through two independent effector arms, RhoA and p150(Glued) dynactin, unifying its cytoskeletal outputs.

    Evidence Knockdown/inhibition with RhoA and dynactin functional assays and migration tracking

    PMID:26818812

    Open questions at the time
    • How the two arms are coordinated spatially not defined
    • Substrate-level basis of independence not dissected
  24. 2016 Medium

    Revealed a survival feedback loop in which SLK activates HSF1-Hsp70 via Plk1, attenuating its own pro-apoptotic effect.

    Evidence HSF1/Hsp70 reporters, Plk1 inhibitors, kinase-dead SLK, HSF1 shRNA, Hsp70 inhibitor

    PMID:27216364

    Open questions at the time
    • Direct versus Plk1-relayed signal to HSF1 not separated
    • Physiological setting of feedback untested
  25. 2017 High

    Tied activation mechanism to substrate phosphorylation by showing dimerization-impairing coiled-coil mutations reduce ERM/ezrin phosphorylation, with in vivo disease relevance in membranous nephropathy.

    Evidence Regulated dimerization, in vitro ezrin kinase assay, coiled-coil and activation-segment mutagenesis, rat nephropathy model

    PMID:28475647

    Open questions at the time
    • Whether endogenous SLK dimerizes natively not settled here
  26. 2017 Medium

    Uncovered a kinase-activity-independent role for SLK in TGFbeta-induced EMT, where SLK supports Snai1/vimentin expression without affecting Smad3 nuclear translocation.

    Evidence siRNA knockdown, kinase-dead rescue, Smad3 translocation, migration/invasion assays

    PMID:29228724

    Open questions at the time
    • Scaffolding mechanism for kinase-independent function unknown
    • How SLK regulates Snai1 transcription unresolved
  27. 2021 High

    Provided structural definition of the SLK ATP-binding site via inhibitor co-crystal structures, rationalizing selectivity versus STK10.

    Evidence X-ray crystallography of inhibitor-bound SLK and STK10, selectivity profiling, target engagement

    PMID:34463505

    Open questions at the time
    • Apo/active-state and full-length structure not determined
    • Regulatory C-terminal domain not structurally captured
  28. 2024 High

    Directly refuted obligate homodimerization in cells and showed via a CRISPR kinase-dead knock-in that SLK activity controls Rac1/RhoA balance, stress fibers, and focal adhesion turnover, and is essential for development.

    Evidence CRISPR/Cas9 kinase-dead knock-in, dimerization assay, kinase and Rac1/RhoA pull-downs, focal adhesion imaging

    PMID:38871226

    Open questions at the time
    • How native SLK is activated if not by stable dimerization unresolved
    • Cause of embryonic lethality molecularly undefined
  29. 2025 Medium

    Showed isoform-level regulation: HNRNPL-driven exon 13 skipping generates SLK-S that activates ERK and promotes HCC metastasis, opposing the suppressive long isoform SLK-L.

    Evidence Splicing reporters, isoform-specific manipulation, ERK blots, invasion assays, in vivo metastasis model

    PMID:41046074

    Open questions at the time
    • Mechanistic basis for opposing isoform effects on ERK not defined
    • Whether SLK-S/SLK-L differ in kinase activity unclear
  30. 2026 High

    Defined an extracellular activation input in muscle regeneration, where macrophage-secreted RNAseT2 binds SLK to drive paxillin/N-WASP phosphorylation and actin bundling for myoblast fusion.

    Evidence RNAseT2-SLK binding assay, N-WASP/paxillin phosphorylation, actin imaging, mouse and zebrafish models

    PMID:41980967

    Open questions at the time
    • Mechanism of RNAseT2-induced SLK activation not structurally defined
    • Receptor mediating RNAseT2 access to intracellular SLK unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SLK is activated at specific subcellular sites and cell-cycle stages in the absence of stable homodimerization, and how its positive (LMO4, RNAseT2) and negative (Ldb1/2, Tpr, CK2) regulators are integrated, remain unresolved.
  • No unified model of native activation mechanism
  • Spatial coordination of competing regulators undefined
  • Full-length/active-state structure unavailable

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016740 transferase activity 4 GO:0008092 cytoskeletal protein binding 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005856 cytoskeleton 3 GO:0005815 microtubule organizing center 2 GO:0005829 cytosol 2 GO:0005886 plasma membrane 2 GO:0005635 nuclear envelope 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1640170 Cell Cycle 3 R-HSA-5357801 Programmed Cell Death 3
Partners
DCTN1EZRLDB1LMO4PLK1PXNRHOATPR

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 SLK overexpression activates c-Jun N-terminal kinase 1 (JNK1), and prolonged overexpression induces apoptosis in cultured fibroblasts. SLK colocalizes to distinct cytosolic domains, preferentially at the cell periphery. In vitro kinase assay, immunofluorescence, annexin-V/TUNEL staining Oncogene Medium 10602516
2000 Caspase 3 cleaves SLK in vitro and in vivo during apoptosis, releasing an activated N-terminal kinase domain that promotes apoptosis and cytoskeletal rearrangements, and a C-terminal domain (AT1-46 homology domain) that independently disassembles actin stress fibers. SLK overexpression also activates the JNK signaling pathway. Caspase 3 cleavage assay in vitro and in vivo, annexin V/TUNEL, dominant-domain overexpression, immunofluorescence Molecular and cellular biology High 10611247
2000 SLK can phosphorylate and activate murine Plk1. Endogenous SLK activity increases during G2 phase progression. SLK protein levels decrease in quiescent and differentiating cells. Okadaic acid treatment induces phosphorylation-dependent enhancement of SLK activity. In vitro kinase assay (SLK phosphorylating Plk1), cell cycle synchronization with kinase activity measurement Genes to cells Medium 10886374
2002 SLK associates with the microtubule network and co-precipitates with alpha-tubulin. SLK redistributes to podosome-like adhesion sites in fibronectin-stimulated fibroblasts but its kinase activity is not modulated by fibronectin. Ectopic expression of activated SLK induces actin stress fiber disassembly that is inhibited by dominant negative Rac1, and endogenous SLK colocalizes with Rac1 in spreading cells. Co-immunoprecipitation with alpha-tubulin, immunofluorescence, microinjection with dominant negative Rac1, adenoviral overexpression The Journal of biological chemistry Medium 12151406
2005 SLK phosphorylates and increases activity of apoptosis signal-regulating kinase-1 (ASK1), which in turn stimulates p38 MAPK phosphorylation (but not JNK or ERK). SLK undergoes homodimerization via its C-terminal domain, and dimerization enhances SLK kinase activity. SLK activity is stimulated by chemical anoxia/recovery (ischemia-reperfusion in cell culture). In vitro kinase assay, co-immunoprecipitation for dimerization, ASK1 phosphorylation assay, p38/JNK/ERK phosphorylation Western blot The Journal of biological chemistry Medium 16316999
2005 SLK co-localizes with the mitotic spindle during mitosis. Expression of kinase-inactive SLK or SLK siRNA causes G2 accumulation with failure to down-regulate cyclin A, low phospho-H3 and low active p34/cdc2. Overexpression of active SLK induces ectopic spindle assembly and triggers cell cycle re-entry in Xenopus oocytes, placing SLK upstream of H1 kinase activation. Immunofluorescence, kinase-dead mutant/siRNA knockdown, cyclin expression Western blot, Xenopus oocyte microinjection The Journal of biological chemistry Medium 16236704
2006 v-Src expression down-regulates SLK kinase activity indirectly by inducing casein kinase II (CK2) to phosphorylate SLK at serine residues 347/348. CK2 directly phosphorylates SLK at these positions, and CK2 inhibition in v-Src-transformed cells restores normal SLK activity. CK2 and SLK co-localize in fibroblasts spreading on fibronectin. In vitro kinase assay, deletion analysis, CK2 inhibitor treatment, immunofluorescence co-localization The Journal of biological chemistry Medium 16837460
2008 SLK phosphorylates RhoA on Ser188 downstream of angiotensin II type 2 receptor (AT2R) activation, independently of cAMP/cGMP-activated kinases. The signaling cascade involves SHP-1 and casein kinase II activating SLK, which then phosphorylates RhoA to induce GDI-mediated cytosolic sequestration of RhoA and inhibition of arterial contraction/vasodilation. In vitro kinase assay, site-directed mutagenesis of RhoA Ser188, signaling inhibitor experiments in vascular smooth muscle cells Circulation research High 18420945
2008 SLK phosphorylates Plk1 on Thr210 in its activation segment, increasing Plk1 catalytic efficiency ~202-fold (k_cat increase 88-fold, K_M decrease 2.3-fold). The presence of a polo-box domain-binding phosphopeptide further amplifies the effect of Slk phosphorylation (combined 1515-fold increase in catalytic efficiency). In vitro reconstituted kinase assay with purified Plk1 and Slk, quantitative k_cat/K_M measurements using TCTP as substrate Biochemistry High 18298087
2008 SLK (LOSK) associates with centrosomes and microtubules. Inhibition of SLK activity (dominant-negative K63R or RNAi) results in loss of dynactin from centrosomes, inability of centrosomes to anchor/cap microtubules (though nucleation is preserved), and disorganization of the microtubule radial array. Cells with suppressed SLK cannot polarize the Golgi complex at the wound edge. Dominant-negative expression, RNAi knockdown, immunofluorescence of dynactin/centrosomes/microtubules Molecular biology of the cell Medium 18287541
2008 SLK is required for focal adhesion turnover and cell migration downstream of the FAK/c-Src complex. SLK co-localizes with paxillin, Rac1, and microtubules at the leading edge. SLK is activated by scratch wounding, dependent on FAK/c-Src/MAPK signaling, while recruitment to the leading edge is Src-dependent but FAK-independent. Knockdown, dominant-negative SLK, scratch wound kinase activity assay, co-localization immunofluorescence, signaling inhibitor dissection PloS one Medium 18382658
2009 SLK is required for ErbB2/Neu-dependent cell migration. Heregulin treatment or activated Neu overexpression stimulates SLK activity via MEK, PI3K, PLCγ, Shc, FAK, and Src signaling. Phosphorylation of Neu at Y1201 or Y1226/7 is required for SLK activation and cancer cell migration/invasion. SLK knockdown, kinase-inactive SLK overexpression, signaling pathway inhibitors, migration/invasion assays, phospho-FAK analysis Oncogene Medium 19525980
2009 SLK promotes p53 phosphorylation on Ser-33 and Ser-315, and stimulates p53 transcriptional activity. Mutation of both S33A and S315A abolishes SLK-induced p53 transactivation. SLK-induced p53 activation is attenuated by JNK inhibition. SLK overexpression amplifies ischemia-reperfusion-induced apoptosis in a p53-dependent manner. p53 reporter (luciferase), site-directed mutagenesis of p53, JNK inhibitor, dominant-negative SLK, pifithrin-alpha inhibitor American journal of physiology. Renal physiology Medium 19640899
2009 SLK interacts directly with the transcriptional cofactors Ldb1/CLIM2 and Ldb2/CLIM1 via its C-terminal AT1-46 homology domain, as demonstrated in vitro and in vivo. Ldb1/2 co-localize with SLK in migrating cells, and both knockdown and overexpression of Ldb1/2 increase cell motility. Ldb1/2 are proposed to maintain SLK in an inactive state. In vitro binding assay, co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown migration assay Molecular biology of the cell Medium 19675209
2011 Controlled homodimerization of the SLK catalytic domain (via FK506-binding protein fusion) enhances kinase activity, activation-specific phosphorylation of JNK and p38, Bax promoter activity, and apoptosis compared to monomeric SLK. Regulated dimerization system (Fv-SLK + AP20187), in vitro kinase assay, Western blot for JNK/p38 phosphorylation, apoptosis assay American journal of physiology. Renal physiology Medium 21677149
2011 Phosphorylation of Thr-183 and Ser-189 in the SLK activation segment is required for kinase activity and downstream signaling. T183A, S189A, and T183A/S189A mutants show reduced kinase activity, fail to activate JNK/p38 or AP-1, and do not induce apoptosis. Homodimerization enhances SLK autophosphorylation at T183/S189; the T183A/S189A double mutant is not activated by dimerization. Site-directed mutagenesis of activation segment, in vitro kinase assay, JNK/p38 phosphorylation Western blot, AP-1 reporter, regulated dimerization The Journal of biological chemistry High 22203681
2012 LOK and SLK are the relevant kinases that phosphorylate ezrin at the apical membrane of polarized epithelial cells, restricting microvilli to the apical domain. Both kinases are enriched in microvilli and locally activated there. Unregulated kinase activity causes ezrin mislocalization to the basolateral domain, while expression of kinase regulatory regions inhibits endogenous ezrin phosphorylation locally. Proteomic identification, RNAi knockdown, drug-resistant kinase variants, live imaging, subcellular fractionation The Journal of cell biology High 23209304
2012 SLK phosphorylates paxillin on Ser-250 in vitro, and this phosphorylation is required for paxillin redistribution and cell motility. S250A paxillin mutation prevents SLK-dependent phosphorylation and results in impaired migration and accumulation of phospho-FAK-Tyr397, indicating altered focal adhesion dynamics. In vitro kinase assay with paxillin S250 as substrate, S250A mutant in migration assay, phospho-FAK Western blot, focal adhesion turnover analysis Oncogene High 23128389
2013 SLK (LOSK) phosphorylates the p150(Glued) subunit of dynactin (isoform 1A only), targeting it to the centrosome to maintain microtubule radial organization. Phosphorylation is required only for centrosomal localization of p150(Glued), not for its microtubule-organizing properties. Artificial targeting of non-phosphorylatable p150(Glued) to the centrosome rescues microtubule organization in SLK-inhibited cells. Dynactin phosphorylation is also involved in Golgi reorientation in polarized cells. In vitro kinase assay (SLK phosphorylating p150(Glued)), isoform-specific phosphorylation analysis, artificial centrosomal targeting rescue experiment, immunofluorescence Molecular biology of the cell High 23985322
2014 SLK directly and strongly activates ERM proteins (ezrin/radixin/moesin) at mitotic entry in mammalian cells. ERM activation by SLK promotes polarized association of LGN and NuMA at the mitotic cortex, which is required for correct spindle orientation. Impairing ERM activation in mouse embryonic neocortical apical progenitors severely disrupts spindle orientation in vivo. In vitro kinase assay, microfabricated adhesive substrates for spindle axis control, LGN/NuMA immunofluorescence at cortex, in vivo mouse cortex analysis The Journal of cell biology High 24958772
2015 LMO4 directly binds to SLK and activates its kinase activity in vitro and in vivo. LMO4 co-precipitates with SLK after scratch wounding. Cre-mediated deletion of LMO4 inhibits cell migration, SLK activation, and recruitment of SLK and Ldb1 to the leading edge. Src/Yes/Fyn-deficient (SYF) cells with low LMO4 fail to recruit SLK to the leading edge; re-expression of wild-type LMO4 but not a mutant restores SLK localization and activity. In vitro kinase assay, Co-IP after wounding, conditional LMO4 knockout, SYF cells re-expression, immunofluorescence of leading edge localization Biochimica et biophysica acta Medium 25882817
2015 SLK interacts with nucleoporin Tpr and cytoskeletal protein α-actinin-4 via its 350 amino acid C-terminal coiled-coil domain. Subsets of SLK colocalize with Tpr at the nuclear envelope and with α-actinin-4 in the cytoplasm. Tpr expression attenuates SLK autophosphorylation and blocks SLK-induced apoptosis and AP-1 activity, while α-actinin-4 does not affect SLK autophosphorylation. Mass spectrometry identification, protein complementation assay, Co-immunoprecipitation, immunofluorescence, autophosphorylation assay, apoptosis/AP-1 reporter Biochimica et biophysica acta Medium 26094769
2016 SLK/LOSK regulates cell motility through RhoA and the dynactin subunit p150(Glued). These two downstream effectors act independently of each other. SLK is an indispensable regulator of directional cell locomotion. SLK knockdown/inhibition, RhoA and dynactin functional assays, cell migration tracking Cytoskeleton (Hoboken, N.J.) Medium 26818812
2016 Increased SLK expression/activity activates the HSF1-Hsp70 pathway via polo-like kinase-1 (Plk1). This induction depends on SLK kinase activity. The resulting Hsp70 upregulation attenuates the proapoptotic effect of SLK, representing a negative feedback. HSF1/Hsp70 reporter (luciferase), Plk1 pathway inhibitors, SLK kinase-dead mutant, shRNA knockdown of HSF1, Hsp70 inhibitor Biochimica et biophysica acta Medium 27216364
2017 Controlled dimerization of the SLK catalytic domain enhances autophosphorylation at T183 and S189 (activation segment). Full-length SLK is also autophosphorylated at T183 and S189. Mutations in the coiled-coil region (particularly I848G) that impair dimerization significantly reduce ezrin phosphorylation by SLK. T183A, S189A, and T193A mutations reduce both autophosphorylation and exogenous substrate (ezrin) phosphorylation. Regulated dimerization, in vitro kinase assay with ezrin as substrate, autophosphorylation site mapping, coiled-coil dimerization-impairing mutagenesis, experimental membranous nephropathy rat model PloS one High 28475647
2017 SLK depletion in NMuMG mammary epithelial cells significantly impairs TGFβ-induced migration and invasion and reduces Snai1 mRNA and vimentin protein expression, but does not affect Smad3 nuclear translocation. Kinase-inactive SLK does not impair tight junction breakdown and rescues Snai1 mRNA levels, indicating a kinase-activity-independent role for SLK in TGFβ-induced EMT. siRNA knockdown, dominant-negative kinase expression, Smad3 nuclear translocation assay, immunofluorescence, migration/invasion assays Oncotarget Medium 29228724
2021 Crystal structures of SLK and STK10 bound to 3-anilino-4-arylmaleimide inhibitors were solved, defining the inhibitor binding mode in the ATP-binding site and rationalizing selectivity between SLK and STK10. X-ray crystallography of inhibitor-bound SLK and STK10, kinome-wide selectivity profiling, cellular target engagement assay Journal of medicinal chemistry High 34463505
2024 Expression of a CRISPR/Cas9-generated kinase-dead allele (SLKK63R) reveals that SLK does not form homodimers and that the kinase-defective allele does not act in a dominant-negative fashion. Heterozygous SLKK63R cells show 50% reduced kinase activity, altered Rac1 and RhoA activity, increased stress fiber formation, and delayed focal adhesion turnover. Homozygous SLKK63R is embryonic lethal. CRISPR/Cas9 knock-in of kinase-dead allele, dimerization assay, kinase activity assay, Rac1/RhoA activity pull-down, focal adhesion turnover imaging Biochimica et biophysica acta. Molecular cell research High 38871226
2025 The RNA-binding protein HNRNPL promotes skipping of exon 13 in SLK pre-mRNA, generating the short isoform SLK-S (lacking exon 13). SLK-S activates the ERK signaling pathway and enhances HCC cell invasion/metastasis, while the long isoform SLK-L (containing exon 13) suppresses these effects through ERK pathway inhibition. In vivo targeting of the HNRNPL/SLK-S/Rac1/ERK axis inhibits HCC metastasis. Splicing reporter assays, isoform-specific overexpression/knockdown, ERK pathway Western blot, invasion/migration assays, in vivo metastasis model Biochemical pharmacology Medium 41046074
2026 Macrophage-secreted RNAseT2 binds directly to SLK in muscle stem cells, triggering SLK-mediated phosphorylation and activation of N-WASP (via paxillin phosphorylation), which enables actin bundle formation required for myoblast/muscle stem cell fusion. Binding assay (RNAseT2-SLK interaction), phosphorylation assays for N-WASP and paxillin, actin bundle imaging, in vivo mouse and zebrafish overexpression/KO Nature communications High 41980967

Source papers

Stage 0 corpus · 52 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Caspase 3 cleavage of the Ste20-related kinase SLK releases and activates an apoptosis-inducing kinase domain and an actin-disassembling region. Molecular and cellular biology 95 10611247
2012 Local phosphocycling mediated by LOK/SLK restricts ezrin function to the apical aspect of epithelial cells. The Journal of cell biology 88 23209304
2014 SLK-dependent activation of ERMs controls LGN-NuMA localization and spindle orientation. The Journal of cell biology 78 24958772
2012 Kaposi's sarcoma-derived cell line SLK is not of endothelial origin, but is a contaminant from a known renal carcinoma cell line. International journal of cancer 77 22987579
1999 Induction of apoptosis by SLK, a Ste20-related kinase. Oncogene 77 10602516
2000 Ste20-like kinase (SLK), a regulatory kinase for polo-like kinase (Plk) during the G2/M transition in somatic cells. Genes to cells : devoted to molecular & cellular mechanisms 76 10886374
2008 Ste20-related kinase SLK phosphorylates Ser188 of RhoA to induce vasodilation in response to angiotensin II Type 2 receptor activation. Circulation research 66 18420945
2002 Association of the Ste20-like kinase (SLK) with the microtubule. Role in Rac1-mediated regulation of actin dynamics during cell adhesion and spreading. The Journal of biological chemistry 61 12151406
2005 Induction of apoptosis by the Ste20-like kinase SLK, a germinal center kinase that activates apoptosis signal-regulating kinase and p38. The Journal of biological chemistry 60 16316999
2008 FAK/src-family dependent activation of the Ste20-like kinase SLK is required for microtubule-dependent focal adhesion turnover and cell migration. PloS one 50 18382658
2005 The Ste20-like kinase SLK is required for cell cycle progression through G2. The Journal of biological chemistry 48 16236704
2012 Ste20-like kinase SLK, at the crossroads: a matter of life and death. Cell adhesion & migration 40 23154402
2012 SLK-mediated phosphorylation of paxillin is required for focal adhesion turnover and cell migration. Oncogene 37 23128389
2009 The Ste20-like kinase SLK is required for ErbB2-driven breast cancer cell motility. Oncogene 36 19525980
2009 The Ldb1 and Ldb2 transcriptional cofactors interact with the Ste20-like kinase SLK and regulate cell migration. Molecular biology of the cell 31 19675209
2008 Plk1 activation by Ste20-like kinase (Slk) phosphorylation and polo-box phosphopeptide binding assayed with the substrate translationally controlled tumor protein (TCTP). Biochemistry 27 18298087
2008 Ste20-related protein kinase LOSK (SLK) controls microtubule radial array in interphase. Molecular biology of the cell 25 18287541
2002 Expression of the Ste20-like kinase SLK during embryonic development and in the murine adult central nervous system. Brain research. Developmental brain research 23 12480135
2006 v-Src-dependent down-regulation of the Ste20-like kinase SLK by casein kinase II. The Journal of biological chemistry 22 16837460
2011 Activity of the Ste20-like kinase, SLK, is enhanced by homodimerization. American journal of physiology. Renal physiology 21 21677149
2011 Regulation of the Ste20-like kinase, SLK: involvement of activation segment phosphorylation. The Journal of biological chemistry 21 22203681
2009 The Ste20-like kinase SLK promotes p53 transactivation and apoptosis. American journal of physiology. Renal physiology 21 19640899
2013 Ste20-like protein kinase SLK (LOSK) regulates microtubule organization by targeting dynactin to the centrosome. Molecular biology of the cell 19 23985322
2010 Podocyte injury and albuminuria in mice with podocyte-specific overexpression of the Ste20-like kinase, SLK. The American journal of pathology 19 20889563
2004 Ste20-like kinase SLK displays myofiber type specificity and is involved in C2C12 myoblast differentiation. Muscle & nerve 19 15052621
2017 Regulation of Ste20-like kinase, SLK, activity: Dimerization and activation segment phosphorylation. PloS one 17 28475647
2019 Design and Analysis of the 4-Anilinoquin(az)oline Kinase Inhibition Profiles of GAK/SLK/STK10 Using Quantitative Structure-Activity Relationships. ChemMedChem 16 31675459
2017 Deletion of the Ste20-like kinase SLK in skeletal muscle results in a progressive myopathy and muscle weakness. Skeletal muscle 16 28153048
2014 Essential role for the SLK protein kinase in embryogenesis and placental tissue development. Developmental dynamics : an official publication of the American Association of Anatomists 16 24868594
2006 The 3'-untranslated region of the Ste20-like kinase SLK regulates SLK expression. American journal of physiology. Renal physiology 14 17003224
2017 Transforming growth factor β-induced epithelial to mesenchymal transition requires the Ste20-like kinase SLK independently of its catalytic activity. Oncotarget 13 29228724
2020 Genetic ablation of SLK exacerbates glomerular injury in adriamycin nephrosis in mice. American journal of physiology. Renal physiology 11 32308020
2021 Discovery of a Potent Dual SLK/STK10 Inhibitor Based on a Maleimide Scaffold. Journal of medicinal chemistry 10 34463505
2013 Distinct roles for Ste20-like kinase SLK in muscle function and regeneration. Skeletal muscle 10 23815977
2009 A novel role for the Ste20 kinase SLK in adhesion signaling and cell migration. Cell adhesion & migration 10 19262175
2017 Ste20-like kinase, SLK, a novel mediator of podocyte integrity. American journal of physiology. Renal physiology 9 29187370
2016 SLK/LOSK kinase regulates cell motility independently of microtubule organization and Golgi polarization. Cytoskeleton (Hoboken, N.J.) 9 26818812
2015 Recruitment and activation of SLK at the leading edge of migrating cells requires Src family kinase activity and the LIM-only protein 4. Biochimica et biophysica acta 9 25882817
1997 Chinese hamster protein homologous to human putative protein kinase KIAA0204 is associated with nuclei, microtubules and centrosomes in CHO-K1 cells. FEBS letters 9 9305747
2015 Identification of Tpr and α-actinin-4 as two novel SLK-interacting proteins. Biochimica et biophysica acta 7 26094769
2011 Sulfated polymannuroguluronate inhibits Tat-induced SLK cell adhesion via a novel binding site, a KKR spatial triad. Acta pharmacologica Sinica 7 21499289
2024 Association analysis of polymorphisms in SLK, ARHGEF9, WWC2, GAB3, and FSHR genes with reproductive traits in different sheep breeds. Frontiers in genetics 5 38680425
2018 MicroRNA-126 regulates the phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT) pathway in SLK cells in vitro and the expression of its pathway members in Kaposi's sarcoma tissue. Medicine 5 30170375
2016 Ste20-like kinase, SLK, activates the heat shock factor 1 - Hsp70 pathway. Biochimica et biophysica acta 5 27216364
2020 Muscle-specific deletion of SLK/Stk2 enhances p38 activity and myogenesis in mdx mice. Biochimica et biophysica acta. Molecular cell research 4 33259860
2025 Exon 13 skipping mediated by HNRNPL facilitates truncated SLK-induced metastasis in hepatocellular carcinoma. Biochemical pharmacology 3 41046074
2025 SLK is mutated in individuals with a neurodevelopmental disorder. EBioMedicine 2 40347834
2025 Photoproximity labeling of c-Myc reveals SLK as a cancer specific co-regulator. bioRxiv : the preprint server for biology 1 41256636
2024 Role of the Ste20-like kinase SLK in podocyte adhesion. Physiological reports 1 38163671
2024 Expression of a kinase inactive SLK is embryonic lethal and impairs cell migration in fibroblasts. Biochimica et biophysica acta. Molecular cell research 1 38871226
2026 Restorative macrophage-derived RNAseT2 stimulates muscle stem cell fusion via an SLK/N-WASP/actin bundling dependent axis. Nature communications 0 41980967
2025 ITGA5 drives glioblastoma progression through SLK-mediated activation of the PI3K-Akt pathway. Neurological research 0 40544320

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