STK10

STK10 (LOK) is a STE20-family serine/threonine kinase whose principal characterized function is acting as a major ERM (ezrin/radixin/moesin) kinase that couples plasma-membrane signaling to cortical actin organization, cell adhesion, and migration (PMID:19255442, PMID:23209304). It autophosphorylates and uses an N-terminal kinase domain to directly phosphorylate the regulatory C-terminal threonine of ERM proteins with distinctive substrate specificity, and its loss reduces ERM phosphorylation by more than half in lymphocytes while enhancing chemokine-driven migration and polarization (PMID:9278426, PMID:19255442). STK10 achieves spatial fidelity through a multi-step wedge mechanism in which PIP2 binding primes ezrin, the kinase's C-terminal domain inserts to separate the membrane- and actin-binding lobes, and the kinase domain then accesses a non-consensus phosphosite, ensuring phosphorylation occurs only at the membrane (PMID:28430576); the same C-terminal domain dimerizes, binds anionic phospholipids, resembles an inverse-BAR domain, and drives apical colocalization with ezrin in epithelial cells (PMID:41958020, PMID:23209304). Beyond ERM regulation, STK10 negatively regulates LFA-1 clustering and lymphocyte adhesion (PMID:10692593), associates with and phosphorylates PLK1 as a polo-like kinase kinase (PMID:12639966), and in platelets is activated downstream of calcium/PKC/PI3K signaling to directly phosphorylate integrin-linked kinase (ILK) at Ser343, controlling aggregation, granule release, integrin activation, and both arterial-type and deep-vein thrombosis (PMID:41055696, PMID:41791658). STK10 also suppresses NF-κB activity and promotes apoptosis, an activity attenuated by lymphoma-associated missense mutations (PMID:23842845). In tumor settings, host STK10 supports anti-tumor cytotoxic T-cell activity and restrains tumor angiogenesis (PMID:36421382).

1. 1997 Medium

   Established the basic biochemical identity of STK10/LOK, answering whether it was a tyrosine or serine/threonine kinase and where it sat among kinase families.

   Evidence In vitro kinase assays on generic substrates and co-expression in COS7 cells

   PMID:9278426

   Open questions at the time

   • No physiological substrate identified
   • No cellular function defined
   • MAP kinase pathways explicitly excluded but true effectors unknown
2. 2000 Medium

   Connected STK10 to lymphocyte adhesion by showing it negatively regulates LFA-1 clustering, giving the kinase its first in vivo cellular role.

   Evidence LOK knockout mice with ICAM-1 binding and aggregation assays

   PMID:10692593

   Open questions at the time

   • No molecular substrate linking the kinase to LFA-1 regulation
   • Mechanism of clustering control unknown
3. 2003 Medium

   Identified STK10 as a candidate cell-cycle regulator acting upstream of PLK1, addressing whether the kinase had mitotic functions.

   Evidence Co-immunoprecipitation, in vitro kinase assay, and dominant-negative expression in NIH-3T3 cells

   PMID:12639966

   Open questions at the time

   • PLK1 phosphosite not mapped
   • Physiological relevance of PLK1 activation in cycling cells not established
4. 2009 High

   Defined STK10's central function as a major ERM kinase, answering what its key physiological substrate is and linking it to lymphocyte migration.

   Evidence In vitro peptide kinase assay with specificity profiling, MS localization, and LOK knockout mice

   PMID:19255442

   Open questions at the time

   • Residual ERM phosphorylation indicates redundant kinases
   • How membrane enrichment restricts activity not yet defined
5. 2012 High

   Showed how STK10 (with SLK) enforces spatial control of ERM activation, restricting ezrin phosphorylation to the apical/microvillar domain.

   Evidence RNAi, drug-resistant kinase rescue variants, and localization in polarized epithelial cells

   PMID:23209304

   Open questions at the time

   • Molecular basis of local activation not resolved at this stage
   • Functional overlap between LOK and SLK not fully separated
6. 2017 High

   Resolved the mechanistic basis for membrane-restricted ERM phosphorylation through a PIP2-dependent multi-step wedge mechanism.

   Evidence In vitro reconstitution, domain mapping, mutagenesis, and lipid-binding assays

   PMID:28430576

   Open questions at the time

   • Structure of the kinase-ezrin complex not solved
   • Regulation of the kinase by upstream signals not addressed
7. 2026 Medium

   Defined the structural and biophysical properties of the LOK C-terminal domain that target the kinase to ezrin at membranes.

   Evidence Lipid-binding and dimerization assays, MD simulations, and cell-based colocalization

   PMID:41958020

   Open questions at the time

   • IBAR-like assignment based on prediction/simulation rather than experimental structure
   • Membrane curvature sensing not directly demonstrated
8. 2013 Medium

   Linked STK10 to NF-κB suppression and apoptosis and to lymphoma-associated mutations, addressing a possible tumor-suppressive role.

   Evidence NF-κB reporter and dexamethasone apoptosis assays with site-directed PTCL mutants

   PMID:23842845

   Open questions at the time

   • No direct biochemical target in the NF-κB pathway identified
   • Overexpression-based, kinase substrate unknown
9. 2021 High

   Provided structural tools and chemical probes for STK10, addressing the lack of selective inhibitors and SLK/STK10 discrimination.

   Evidence X-ray crystallography of inhibitor complexes with cellular target engagement (extended by a 2025 macrocycle co-structure)

   PMID:34463505 PMID:41256983

   Open questions at the time

   • Probes characterize binding, not in vivo pathway consequences
   • Selectivity beyond SLK not exhaustively profiled
10. 2021 Medium

    Extended STK10's ERM and migration role to cancer cells, showing knockout alters migration/proliferation via p38 and phospho-ERM.

    Evidence CRISPR knockout in DU145 prostate cancer cells with phospho-signaling and phenotype readouts

    PMID:34149897

    Open questions at the time

    • Mechanism linking STK10 to p38 not defined
    • Single cell line
11. 2022 Medium

    Defined a host immune role for STK10 in anti-tumor immunity through cytotoxic T-cell activity and angiogenesis control.

    Evidence Stk10 knockout mice with tumor implantation and immune cell phenotyping

    PMID:36421382

    Open questions at the time

    • Cell-intrinsic vs systemic contributions not separated
    • No substrate linking STK10 to CTL or vessel phenotypes
12. 2026 High

    Identified a direct, physiologically validated STK10 substrate in platelets (ILK Ser343) and placed STK10 in hemostasis and arterial/venous thrombosis.

    Evidence Platelet-specific conditional KO, phosphoproteomics, IP-MS, in vitro kinase assay, and DVT/thrombosis models

    PMID:41055696 PMID:41791658

    Open questions at the time

    • How ILK Ser343 phosphorylation drives downstream integrin/granule responses not fully resolved
    • Relationship between ERM and ILK substrate functions in platelets unclear

• How STK10's distinct activities — ERM phosphorylation, ILK phosphorylation, PLK1 activation, and NF-κB suppression — are integrated within single cell types and which upstream signals select among them remains unresolved.
• No unified model linking substrate choice to cellular context
• Upstream activating signals defined only for platelet (Ca/PKC/PI3K) and ERK-tail inhibition contexts