Affinage

TESK1

Dual specificity testis-specific protein kinase 1 · UniProt Q15569

Length
626 aa
Mass
67.7 kDa
Annotated
2026-06-10
15 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TESK1 is a serine/threonine kinase with an N-terminal catalytic domain structurally related to the LIM kinases and a C-terminal proline-rich region, and it regulates actin cytoskeletal organization by phosphorylating cofilin (PMID:8537404, PMID:11511097). Across podocytes and other cell systems it phosphorylates cofilin-1 at the same serine targeted by LIM kinases, acting as a Rho-kinase-independent route to cofilin inactivation that stabilizes F-actin and governs cell motility, spreading, and adhesion (PMID:30115939, PMID:17118962). Its kinase activity is held in check by direct binding partners: actopaxin (parvin) binds the C-terminus of TESK1 to inhibit it in a manner relieved by fibronectin adhesion, coupling integrin engagement to cofilin phosphorylation and cell spreading (PMID:15817463), and Spred1 binds and inhibits TESK1 to keep stress fibers dynamic (PMID:18216281). Through binding MARKK/TAO1 and inhibiting it, TESK1 links F-actin control to microtubule regulation within a Spred1–MARKK–TESK1 module (PMID:18216281). Independently of its catalytic activity, TESK1 binds Sprouty proteins (Spry2, Spry4), relocalizing them to cytoplasmic vesicles/endosomes and blocking their Grb2 interaction and PP2A-mediated dephosphorylation, thereby abrogating Sprouty's inhibition of ERK and promoting growth-factor-induced neurite outgrowth (PMID:12027893, PMID:17974561). Genetic epistasis in the Drosophila ortholog Cdi places TESK1 downstream of Rac1 in a Rac1–Cdi–cofilin pathway controlling spermatogenesis and epithelial actin/junction organization (PMID:15169836, PMID:17118962).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1995 High

    Established that TESK1 is an active serine/threonine kinase and defined its domain architecture, placing it structurally near the LIM kinase family and framing the search for physiological substrates.

    Evidence In vitro kinase assay using myelin basic protein plus sequence analysis of the N-terminal kinase domain and C-terminal proline-rich region

    PMID:8537404

    Open questions at the time
    • MBP is a generic substrate; physiological substrate not identified
    • Upstream regulators and activation mechanism unknown
    • No structural model of the kinase domain
  2. 2001 Medium

    Linked TESK1 to cofilin-driven actin reorganization and to a defined developmental context by mapping a germ-cell, pachytene-stage-specific promoter, suggesting a spermatogenic role.

    Evidence Transgenic mouse lacZ reporter assay driven by a 9.0-kb 5'-flanking region

    PMID:11511097

    Open questions at the time
    • Cofilin phosphorylation stated but not directly demonstrated in this work
    • Promoter activity does not establish endogenous protein function in germ cells
  3. 2002 Medium

    Identified the first non-cytoskeletal interactor, Sprouty4, connecting TESK1 to RTK signaling and showing the interaction is growth-factor responsive and vesicular.

    Evidence Yeast two-hybrid screen, reciprocal co-immunoprecipitation, and colocalization imaging in cytoplasmic vesicles

    PMID:12027893

    Open questions at the time
    • Functional consequence of the interaction for ERK signaling not yet resolved
    • Single-lab interaction without orthogonal validation at the time
  4. 2004 Medium

    Used Drosophila genetics to position the TESK1 ortholog Cdi epistatically downstream of Rac1, defining a Rac1–Cdi–cofilin signaling axis in spermatogenesis.

    Evidence Genetic epistasis: dominant-negative Rac1(N17) suppression by Cdi and enhancement of Rac1 mutant infertility by cdi loss-of-function

    PMID:15169836

    Open questions at the time
    • Direct biochemical link from Rac1 to TESK1 activation not shown
    • Mammalian conservation of the Rac1-TESK1 epistasis not tested
  5. 2005 High

    Resolved how TESK1 activity is gated by adhesion: actopaxin directly binds and inhibits TESK1, coupling matrix engagement to cofilin phosphorylation and cell spreading.

    Evidence GST pulldown for direct binding, in vitro kinase inhibition, deletion/point mutant mapping, fibronectin-regulated binding, and overexpression rescue of cell spreading

    PMID:15817463

    Open questions at the time
    • Mechanism by which the actopaxin C-terminus structurally inhibits the kinase not defined
    • In vivo relevance of the adhesion switch not tested
  6. 2006 Medium

    Confirmed in the ortholog that Cdi/TESK1 phosphorylates ADF/cofilin to organize epithelial actin and junctions and to suppress activated Sevenless RTK signaling, reinforcing both the cytoskeletal and RTK-modulatory roles.

    Evidence Drosophila gain- and loss-of-function genetics with actin and adherens-junction (DE-cadherin, β-catenin) immunostaining and Sevenless localization readouts

    PMID:17118962

    Open questions at the time
    • Direct phosphorylation of cofilin by Cdi not biochemically reconstituted here
    • Link between junction effects and RTK suppression mechanistically unresolved
  7. 2007 High

    Defined a kinase-independent function: TESK1 sequesters Spry2 on endosomes, blocking Spry2–Grb2 binding and PP2A dephosphorylation to relieve Sprouty inhibition of ERK and promote neurite outgrowth.

    Evidence Endogenous co-IP across cell lines and mouse tissue, kinase-dead mutant analysis, localization imaging, siRNA knockdown, and bFGF-induced neurite outgrowth assay in PC12 cells

    PMID:17974561

    Open questions at the time
    • Structural basis of TESK1-Spry2 binding not defined
    • Whether cytoskeletal and Sprouty functions are coordinated in the same cell unknown
  8. 2008 Medium

    Integrated TESK1 into a cross-cytoskeletal regulatory module: TESK1 binds and inhibits MARKK/TAO1 while Spred1 binds and inhibits TESK1, coupling F-actin and microtubule dynamics.

    Evidence Yeast two-hybrid, co-immunoprecipitation, in vitro kinase inhibition, and overexpression in CHO cells with actin and microtubule readouts

    PMID:18216281

    Open questions at the time
    • Stoichiometry and order of the three-way Spred1-MARKK-TESK1 interactions unresolved
    • Physiological context where this module operates not established
  9. 2018 Medium

    Established TESK1 as a ROK-independent cofilin-1 kinase in podocytes, showing it accounts for a Y27632-resistant pool of phospho-cofilin and controls cell motility.

    Evidence TESK1 knockout podocyte line, Y27632 inhibition, phospho-CFL1 western blot, and motility assay

    PMID:30115939

    Open questions at the time
    • Upstream activator of TESK1 in podocytes unknown
    • Relevance to glomerular disease not directly demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TESK1 is activated and how its cytoskeletal kinase activity is coordinated with its kinase-independent Sprouty/ERK function within a single cell remains unresolved.
  • No defined activating signal or activation-loop phosphorylation mechanism
  • No structure of the kinase or its inhibitory complexes
  • No human disease association demonstrated by direct genetic evidence in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0016740 transferase activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0031410 cytoplasmic vesicle 2 GO:0005768 endosome 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 2
Partners
CFL1PARVASPRED1SPRY2SPRY4TAOK1

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 TESK1 is a serine/threonine kinase; protein expressed in COS cells exhibited serine/threonine kinase activity using myelin basic protein as a substrate. The protein contains an N-terminal kinase domain structurally similar to LIMK1/LIMK2 (49-50% identity) followed by a C-terminal proline-rich region. In vitro kinase assay with myelin basic protein as substrate; sequence analysis The Journal of biological chemistry High 8537404
2001 TESK1 has the potential to phosphorylate cofilin and induce actin cytoskeletal reorganization, with stage-specific expression in testicular germ cells driven by a 9.0-kb 5'-flanking region active after pachytene spermatocytes. Transgenic mouse lacZ reporter assay; promoter-driven cell-type-specific expression Biochemical and biophysical research communications Medium 11511097
2002 TESK1 interacts with human Sprouty 4 (hSPRY4); the interaction was identified by yeast two-hybrid screen and confirmed by co-immunoprecipitation. The two proteins colocalize in cytoplasmic vesicles, and the interaction increases upon growth factor stimulation. Yeast two-hybrid, co-immunoprecipitation, colocalization imaging European journal of biochemistry Medium 12027893
2004 Drosophila Cdi (TESK1 ortholog) functions as a downstream effector of Rac1 in spermatogenesis; eye-directed Cdi expression suppressed phenotypes of dominant-negative Rac1(N17), and Rac1 mutant infertility was enhanced by cdi loss-of-function, placing Cdi/TESK1 downstream of Rac1 in a Rac1-Cdi-Cofilin pathway. Drosophila genetic epistasis (gain-of-function screen, dominant-negative suppression, double-mutant fertility assay) Journal of cell science Medium 15169836
2005 Actopaxin (parvin) directly binds TESK1 via the C-terminal regions of both proteins; this interaction inhibits TESK1 kinase activity in vitro, is negatively regulated by fibronectin adhesion, and a phosphomimetic actopaxin mutant shows impaired TESK1 binding. Retention of TESK1 by the actopaxin C-terminus prevents cofilin phosphorylation upon matrix adhesion and retards cell spreading, which is rescued by TESK1 overexpression. Co-immunoprecipitation, GST pulldown (direct binding), in vitro kinase assay, deletion/point mutant mapping, cell spreading assay, overexpression rescue The Journal of biological chemistry High 15817463
2006 Drosophila Cdi (TESK1 ortholog) phosphorylates ADF/cofilin to regulate actin organization; loss- and gain-of-function of cdi alters actin organization, adherens junction proteins (DE-cadherin, β-catenin), and apical localization of Sevenless RTK in the eye epithelium. Cdi acts as a suppressor of activated Sevenless signaling. Drosophila EP gain-of-function screen, loss-of-function genetics, immunostaining of actin and junction proteins Journal of cell science Medium 17118962
2007 TESK1 forms an endogenous complex with Spry2 in cell lines and mouse tissues; TESK1 co-expression relocalizes Spry2 to vesicles/endosomes, preventing its translocation to membrane ruffles upon growth factor stimulation. Independent of its kinase activity, TESK1 binding abrogates Spry2's inhibition of ERK phosphorylation by blocking Spry2–Grb2 interaction and impeding Spry2 dephosphorylation by PP2A catalytic subunit. TESK1 depletion in PC12 cells reduces bFGF-induced neurite outgrowth. TESK1 does not affect Spry2–c-Cbl interaction. Co-immunoprecipitation of endogenous proteins, subcellular localization imaging, kinase-dead mutant analysis, siRNA knockdown, neurite outgrowth assay, interaction mapping The Journal of biological chemistry High 17974561
2008 TESK1 binds to and inhibits MARKK/TAO1 kinase; Spred1 binds TESK1 and inhibits its activity, thereby making F-actin stress fibers dynamic. The three-way Spred1–MARKK–TESK1 interaction links regulation of both microtubule (via MARK/Par1-MAPs) and F-actin (via TESK1-cofilin) cytoskeletons: elevated TESK1 increases stress fibers via cofilin phosphorylation, blocked by Spred1; elevated MARKK disrupts microtubules, blocked by TESK1. Yeast two-hybrid, co-immunoprecipitation, in vitro kinase assay, overexpression in CHO cells with cytoskeletal readouts Molecular biology of the cell Medium 18216281
2018 TESK1 phosphorylates cofilin-1 (CFL1) at the same serine residue as LIM kinases in glomerular podocytes; TESK1 knockout podocytes showed reduced phospho-CFL1 levels that were now sensitive to ROK inhibitor Y27632, and the motility-promoting effect of Y27632 was absent in TESK1 KO cells, establishing TESK1 as a ROK-independent regulator of podocyte cytoskeletal dynamics. TESK1 knockout cell line, Y27632 pharmacological inhibition, phospho-CFL1 western blot, podocyte motility assay Scientific reports Medium 30115939

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Human sprouty 4, a new ras antagonist on 5q31, interacts with the dual specificity kinase TESK1. European journal of biochemistry 89 12027893
1995 Identification and characterization of a novel protein kinase, TESK1, specifically expressed in testicular germ cells. The Journal of biological chemistry 70 8537404
2008 Spred1 and TESK1--two new interaction partners of the kinase MARKK/TAO1 that link the microtubule and actin cytoskeleton. Molecular biology of the cell 54 18216281
2005 Actopaxin interacts with TESK1 to regulate cell spreading on fibronectin. The Journal of biological chemistry 42 15817463
2007 Tesk1 interacts with Spry2 to abrogate its inhibition of ERK phosphorylation downstream of receptor tyrosine kinase signaling. The Journal of biological chemistry 33 17974561
1998 Stage-specific expression of testis-specific protein kinase 1 (TESK1) in rat spermatogenic cells. Biochemical and biophysical research communications 33 9705840
2004 A screen for modifiers of RacGAP(84C) gain-of-function in the Drosophila eye revealed the LIM kinase Cdi/TESK1 as a downstream effector of Rac1 during spermatogenesis. Journal of cell science 21 15169836
2014 Cloning and characterization of tesk1, a novel spermatogenesis-related gene, in the tongue sole (Cynoglossus semilaevis). PloS one 20 25271995
2001 Cell-type-specific expression of a TESK1 promoter-linked lacZ gene in transgenic mice. Biochemical and biophysical research communications 19 11511097
2018 Decreased TESK1-mediated cofilin 1 phosphorylation in the jejunum of IBS-D patients may explain increased female predisposition to epithelial dysfunction. Scientific reports 18 29396473
1999 Drosophila center divider gene is expressed in CNS midline cells and encodes a developmentally regulated protein kinase orthologous to human TESK1. DNA and cell biology 17 10390152
1998 Structural organization and chromosomal localization of the mouse tesk1 (testis-specific protein kinase 1) gene. Gene 12 9469938
2018 Regulation of cofilin phosphorylation in glomerular podocytes by testis specific kinase 1 (TESK1). Scientific reports 10 30115939
2006 The Cdi/TESK1 kinase is required for Sevenless signaling and epithelial organization in the Drosophila eye. Journal of cell science 7 17118962
2016 Expression analysis and characterization of an autosome-localized tesk1 gene in half-smooth tongue sole (Cynoglossus semilaevis). Gene 5 26869317

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