Affinage

TNK2

Activated CDC42 kinase 1 · UniProt Q07912

Length
1038 aa
Mass
114.6 kDa
Annotated
2026-06-10
100 papers in source corpus 45 papers cited in narrative 45 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TNK2/ACK1 is a non-receptor tyrosine kinase that acts as a cytoplasmic effector of GTP-loaded Cdc42 and an integrator of signals from receptor tyrosine kinases, integrins, and adhesion cues to drive cytoskeletal remodeling, receptor trafficking, and growth-promoting transcriptional programs (PMID:10360579, PMID:17494760, PMID:10085085). It binds selectively to Cdc42-GTP through an intercalated extended strand from its CRIB region, a 'dock and coalesce' recognition mode that discriminates Cdc42 from Rac (PMID:10360579, PMID:28539360). The kinase domain adopts a constitutively activation-competent conformation (PMID:15308621), but full-length ACK1 is held in check by intramolecular autoinhibition involving the C-lobe and the C-terminal Mig6-homology region (MHR), which cancer mutations such as E346K disrupt to yield constitutive activity (PMID:20110370); activation in cells requires N-terminal SAM-domain-dependent membrane targeting and dimerization together with Cdc42 binding, and Src-mediated phosphorylation of the activation-loop Tyr284 rather than autophosphorylation (PMID:20979614, PMID:21309750, PMID:17494760). Once active, ACK1 phosphorylates a broad substrate set to amplify oncogenic signaling: androgen receptor at Tyr267/Tyr363 to drive androgen-independent and radioresistant transcription (PMID:17494760, PMID:22566699), AKT at Tyr176 to promote its membrane recruitment and activation (PMID:20333297), the tumor suppressor Wwox (triggering its degradation) (PMID:16288044), and the Rho/Ras GEFs Dbl and Ras-GRF1 to elevate GTP-loading of Rho/Rac and Ras (PMID:10652228, PMID:10882715); it also reprograms chromatin via KDM3A Tyr1114 phosphorylation and pY88-H4 deposition at cell-cycle gene promoters (PMID:25148682, PMID:37330596). In parallel, ACK1 organizes clathrin-mediated endocytosis by binding clathrin heavy chain through clathrin-box motifs (competing with beta-arrestin) and assembling with Nck, SNX9, cortactin, and WASP/N-WASP to couple receptor internalization to actin nucleation (PMID:11278436, PMID:16137687, PMID:22952966, PMID:16257963); it stabilizes EGFR at the plasma membrane and early endosomes (PMID:18435854, PMID:18262180) and serves as an endocytic brake for the dopamine transporter (PMID:26621748). ACK1 levels are tightly controlled by multiple E3 ligases—Nedd4-1 (lysosomal), Nedd4-2 and SIAH1/2 (proteasomal)—acting through PPXY and SIAH-binding motifs (PMID:20086093, PMID:19144635, PMID:23208506). Beyond cancer, ACK1 functions in T-cell receptor signaling and immune checkpoint resistance via SLP-76 and CSK Tyr18 phosphorylation (PMID:28188290, PMID:36376335), supports mitochondrial energy output through ATP5F1A Tyr243/246 phosphorylation (PMID:35895804), and is required for picornavirus entry through a TNK2-WASL-NCK1 actin-nucleation pathway (PMID:31769754).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1999 High

    Established the structural basis for how ACK1 reads out an activated Rho-family GTPase, defining it as a selective Cdc42 effector.

    Evidence NMR solution structure of the Cdc42-ACK1 GTPase-binding domain complex with binding-specificity validation

    PMID:10360579

    Open questions at the time
    • Does not address how Cdc42 binding is coupled to kinase catalytic activation
    • Full-length ACK1 conformation not resolved
  2. 1999 Medium

    Linked ACK1 to upstream adhesion receptors, showing integrin/Cdc42 engagement and adhesion-driven signaling complexes activate the kinase.

    Evidence Co-IP with integrin beta1, RGD/antibody inhibition and kinase assays; dominant-negative analysis of MCSP-induced p130Cas/Cdc42 signaling

    PMID:10085085 PMID:10587647

    Open questions at the time
    • Direct ACK1 substrates downstream of adhesion not defined here
    • Single-lab readouts
  3. 2000 Medium

    Identified GEF substrates as a mechanism by which ACK1 amplifies small-GTPase signaling, phosphorylating Dbl and Ras-GRF1 to elevate Rho/Rac and Ras-GTP.

    Evidence In vitro GEF assays, RBD pull-downs for GTP-loaded GTPases, and JNK/ERK activation readouts with kinase-dead controls

    PMID:10652228 PMID:10882715

    Open questions at the time
    • Phosphosites on the GEFs not mapped
    • In vivo relevance of GEF phosphorylation not established
  4. 2001 High

    Placed ACK1 physically within the clathrin endocytic machinery via direct clathrin-heavy-chain and Nck binding, revealing a trafficking role distinct from kinase signaling.

    Evidence Direct binding/competition assays versus beta-arrestin, GFP-ACK1 imaging on clathrin/AP-2 vesicles, transferrin uptake

    PMID:11278436

    Open questions at the time
    • Whether kinase activity is required for clathrin function not resolved here
    • Cargo specificity not addressed
  5. 2003 High

    Defined Tyr284 as the principal activation-loop autophosphorylation site and characterized ACK1 substrate specificity and an Hck regulatory interaction.

    Evidence In vitro kinase assays with purified ACK1, MS phosphosite mapping, Y284F mutagenesis, SH3 binding screens

    PMID:14506255

    Open questions at the time
    • Whether Tyr284 is filled by autophosphorylation or a trans-kinase in vivo left open (later contested)
    • Physiological role of Hck unconfirmed in other systems
  6. 2004 High

    Showed the isolated kinase domain is intrinsically activation-competent independent of phosphorylation, reframing regulation as a problem of conformational/intramolecular control.

    Evidence X-ray crystallography of phosphorylated/unphosphorylated and inhibitor-bound kinase domains

    PMID:15308621

    Open questions at the time
    • Full-length autoinhibitory architecture not captured
    • How cellular activation is gated not addressed
  7. 2005 High

    Demonstrated ACK1 drives degradation of the tumor suppressor Wwox and possesses unexpected dual-specificity (Ser as well as Tyr) toward WASP, coupling it to actin dynamics.

    Evidence In vitro kinase/ubiquitination assays, phosphosite mutagenesis (Wwox Y287, WASP Y256/S242), actin polymerization assays, xenograft

    PMID:16257963 PMID:16288044

    Open questions at the time
    • Structural basis of serine kinase activity unexplained
    • Wwox degradation E3 ligase not identified here
  8. 2006 High

    Resolved the activation requirements—SAM-domain membrane targeting plus Cdc42 binding with an autoinhibitory SH3 role—and showed RTK/adhesion stimuli recruit ACK1 via Nck.

    Evidence Domain-deletion mutants, EGF/PDGF stimulation, fibronectin adhesion, reciprocal co-IP with Nck

    PMID:16777958

    Open questions at the time
    • Quantitative contribution of each input to activation not dissected
    • SH3 autoinhibition mechanism later debated
  9. 2008 Medium

    Established ACK1 as a positive regulator of EGFR surface levels and trafficking, retaining receptor at the plasma membrane and early endosomes.

    Evidence siRNA knockdown, flow cytometry of surface EGFR, radioligand internalization/recycling/degradation assays, invasion/migration

    PMID:18262180 PMID:18435854

    Open questions at the time
    • Reconciling EGFR stabilization with ACK1's pro-degradation role (via Nedd4) unresolved
    • Kinase dependence partially conflicting
  10. 2010 High

    Mapped the autoinhibition–degradation logic of ACK1: an MHR-kinase intramolecular clamp restrains activity (released by E346K), while Nedd4-1/Nedd4-2 ubiquitinate ACK1 for lysosomal/proteasomal turnover.

    Evidence In vitro domain pulldowns, cancer-mutant kinase assays, ubiquitination assays, RNAi rescue with PPXY/UBA mutants, inhibitor experiments

    PMID:19144635 PMID:20086093 PMID:20110370

    Open questions at the time
    • Crosstalk between autoinhibition release and ligase recruitment not integrated
    • Which degradation route dominates in vivo unclear
  11. 2010 High

    Showed ACK1 phosphorylates AKT at Tyr176 to promote membrane localization and full activation, connecting ACK1 to a major oncogenic axis.

    Evidence In vitro kinase assay, phospho-specific antibody, membrane fractionation, mutagenesis, prostate-specific transgenic mouse

    PMID:20333297

    Open questions at the time
    • Generality across tissues not established
    • Stoichiometry relative to PDK1/mTORC2 inputs unknown
  12. 2011 Medium

    Challenged the autophosphorylation model by showing Src, not ACK1 itself, phosphorylates Tyr284 in cells and is required for ACK1 activation and turnover.

    Evidence Endogenous Src-ACK1 co-IP, Src-deficient SYF cells, Src inhibitors, SH2/SH3 domain mapping

    PMID:21309750

    Open questions at the time
    • Direct conflict with in vitro autophosphorylation data unresolved
    • Single lab
  13. 2012 Medium

    Extended ACK1's regulatory repertoire and disease links: SIAH1/2-mediated proteasomal degradation, SH3-EBD/Grb2 autoinhibition release, AR-driven radioresistance, PDGFR-beta/PDK1-AKT signaling, and cortactin phosphorylation for endocytic actin.

    Evidence Y2H/co-IP/mutagenesis (SIAH, Grb2, PDK1), ChIP at the ATM enhancer, transgenic mice, in vitro kinase assays and EGFR internalization assays

    PMID:22553920 PMID:22566699 PMID:22952966 PMID:23208506 PMID:25257795

    Open questions at the time
    • Conflicting autoinhibition models (SH3-EBD vs MHR) not reconciled
    • Substrate hierarchy across contexts undefined
  14. 2014 Medium

    Identified epigenetic and autophagy/trafficking functions: KDM3A Tyr1114 phosphorylation reprogramming H3K9me2 for tamoxifen resistance, and UBA-domain engagement of p62/NBR1 linking ACK1 to EGFR autophagic handling.

    Evidence Co-IP of ACK1/ER/KDM3A, histone ChIP, inhibitor/knockdown rescue; p62/NBR1 co-IP, domain mutants, EGFR lysosomal trafficking

    PMID:24413169 PMID:25148682

    Open questions at the time
    • Direct demethylase activity changes downstream of KDM3A phosphorylation not mechanistically resolved
    • Single-lab findings
  15. 2015 High

    Defined ACK1 as an endocytic brake for the dopamine transporter, integrating PKC and Cdc42 inputs and rescuing an ADHD-associated DAT variant.

    Evidence shRNA/pharmacological silencing, DAT surface biotinylation, SERT specificity control, R615C variant rescue

    PMID:26621748

    Open questions at the time
    • Direct ACK1 substrate at the DAT endocytic step not identified
    • Neuronal in vivo relevance limited
  16. 2017 Medium

    Broadened ACK1 signaling to STAT activation and TCR-proximal adaptor SLP-76, implicating it in transcriptional and immune signaling.

    Evidence Endogenous co-IP (STAT1, SLP-76 SAM), nuclear fractionation, PLA, calcium flux/NFAT-AP1 reporters, T-cell motility, HSP90 inhibition

    PMID:28188290 PMID:28739485

    Open questions at the time
    • Direct STAT phosphosites not mapped
    • In vivo immune consequences not tested here
  17. 2018 Medium

    Revealed an ACK1-PTPN11 reciprocal phosphorylation/feedback loop that synergizes with PTPN11 mutations to amplify MAPK signaling in leukemia.

    Evidence Direct-interaction co-IP, phosphorylation and MAPK/colony assays, TNK2 inhibitor and patient dasatinib data

    PMID:30018082

    Open questions at the time
    • PTPN11 phosphosites and ACK1 dephosphorylation sites not mapped
    • Single lab
  18. 2019 High

    Placed TNK2 in a defined WASL-NCK1 actin-nucleation pathway required for picornavirus entry, with in vivo confirmation.

    Evidence CRISPR deletion, genetic epistasis, internalization assays, inhibitors, WASL domain mutants, Tnk2 knockout mice

    PMID:31769754

    Open questions at the time
    • Direct viral or host substrate of TNK2 in entry not identified
    • Receptor specificity across viruses unresolved
  19. 2022 High

    Defined ACK1 as a node of immune checkpoint resistance and mitochondrial energy control via CSK Tyr18 and ATP5F1A Tyr243/246 phosphorylation.

    Evidence Tnk2 knockout mice, phospho-specific antibodies, in vitro kinase assays/mutagenesis, ATP5IF1 co-IP, mitophagy and tumor models, patient samples

    PMID:35895804 PMID:36376335

    Open questions at the time
    • How ACK1 gains access to mitochondrial ATP synthase not defined
    • Tissue specificity of CSK pY18 control incomplete
  20. 2023 Medium

    Showed activated ACK1 deposits pY88-H4 marks at cell-cycle gene promoters to drive their transcription and metastasis, extending its direct chromatin role.

    Evidence ChIP for pY88-H4 at CCNB1/CCNB2/CDC20, expression/cell-cycle analysis, (R)-9b inhibitor, xenograft metastasis

    PMID:37330596

    Open questions at the time
    • Direct enzymatic deposition of pY88-H4 by ACK1 versus an intermediary not distinguished
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the conflicting autoinhibition/activation models (Src-driven Tyr284, MHR-kinase clamp, SH3-EBD/Grb2 release, SAM-mediated dimerization) integrate into one quantitative scheme for cellular ACK1 activation remains unresolved.
  • No unified full-length structure reconciling autoinhibition and dimerization
  • Relative contribution of Src vs autophosphorylation in vivo undefined
  • Context-dependent substrate selection not mechanistically explained

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 5 GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 3 GO:0060090 molecular adaptor activity 2 GO:0140657 ATP-dependent activity 1
Localization
GO:0005886 plasma membrane 4 GO:0031410 cytoplasmic vesicle 4 GO:0005768 endosome 2 GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 2
Partners
CDC42CLTCEGFRGRB2NCK1PTPN11SNX9SRC
Complex memberships
ACK1-Cdc42-p130Cas-Crk adhesion signaling complexACK1-ER-KDM3A transcriptional complexclathrin coat / AP-2 endocytic complex

Evidence

Reading pass · 45 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 NMR solution structure of Cdc42 bound to the GTPase-binding domain of ACK1 revealed that both proteins undergo significant conformational changes on binding, forming a new type of G-protein/effector complex in which an extended strand from ACK intercalates into the beta-sheet of Cdc42; this defines the structural basis for selective Cdc42 (not Rac) binding. NMR structure determination with functional validation of binding specificity Nature High 10360579
2003 ACK1 autophosphorylates at Tyr284 in the activation loop (identified by mass spectrometry); this is the primary autophosphorylation site and its mutation (Y284F) dramatically reduces tyrosine phosphorylation in cells. ACK1 substrate specificity most closely resembles Abl. ACK1 interacts with Hck SH3 domains via its proline-rich C-terminal domain, and Hck can phosphorylate ACK1, suggesting Hck as an upstream regulator. In vitro kinase assay with purified baculovirus-expressed ACK1, mass spectrometry phosphosite mapping, site-directed mutagenesis, SH2/SH3 domain binding screens, co-expression in mammalian cells The Journal of biological chemistry High 14506255
2004 Crystal structures of human ACK1 kinase domain in both unphosphorylated and phosphorylated states revealed that ACK1 adopts an activated conformation independent of phosphorylation, with the unphosphorylated activation loop structured and resembling that of activated tyrosine kinases. Inhibitor-bound co-crystal structures (with AMPPCP and debromohymenialdisine) defined the ATP-binding cleft. X-ray crystallography of phosphorylated and unphosphorylated kinase domain; inhibitor co-crystal structures The Journal of biological chemistry High 15308621
2001 ACK1 associates directly with clathrin heavy chain via a central adaptor motif that competes with beta-arrestin for a common binding site on the clathrin N-terminal head domain; ACK1 also interacts with the adaptor Nck via SH3 interactions; stable low-level GFP-ACK1 expression localizes to clathrin/AP-2-containing vesicles and increases receptor-mediated transferrin uptake. Direct binding assays, competition assays with beta-arrestin, GFP-ACK1 live-cell imaging, co-localization with clathrin and AP-2, transferrin uptake assay The Journal of biological chemistry High 11278436
2006 ACK1 activation loop autophosphorylation requires both the amino-terminal SAM-like domain (for membrane targeting) and Cdc42 binding via the CRIB domain; the SH3 domain plays an autoinhibitory role. Cell adhesion on fibronectin leads to strong tyrosine phosphorylation and activation of ACK1; EGF or PDGF stimulation recruits ACK1 to activated receptors; tyrosine-phosphorylated ACK1 forms a stable complex with adaptor Nck via its SH2 domain. Domain deletion mutant analysis, immunoprecipitation, kinase assays, EGF/PDGF stimulation of cells, fibronectin adhesion assays Proceedings of the National Academy of Sciences of the United States of America High 16777958
2005 Activated ACK1 tyrosine-phosphorylates tumor suppressor Wwox at Tyr287 (identified by site-directed mutagenesis), leading to rapid Wwox polyubiquitination and proteasomal degradation. Hsp90beta associates with ACK1 and its inhibition (geldanamycin) blocks ACK1 kinase activity. A splice variant (WwoxΔ5-8) not phosphorylated by ACK1 is not ubiquitinated or degraded. Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, ubiquitination assay, Hsp90 inhibitor treatment, xenograft tumor model Cancer research High 16288044
2007 Activated ACK1 directly phosphorylates androgen receptor (AR) at Tyr267 and Tyr363 within the transactivation domain. Mutation of Tyr267 completely abrogates, and Tyr363 mutation reduces, Ack1-induced AR reporter activation and AR recruitment to androgen-responsive enhancers. Heregulin-stimulated HER2 activates ACK1, which then phosphorylates AR to drive androgen-independent gene expression and tumor growth. Site-directed mutagenesis of AR, AR reporter assays, ChIP (AR recruitment to enhancers), ACK1 knockdown by siRNA, xenograft tumor models, phospho-specific antibodies Proceedings of the National Academy of Sciences of the United States of America High 17494760
2005 ACK1 phosphorylates WASP at both Tyr256 (tyrosine kinase activity) and Ser242 (serine kinase activity, demonstrating dual-specificity), with serine phosphorylation enhanced by Cdc42 or PIP2 (which releases WASP autoinhibition). Serine phosphorylation of WASP at Ser242 enhances WASP-stimulated actin polymerization in cell lysates. ACK1 expressed in bacteria retains serine kinase activity. In vitro kinase assay with purified proteins, phosphosite mapping by mutagenesis, bacterially expressed ACK1 kinase assay, actin polymerization assay in cell lysates The Journal of biological chemistry High 16257963
2010 ACK1 directly phosphorylates AKT at the evolutionarily conserved Tyr176 in the kinase domain. Tyr176-phosphorylated AKT localizes to the plasma membrane and promotes Thr308/Ser473 phosphorylation leading to full AKT activation. This pathway operates downstream of RTK/growth factor signaling. In vitro kinase assay, phospho-specific antibody generation, plasma membrane fractionation, site-directed mutagenesis, transgenic mouse model (prostate-specific activated Ack1), co-immunoprecipitation PloS one High 20333297
2010 HECT E3 ubiquitin ligase Nedd4-1 ubiquitinates ACK1 via a conserved PPXY WW-binding motif (WW3 domain of Nedd4-1 is critical); EGF-induced ACK1 degradation is processed by lysosomes, not proteasomes. The UBA domain of ACK1 suppresses Nedd4-1-mediated ubiquitination. Nedd4-1 (not Nedd4-2) knockdown inhibits degradation of both EGFR and ACK1, and ACK1 mutants deficient in Nedd4-1 binding block EGF-induced EGFR degradation. Co-immunoprecipitation, ubiquitination assay, RNAi knockdown, proteasome/lysosome inhibitors, EGFR degradation assay, deletion mutant analysis Molecular and cellular biology High 20086093
2009 E3 ubiquitin ligase Nedd4-2 binds ACK1 via its PPXY motif, co-localizes with ACK1 in clathrin-rich vesicles, and strongly down-regulates ACK1 levels via proteasomal degradation that is driven by ACK1 kinase activity. Dominant-inhibitory Nedd4 blocks endogenous ACK1 turnover in response to EGF. Co-immunoprecipitation, co-localization imaging, proteasome inhibitor (MG132), ACK1 PPXY mutants, dominant-negative Nedd4 The Journal of biological chemistry High 19144635
2012 SIAH1 and SIAH2 ubiquitin ligases interact with ACK1 via a conserved SIAH-binding motif in the far C-terminus of ACK1 and induce proteasomal (not lysosomal) degradation of ACK1 in a manner independent of ACK1 kinase activity. SIAH2 expression induced by estrogen receptor activation decreases ACK1 levels in breast cancer cells. Yeast two-hybrid, co-immunoprecipitation, deletion/point mutants of ACK1, proteasome inhibitor, SIAH2 knockdown, ER activation Oncogene High 23208506
2010 ACK1 kinase activity is autoinhibited by an intramolecular interaction between the kinase domain C-lobe and the C-terminal Mig6 homology region (MHR, residues 802-990); cancer-associated mutation E346K prevents kinase-MHR binding and constitutively activates ACK1. The MHR-kinase domain interaction was demonstrated by direct binding of purified domains in vitro. In vitro pulldown with purified kinase domain and MHR fragments, immune complex kinase assays, cancer-associated mutant characterization (E346K, F820A), cell migration and proliferation assays The Journal of biological chemistry High 20110370
2012 ACK1 activates AKT-mediated signaling in glioma cells downstream of PDGFR-β; PDGFR-β phosphorylates ACK1 at Y635, and this phosphorylation is required for sequential AKT activation. PDK1 interacts with ACK1 (via T325 of ACK1) during PDGF stimulation and is required for ACK1-PDGFR-β binding. Y635F or T325A ACK1 mutants abolish PDGFR-β-induced AKT activation and downstream β-catenin nuclear translocation. Co-immunoprecipitation, site-directed mutagenesis (Y635F, T325A), reporter and western blot assays, in vivo glioma model International journal of cancer Medium 25257795
2012 ACK1 activation mechanism involves an autoinhibitory interaction between the SH3 domain and the EGFR-binding domain (EBD); release of this autoinhibition activates ACK1. Cell adhesion-mediated activation occurs through releasing this autoinhibition. Grb2 mediates ACK1 interaction with EGFR by binding the EBD and releasing autoinhibition. The N-terminal region (Leu10-Leu14) is essential for cell adhesion-mediated activation. Ser445Pro mutation causes constitutive ACK1 activation. SH3/EBD domain deletion and point mutants, kinase activity assays, co-immunoprecipitation with Grb2 and EGFR, cell adhesion assays The Biochemical journal Medium 22553920
2011 Src kinase (not ACK1 autophosphorylation) is required for phosphorylation of ACK1 activation loop Tyr284 in vivo; Src SH2 and SH3 domains interact with ACK1 Tyr518 and residues 623-652, respectively. ACK1 fails to undergo significant Tyr284 autophosphorylation in vivo because its activation loop is basophilic (while Src is acidophilic). ACK1 activation downstream of EGFR/integrin requires Src; ACK1 turnover is blocked by Src inhibitors and is impaired in Src-deficient SYF cells. Co-immunoprecipitation of endogenous Src-ACK1, Src-deficient SYF cell line analysis, Src inhibitor treatment, domain mapping with SH2/SH3 domains The Biochemical journal Medium 21309750
2010 ACK1 activity is required for N-terminal SAM domain-mediated plasma membrane localization and dimerization; the isolated kinase domain (without N-terminus) fails to autophosphorylate and shows cytosolic localization, while the N-terminus+kinase domain (NKD) localizes to plasma membrane and undergoes autophosphorylation. Increasing local concentration of purified ACK1 kinase domain at lipid vesicle surfaces stimulates autophosphorylation and activity, consistent with dimerization and trans-phosphorylation. Deletion mutant immunofluorescence, western blotting for autophosphorylation, co-immunoprecipitation (dimerization), lipid vesicle reconstitution assay BMC biochemistry Medium 20979614
1999 ACK-2 (the shorter Cdc42-associated kinase) is activated by cell adhesion via integrin beta1 in a Cdc42-dependent manner; ACK-2 co-immunoprecipitates with integrin beta1. Activation is F-actin-independent and does not require cell spreading. Overexpression of ACK-2 activates c-Jun kinase (not ERK). Anti-integrin beta1 antibodies and RGD peptides inhibit ACK-2 activation by cell adhesion. Co-immunoprecipitation with integrin beta1, RGD peptide/antibody inhibition, kinase assays, actin depolymerization controls The Journal of biological chemistry Medium 10085085
1999 MCSP stimulation recruits tyrosine-phosphorylated p130Cas and activates Cdc42, with MCSP-induced cell spreading dependent on active Cdc42, Ack-1, and tyrosine phosphorylation of p130Cas. Vectors inhibiting Ack-1 or Cdc42 abrogate MCSP-induced p130Cas tyrosine phosphorylation and recruitment. Dominant-negative/inhibitory vectors for Ack-1 and Cdc42, phospho-p130Cas immunoprecipitation, cell spreading assays Nature cell biology Medium 10587647
2006 Ack1 forms a signaling complex with Cdc42, p130Cas, and Crk, whose formation is regulated by collagen stimulation. Ack1 interaction with p130Cas occurs through their respective SH3 domains, while the substrate domain of p130Cas is the major site of Ack1-dependent phosphorylation. siRNA knockdown of either p130Cas or Ack1 blocks Cdc42-induced cell migration on collagen. Co-immunoprecipitation, SH3 domain interaction mapping, siRNA knockdown, p130Cas phosphorylation assay, cell migration assay The Journal of biological chemistry Medium 17038317
2000 ACK1 tyrosine-phosphorylates and activates the guanine nucleotide exchange factor Dbl; in vitro GEF activity of Dbl toward Rho and Cdc42 is augmented after tyrosine phosphorylation. ACK1-dependent Dbl phosphorylation leads to accumulation of GTP-bound Rho and Rac in cells and enhanced JNK activation downstream. Co-expression in cells, in vitro GEF assay, GTP-bound Rho/Rac pull-down (RBD assay), JNK activation assay Biochemical and biophysical research communications Medium 10652228
2000 ACK1 phosphorylates and activates the Ras GEF Ras-GRF1 at tyrosine residues, augmenting Ras-GEF activity (GDP release) specifically toward Ha-Ras (not Rac1). This results in increased GTP-Ras accumulation in cells and enhanced ERK2 activation downstream of Ras-GRF1 when co-expressed with activated ACK1. In vitro GEF assay (GDP binding/release), GTP-Ras pull-down (RBD assay), ERK2 activation assay, kinase-dead ACK1 control The Journal of biological chemistry Medium 10882715
2001 Drosophila Ack (DAck) phosphorylates the sorting nexin DSH3PX1 in vivo and in vitro, with the major phosphorylation site at Tyr56 within the SH3 domain. Tyr56 phosphorylation by DAck diminishes DSH3PX1 SH3 domain binding to WASP while enabling association with Dock (Nck orthologue), targeting DSH3PX1 to a protein complex involved in axonal guidance. Co-immunoprecipitation from fly cell extracts, in vitro kinase assay, domain interaction mapping, site-directed mutagenesis (Y56D/E phosphomimetics), SH3 binding assays The Journal of biological chemistry Medium 11773052
2005 Sorting nexin 9 (SNX9/SH3PX1) acts as an adaptor linking ACK1 to synaptojanin-1; a single SNX9 binding site was identified in human ACK1 (residues 920-955). In the presence of SNX9, synaptojanin co-localizes with ACK1-containing vesicles, linking ACK1 to multiple endocytic trafficking components (clathrin, AP2, synaptojanin-1). In vivo biotinylation/blot overlay for SH3 domain interactions, synthetic peptide arrays for proline-rich binding sites, ACK1 truncation co-localization assays FEBS letters Medium 16137687
2008 ACK1/TNK2 preserves EGFR at the cell surface by blocking its degradation; ACK1 associates with activated EGFR in a kinase-independent manner. TNK2 knockdown reduces cell-surface EGFR, decreasing migratory and invasive capacity of breast cancer cells. siRNA knockdown, flow cytometry for cell-surface EGFR, co-immunoprecipitation, invasion/migration assays, 125I-EGF internalization assay Breast cancer research Medium 18435854
2008 ACK1 over-expression retains EGFR at the limiting membrane of early endosomes, inhibiting sorting to inner vesicles of multivesicular bodies. ACK1 knockdown reduces EGFR internalization rate (but not transferrin internalization) and increases EGFR recycling while inhibiting its degradation, placing ACK1 at an early step in EGFR desensitization. siRNA knockdown, 125I-EGF internalization/recycling/degradation assays, 125I-transferrin assay (negative control), fluorescence co-localization in early endosomes Experimental cell research Medium 18262180
2009 ACK1 interacts with multiple receptor tyrosine kinases (Axl, LTK, ALK, EGFR) via its C-terminal MIG6 homology region; interaction with Axl, LTK, and ALK (but not EGFR) requires Grb2 as adaptor, which binds conserved proline-rich regions. ACK1 controls Axl receptor levels; knockdown of endogenous ACK1 blocks GAS6-stimulated Axl downregulation and inhibits ruffling and migration. Co-immunoprecipitation, domain deletion mapping, ACK1 siRNA knockdown, receptor degradation assays, cell migration assays The Journal of biological chemistry Medium 19815557
2010 Ack phosphorylation at endocytic clathrin-coated pits requires both clathrin assembly into pits and active Cdc42; in cells lacking dynamin (frozen deeply invaginated pits), ACK is constitutively phosphorylated and activated. ACK is concentrated at clathrin-coated pits and binds clathrin heavy chain via two clathrin boxes. Dynamin 1/2 double conditional knockout fibroblasts, mass spectrometry for phosphoproteomic changes, RNAi knockdown, pharmacological Cdc42 inhibition, clathrin box mutant analysis Molecular biology of the cell Medium 21169560
2014 Drosophila Ack (DAck) localizes to CTP synthase (CTPS) filaments in ovarian germline cells; DAck catalytic activity regulates CTPS filament architecture. Flies deficient in DAck or lacking DAck kinase activity exhibit disrupted CTPS filament architecture, morphological defects correlating with reduced fertility, and reduced total RNA levels. Genetic loss-of-function (DAck mutant flies), kinase-dead DAck transgenes, fluorescence localization to CTPS filaments, fertility and RNA level measurements EMBO reports Medium 25223282
2014 ACK1 phosphorylates KDM3A (H3K9 demethylase) at Tyr1114 in a heregulin-dependent manner, decreasing H3K9me2 deposition. This ACK1-KDM3A-ER complex regulates HOXA1 transcription to promote tamoxifen resistance in breast cancer. Inhibition of ACK1 by AIM-100 or dasatinib restores H3K9me2 marks and suppresses HOXA1 expression. Co-immunoprecipitation of ACK1/ER/KDM3A complex, phospho-specific detection, histone methylation ChIP, ACK1 knockdown/inhibitor, HOXA1 expression analysis The Journal of biological chemistry Medium 25148682
2012 ACK1-mediated phosphorylation of AR at Tyr267 promotes AR recruitment to the ATM enhancer, up-regulating ATM expression and conferring radioresistance in castration-resistant prostate cancer. ACK1 inhibitor AIM-100 suppresses pTyr267-AR and reduces ATM expression, sensitizing CRPC tumors to radiotherapy. ChIP (AR recruitment to ATM enhancer), ACK1 transgenic mice (pTyr267-AR and ATM levels), ACK1 inhibitor AIM-100, primary human CRPC tissue analysis The Journal of biological chemistry Medium 22566699
2013 ACK1 interacts with Trk receptors and becomes tyrosine-phosphorylated in response to neurotrophins; ACK1 acts upstream of AKT and MAPK pathways in neurotrophin signaling. ACK1 overexpression induces neuritic outgrowth and branching in neurotrophin-treated neurons, while dominant-negative ACK1 or shRNA knockdown counteracts neurotrophin-stimulated differentiation. Co-immunoprecipitation with Trk receptors, kinase activity assays in response to neurotrophins, ACK1 overexpression/dominant-negative/shRNA in primary neurons and PC12 cells Cell death & disease Medium 23598414
2015 ACK1 (Ack1) is a DAT (dopamine transporter) endocytic brake that stabilizes DAT at the plasma membrane; both pharmacological and shRNA-mediated Ack1 silencing enhances basal DAT internalization. PKC activation and cdc42 activation converge on Ack1 to control DAT endocytic capacity; Ack1 inactivation is required for PKC-stimulated DAT internalization. Constitutively active Ack1 rescues the gain-of-function endocytic phenotype of the ADHD DAT coding variant R615C. Ack1 effects are specific for DAT (not SERT). shRNA knockdown, pharmacological Ack1 inhibition, DAT surface biotinylation, SERT internalization assay (specificity control), gain-of-function DAT variant rescue Proceedings of the National Academy of Sciences of the United States of America High 26621748
2017 ACK1 (TNK2) phosphorylates STAT1 and STAT3, promoting their nuclear accumulation and STAT1-dependent gene expression. ACK1 physically interacts with endogenous STAT1. SIAH2 (which targets ACK1 for proteasomal degradation via Val909) attenuates the ACK1-STAT1 signaling node. HSP90 (HSP90α/β) is an upstream regulator of the ACK1-dependent STAT1/STAT3 phosphorylation axis; HSP90 inhibitor Onalespib suppresses this signaling. Co-immunoprecipitation (endogenous STAT1-ACK1), nuclear fractionation, reporter assays, SIAH2 degradation assay, HSP90 inhibitor treatment, global interactome analysis Cellular signalling Medium 28739485
2017 ACK1 binds the SAM domain of adaptor SLP-76 and phosphorylates SLP-76 N-terminal tyrosines (Tyr113, Tyr128, Tyr145); interaction is induced by TCR ligation and requires the SLP-76 SAM domain. ACK1 promotes calcium flux and NFAT-AP1 promoter activity and decreases CD4+ T cell motility on ICAM-1, effects reversed by ACK1 inhibitor AIM-100. Co-precipitation, laser-scanning confocal microscopy, in situ proximity ligation assay, TCR stimulation, SAM domain deletion/3Y3F mutation, calcium flux, NFAT-AP1 reporter, T-cell motility assay The Journal of biological chemistry Medium 28188290
2018 TNK2/ACK1 interacts directly with PTPN11; ACK1 phosphorylates PTPN11, which subsequently dephosphorylates ACK1 in a negative feedback loop. Mutations in PTPN11 increase basal PTPN11 activity such that TNK2-mediated activation is additive, synergistically increasing MAPK signaling. TNK2 inhibition blocks MAPK signaling and colony formation in PTPN11-mutant leukemia cells. Co-immunoprecipitation (direct interaction), phosphorylation assays, MAPK signaling assays, colony formation, TNK2 inhibitor treatment, patient dasatinib treatment Science signaling Medium 30018082
2022 ACK1 (TNK2) phosphorylates CSK (C-terminal Src kinase) at Tyr18 (pY18-CSK), enhancing CSK function and constraining T-cell activation. Tnk2 knockout mice exhibit diminished CSK Y18-phosphorylation and spontaneous activation of CD8+ and CD4+ T cells, inhibiting growth of ICB-resistant tumors. ACK1 inhibitor (R)-9b recapitulates tumor inhibition, identifying ACK1/pY18-CSK as a mechanism of immune checkpoint blockade resistance. Tnk2 knockout mice, phospho-specific antibodies for pY18-CSK, T-cell activation assays, transplanted ICB-resistant tumor models, ACK1 inhibitor (R)-9b treatment, ICB-treated CRPC patient samples Nature communications High 36376335
2022 TNK2/ACK1 phosphorylates ATP5F1A (ATP synthase F1 alpha subunit) at Tyr243 and Tyr246, increasing complex V stability and mitochondrial energy output in cancer cells. Phospho-ATP5F1A prevents binding of its physiological inhibitor ATP5IF1, sustaining mitochondrial activity. ACK1 inhibitor (R)-9b reverses this, inducing mitophagy-based autophagy selectively in cancer cells. In vitro kinase assay (phosphosite identification), Y243/246A mutant analysis, co-immunoprecipitation of ATP5F1A and ATP5IF1, mitophagy assay, TNK2 transgenic mouse model, tumor xenograft, phospho-ATP5F1A antibody Autophagy High 35895804
2014 ACK1 co-localizes and interacts with autophagy receptor p62/SQSTM1 via its UBA domain, and with NBR1 in a manner enhanced by p62 co-expression. ACK1 partially co-localizes with Atg16L-positive isolation membrane structures upon EGF stimulation. Ack1 knockdown accelerates EGFR localization to lysosomes, and the UBA domain is essential for p62/SQSTM1 co-localization, while the Mig6-homology domain and clathrin-binding domain contribute to EGFR co-localization. Co-immunoprecipitation, confocal co-localization, domain deletion mutant analysis, siRNA knockdown, EGF-stimulated EGFR trafficking assay Journal of cell science Medium 24413169
2012 ACK1 directly binds and phosphorylates cortactin; the cortactin SH3 domain mediates binding to ACK1. ACK1 phosphorylates cortactin on key tyrosines that create docking sites for adaptor proteins enhancing Arp2/3 nucleation. ACK1 and cortactin co-localize on internalized EGF/EGFR vesicles. RNAi knockdown of ACK1 or the cortactin SH3 domain blocks EGF-induced EGFR internalization. Co-immunoprecipitation, in vitro kinase assay, phospho-specific antibodies, confocal co-localization, siRNA knockdown, EGFR internalization assay PloS one Medium 22952966
2019 TNK2, WASL (N-WASP), and NCK1 comprise a pathway required for entry of multiple picornaviruses (EMCV, CVB3, poliovirus, EV-D68); CRISPR deletion of TNK2 reduces viral internalization. Genetic epistasis analysis places all three genes in a common pathway. The actin nucleation activity of WASL is necessary for viral infection. Tnk2 knockout mice show reduced EMCV lethality. CRISPR gene deletion, genetic epistasis analysis, virus entry/internalization assays, TNK2/WASL chemical inhibitors, Tnk2 knockout mice, WASL domain mutants eLife High 31769754
2013 Structural and biochemical data indicate ACK1 kinase domain in its monomeric state is autoinhibited (parallel to EGFR and CDK); activation may require N-lobe-mediated symmetric dimerization facilitated by the N-terminal SAM domain. The SH3 domain does not directly control the activation state but may facilitate MIG6 homologous region binding to the kinase domain (allosteric model). X-ray crystallography of kinase domain and kinase+SH3 domain, biochemical activity assays, analytical ultracentrifugation for dimerization PloS one Medium 23342057
2004 ACK-1 and ACK-2 undergo Cdc42-dependent nuclear translocation in semi-confluent glioblastoma cells (cytosolic in confluent cells); interaction of Cdc42 with ACKs is essential for their nuclear localization. A putative nuclear export signal was identified in both ACK-1 and ACK-2. Overexpression of the Cdc42-binding domain (ACK42) inhibits cell growth and movement. Immunocytochemistry, western blot of nuclear/cytosolic fractions, ACK42 overexpression functional assay Biochemical and biophysical research communications Low 14733946
2023 Activated ACK1 deposits pY88-H4 epigenetic marks at cell cycle gene promoters (CCNB1, CCNB2, CDC20), initiating their transcription; this is demonstrated by ChIP. ACK1 inhibitor (R)-9b dampens CCNB1/CCNB2/CDC20 expression, causes G2/M arrest, and suppresses CXCR4 receptor expression to impair breast cancer metastasis. Chromatin immunoprecipitation (ChIP) for pY88-H4 marks at cell cycle gene promoters, gene expression analysis, ACK1 inhibitor (R)-9b treatment, G2/M cell cycle analysis, xenograft metastasis model Oncogene Medium 37330596
2017 ACK1 specificity for Cdc42 over Rac binding requires a combination of at least 7 Cdc42 residues (S41A, A42V, N43T, D47G, N52T, W56F, R174L); hydrophobic interactions at both ends of the binding interface are critical for ACK1-Cdc42 affinity; ACK1 uses a 'dock and coalesce' binding mechanism driven by hydrophobic residues in its intrinsically disordered CRIB region. Panel of Rac gain-of-function mutants, equilibrium binding constant measurements (ITC/fluorescence), based on prior Cdc42-ACK NMR structure The Journal of biological chemistry Medium 28539360

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation. Proceedings of the National Academy of Sciences of the United States of America 206 17494760
2005 Activated tyrosine kinase Ack1 promotes prostate tumorigenesis: role of Ack1 in polyubiquitination of tumor suppressor Wwox. Cancer research 181 16288044
1999 Melanoma chondroitin sulphate proteoglycan regulates cell spreading through Cdc42, Ack-1 and p130cas. Nature cell biology 172 10587647
1999 Structure of the small G protein Cdc42 bound to the GTPase-binding domain of ACK. Nature 155 10360579
2010 Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation. PloS one 137 20333297
2005 Metastatic properties and genomic amplification of the tyrosine kinase gene ACK1. Proceedings of the National Academy of Sciences of the United States of America 120 16247015
2014 ACK1/TNK2 tyrosine kinase: molecular signaling and evolving role in cancers. Oncogene 113 25347744
2001 The tyrosine kinase ACK1 associates with clathrin-coated vesicles through a binding motif shared by arrestin and other adaptors. The Journal of biological chemistry 103 11278436
1997 Cloning and characterization of a novel Cdc42-associated tyrosine kinase, ACK-2, from bovine brain. The Journal of biological chemistry 100 9312079
2019 LncRNA LINC00963 Promotes Tumorigenesis and Radioresistance in Breast Cancer by Sponging miR-324-3p and Inducing ACK1 Expression. Molecular therapy. Nucleic acids 90 31751910
2006 Construction and characterization of ack deleted mutant of Clostridium tyrobutyricum for enhanced butyric acid and hydrogen production. Biotechnology progress 89 17022663
2010 Dasatinib inhibits site-specific tyrosine phosphorylation of androgen receptor by Ack1 and Src kinases. Oncogene 83 20383201
2010 Effect of Ack1 tyrosine kinase inhibitor on ligand-independent androgen receptor activity. The Prostate 79 20623637
2012 Ack1-mediated androgen receptor phosphorylation modulates radiation resistance in castration-resistant prostate cancer. The Journal of biological chemistry 75 22566699
2006 Activation of the nonreceptor protein tyrosine kinase Ack by multiple extracellular stimuli. Proceedings of the National Academy of Sciences of the United States of America 73 16777958
1999 Activation of the Cdc42-associated tyrosine kinase-2 (ACK-2) by cell adhesion via integrin beta1. The Journal of biological chemistry 71 10085085
2015 ACK1 promotes gastric cancer epithelial-mesenchymal transition and metastasis through AKT-POU2F1-ECD signalling. The Journal of pathology 70 25678401
2010 HECT E3 ubiquitin ligase Nedd4-1 ubiquitinates ACK and regulates epidermal growth factor (EGF)-induced degradation of EGF receptor and ACK. Molecular and cellular biology 69 20086093
2010 Shepherding AKT and androgen receptor by Ack1 tyrosine kinase. Journal of cellular physiology 69 20432460
2014 Ack kinase regulates CTP synthase filaments during Drosophila oogenesis. EMBO reports 64 25223282
2003 Biochemical properties of the Cdc42-associated tyrosine kinase ACK1. Substrate specificity, authphosphorylation, and interaction with Hck. The Journal of biological chemistry 64 14506255
2012 Ack1 tyrosine kinase activation correlates with pancreatic cancer progression. The American journal of pathology 59 22322295
2014 ACK1 tyrosine kinase interacts with histone demethylase KDM3A to regulate the mammary tumor oncogene HOXA1. The Journal of biological chemistry 58 25148682
2009 Down-regulation of active ACK1 is mediated by association with the E3 ubiquitin ligase Nedd4-2. The Journal of biological chemistry 56 19144635
2013 ACK1 tyrosine kinase: targeted inhibition to block cancer cell proliferation. Cancer letters 53 23597703
2010 Somatic mutation in the ACK1 ubiquitin association domain enhances oncogenic signaling through EGFR regulation in renal cancer derived cells. Molecular oncology 53 20359967
2006 Ack1 mediates Cdc42-dependent cell migration and signaling to p130Cas. The Journal of biological chemistry 53 17038317
1999 Cloning, sequence analysis, expression and inactivation of the Corynebacterium glutamicum pta-ack operon encoding phosphotransacetylase and acetate kinase. Microbiology (Reading, England) 53 10075432
1996 Tyrosine phosphorylation of ACK in response to temperature shift-down, hyperosmotic shock, and epidermal growth factor stimulation. FEBS letters 53 8647288
1987 Involvement of ack-pta operon products in alpha-ketobutyrate metabolism by Salmonella typhimurium. Molecular & general genetics : MGG 52 3039301
2008 TNK2 preserves epidermal growth factor receptor expression on the cell surface and enhances migration and invasion of human breast cancer cells. Breast cancer research : BCR 50 18435854
2012 Disruption of the acetate kinase (ack) gene of Clostridium acetobutylicum results in delayed acetate production. Applied microbiology and biotechnology 49 22249720
2010 Cancer-associated mutations activate the nonreceptor tyrosine kinase Ack1. The Journal of biological chemistry 49 20110370
2006 Construction and characterization of ack knock-out mutants of Propionibacterium acidipropionici for enhanced propionic acid fermentation. Biotechnology and bioengineering 48 16508995
2004 Crystal structures of the phosphorylated and unphosphorylated kinase domains of the Cdc42-associated tyrosine kinase ACK1. The Journal of biological chemistry 48 15308621
2014 Bosutinib inhibits migration and invasion via ACK1 in KRAS mutant non-small cell lung cancer. Molecular cancer 47 24461128
2000 Activation of the guanine nucleotide exchange factor Dbl following ACK1-dependent tyrosine phosphorylation. Biochemical and biophysical research communications 47 10652228
1999 The CDC42-specific inhibitor derived from ACK-1 blocks v-Ha-Ras-induced transformation. Oncogene 47 10618719
2015 Ack1 is a dopamine transporter endocytic brake that rescues a trafficking-dysregulated ADHD coding variant. Proceedings of the National Academy of Sciences of the United States of America 46 26621748
2005 Phosphorylation of WASP by the Cdc42-associated kinase ACK1: dual hydroxyamino acid specificity in a tyrosine kinase. The Journal of biological chemistry 46 16257963
2018 The positive feedback between lncRNA TNK2-AS1 and STAT3 enhances angiogenesis in non-small cell lung cancer. Biochemical and biophysical research communications 45 30454892
2001 Drosophila Ack targets its substrate, the sorting nexin DSH3PX1, to a protein complex involved in axonal guidance. The Journal of biological chemistry 44 11773052
2005 SNX9 as an adaptor for linking synaptojanin-1 to the Cdc42 effector ACK1. FEBS letters 43 16137687
1995 Transcriptional regulation of the phosphotransacetylase-encoding and acetate kinase-encoding genes (pta and ack) from Methanosarcina thermophila. Journal of bacteriology 42 7896690
2022 Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance. Nature communications 41 36376335
2012 SIAH ubiquitin ligases target the nonreceptor tyrosine kinase ACK1 for ubiquitinylation and proteasomal degradation. Oncogene 41 23208506
2008 Dysregulation of Ack1 inhibits down-regulation of the EGF receptor. Experimental cell research 41 18262180
2009 Cytoplasmic ACK1 interaction with multiple receptor tyrosine kinases is mediated by Grb2: an analysis of ACK1 effects on Axl signaling. The Journal of biological chemistry 40 19815557
2004 AcK-knowledge reversible acetylation. Science's STKE : signal transduction knowledge environment 40 15304664
2001 Epidermal growth factor stimulation of the ACK1/Dbl pathway in a Cdc42 and Grb2-dependent manner. Biochemical and biophysical research communications 40 11394904
2011 Regulation of ack-family nonreceptor tyrosine kinases. Journal of signal transduction 39 21637378
2017 The non-receptor tyrosine kinase TNK2/ACK1 is a novel therapeutic target in triple negative breast cancer. Oncotarget 38 27902967
2022 TNK2/ACK1-mediated phosphorylation of ATP5F1A (ATP synthase F1 subunit alpha) selectively augments survival of prostate cancer while engendering mitochondrial vulnerability. Autophagy 37 35895804
2017 HSP90 is necessary for the ACK1-dependent phosphorylation of STAT1 and STAT3. Cellular signalling 37 28739485
2015 Development of novel ACK1/TNK2 inhibitors using a fragment-based approach. Journal of medicinal chemistry 37 25699576
2000 Stimulation of Ras guanine nucleotide exchange activity of Ras-GRF1/CDC25(Mm) upon tyrosine phosphorylation by the Cdc42-regulated kinase ACK1. The Journal of biological chemistry 37 10882715
2015 Genetics and Physiology of Acetate Metabolism by the Pta-Ack Pathway of Streptococcus mutans. Applied and environmental microbiology 36 25979891
2014 PDGFR-β-activated ACK1-AKT signaling promotes glioma tumorigenesis. International journal of cancer 34 25257795
2014 The non-receptor tyrosine kinase Ack1 regulates the fate of activated EGFR by inducing trafficking to the p62/NBR1 pre-autophagosome. Journal of cell science 33 24413169
2012 The activation mechanism of ACK1 (activated Cdc42-associated tyrosine kinase 1). The Biochemical journal 32 22553920
2010 Constitutive activated Cdc42-associated kinase (Ack) phosphorylation at arrested endocytic clathrin-coated pits of cells that lack dynamin. Molecular biology of the cell 32 21169560
2020 ACK1-AR and AR-HOXB13 signaling axes: epigenetic regulation of lethal prostate cancers. NAR cancer 31 32885168
2015 ACK1 promotes hepatocellular carcinoma progression via downregulating WWOX and activating AKT signaling. International journal of oncology 31 25738261
2014 Androgen receptor activation in castration-recurrent prostate cancer: the role of Src-family and Ack1 tyrosine kinases. International journal of biological sciences 31 24948875
2017 Amplification of ACK1 promotes gastric tumorigenesis via ECD-dependent p53 ubiquitination degradation. Oncotarget 28 26498357
2019 LncRNA TNK2-AS1 regulated ox-LDL-stimulated HASMC proliferation and migration via modulating VEGFA and FGF1 expression by sponging miR-150-5p. Journal of cellular and molecular medicine 27 31468685
2018 Blockade of ACK1/TNK2 To Squelch the Survival of Prostate Cancer Stem-like Cells. Scientific reports 26 29386546
2010 Regulation of Ack1 localization and activity by the amino-terminal SAM domain. BMC biochemistry 26 20979614
2008 Identification and optimization of N3,N6-diaryl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamines as a novel class of ACK1 inhibitors. Bioorganic & medicinal chemistry letters 26 18993068
1994 Construction of Pta-Ack pathway deletion mutants of Escherichia coli and characteristic growth profiles of the mutants in a rich medium. Bioscience, biotechnology, and biochemistry 26 7765717
2018 Actin organization and endocytic trafficking are controlled by a network linking NIMA-related kinases to the CDC-42-SID-3/ACK1 pathway. PLoS genetics 25 29608564
2012 Cortactin is a substrate of activated Cdc42-associated kinase 1 (ACK1) during ligand-induced epidermal growth factor receptor downregulation. PloS one 25 22952966
2020 Comprehensive Analysis of the Immune Implication of ACK1 Gene in Non-small Cell Lung Cancer. Frontiers in oncology 24 32793482
2013 A role for the tyrosine kinase ACK1 in neurotrophin signaling and neuronal extension and branching. Cell death & disease 24 23598414
2013 Mutations in TNK2 in severe autosomal recessive infantile onset epilepsy. Annals of neurology 23 23686771
2011 The Cdc42-associated kinase ACK1 is not autoinhibited but requires Src for activation. The Biochemical journal 23 21309750
2019 Entry by multiple picornaviruses is dependent on a pathway that includes TNK2, WASL, and NCK1. eLife 22 31769754
2013 Ack1: activation and regulation by allostery. PloS one 22 23342057
2019 The non-receptor tyrosine kinase ACK: regulatory mechanisms, signalling pathways and opportunities for attACKing cancer. Biochemical Society transactions 21 31845724
2017 miR-24 represses metastasis of human osteosarcoma cells by targeting Ack1 via AKT/MMPs pathway. Biochemical and biophysical research communications 21 28189676
2023 Epigenetic reprogramming of cell cycle genes by ACK1 promotes breast cancer resistance to CDK4/6 inhibitor. Oncogene 20 37330596
2020 Inhibition of ACK1 delays and overcomes acquired resistance of EGFR mutant NSCLC cells to the third generation EGFR inhibitor, osimertinib. Lung cancer (Amsterdam, Netherlands) 20 33049499
2005 Expression, synaptic localization, and developmental regulation of Ack1/Pyk1, a cytoplasmic tyrosine kinase highly expressed in the developing and adult brain. The Journal of comparative neurology 20 16052498
2002 ACK family tyrosine kinase activity is a component of Dcdc42 signaling during dorsal closure in Drosophila melanogaster. Molecular and cellular biology 20 11997505
2018 Synthetic lethality of TNK2 inhibition in PTPN11-mutant leukemia. Science signaling 18 30018082
2020 Loss of ACK1 Upregulates EGFR and Mediates Resistance to BRAF Inhibition. The Journal of investigative dermatology 17 33159968
2017 Activated Cdc42-associated kinase 1 (ACK1) binds the sterile α motif (SAM) domain of the adaptor SLP-76 and phosphorylates proximal tyrosines. The Journal of biological chemistry 17 28188290
2005 Specificity determinants on Cdc42 for binding its effector protein ACK. Biochemistry 17 16156650
2004 Cdc42-dependent nuclear translocation of non-receptor tyrosine kinase, ACK. Biochemical and biophysical research communications 17 14733946
2008 Leading edge-secreted Dpp cooperates with ACK-dependent signaling from the amnioserosa to regulate myosin levels during dorsal closure. Developmental dynamics : an official publication of the American Association of Anatomists 16 18816840
1988 ack::Mu d1-8 (Apr lac) operon fusions of Salmonella typhimurium LT2. Molecular & general genetics : MGG 16 2830464
2021 Small Molecules Targeting Activated Cdc42-Associated Kinase 1 (ACK1/TNK2) for the Treatment of Cancers. Journal of medicinal chemistry 15 34735773
2017 A dock and coalesce mechanism driven by hydrophobic interactions governs Cdc42 binding with its effector protein ACK. The Journal of biological chemistry 14 28539360
2002 Modulation of HeLa cells spreading by the non-receptor tyrosine kinase ACK-2. Journal of cellular biochemistry 14 11835391
1986 Isolation and characterization of ack and pta mutations in Azotobacter vinelandii affecting acetate-glucose diauxie. Journal of bacteriology 14 3001033
2022 ACK1 Contributes to the Pathogenesis of Inflammation and Autoimmunity by Promoting the Activation of TLR Signaling Pathways. Frontiers in immunology 13 35669783
2020 TNK2-AS1 upregulated by YY1 boosts the course of osteosarcoma through targeting miR-4319/WDR1. Cancer science 13 33164271
2019 Sugar and Fatty Acids Ack-celerate Prophage Induction. Cell host & microbe 13 30763529
2017 A role for the non-receptor tyrosine kinase ACK1 in TNF-alpha-mediated apoptosis and proliferation in human intestinal epithelial caco-2 cells. Cell biology international 13 28921811
2016 Ack promotes tissue growth via phosphorylation and suppression of the Hippo pathway component Expanded. Cell discovery 13 27462444

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