Affinage

MAP4K1

Mitogen-activated protein kinase kinase kinase kinase 1 · UniProt Q92918

Length
833 aa
Mass
91.3 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAP4K1 (HPK1) is a hematopoietic-restricted Ste20-family serine/threonine kinase that functions as a central negative regulator of antigen receptor signaling, integrin activation, and innate immune responses. Activated downstream of TCR/BCR engagement via adaptors SLP-76, BLNK, Grb2, Gads, Crk, and Clnk, and independently by PGE2 through PKA-mediated phosphorylation of Ser171, HPK1 signals through MEKK1/TAK1/MLK3→MKK4→JNK and IKK→NF-κB cascades, while attenuating receptor signaling by phosphorylating BLNK (T152) to trigger its ubiquitination and degradation, competing with ADAP for SLP-76 binding to dampen Rap1/integrin activation, and recruiting DTX4 to promote K48-linked ubiquitination of TBK1/IKKε thereby suppressing type I interferon production (PMID:8824585, PMID:10795738, PMID:22334673, PMID:20957749, PMID:34908452). During apoptosis, caspase-3 cleavage at Asp385 generates a constitutively active N-terminal kinase fragment that sustains JNK/Bad signaling and a C-terminal fragment that sequesters the IKK complex to inhibit NF-κB and promote activation-induced cell death (PMID:10602493, PMID:11278403, PMID:16341093). Structurally, the kinase domain forms an inactive dimer regulated by activation-loop trans-phosphorylation, while the C-terminal citron homology domain adopts a β-propeller fold that restrains kinase activity and docks substrate SLP-76; genetic ablation of HPK1 enhances anti-tumor immunity by preventing T cell exhaustion and augmenting NK cell cytotoxicity (PMID:31018963, PMID:38697971, PMID:32860752, PMID:38828677).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1996 High

    Identifying HPK1 as a novel Ste20-family kinase that specifically activates the JNK/SAPK pathway via MEKK1 and MLK3→SEK1/MKK4 established the initial signaling cascade framework and distinguished it from Rac/Cdc42-dependent MAP4Ks.

    Evidence Overexpression kinase assays, direct in vitro MEKK1 phosphorylation, dominant-negative epistasis in COS cells

    PMID:8824585 PMID:9003777

    Open questions at the time
    • Direct phosphorylation site on MEKK1 not identified
    • Physiological cell type and upstream stimulus not established
  2. 1997 High

    Demonstration that TAK1 functions between HPK1 and MKK4 refined the kinase cascade hierarchy, while identification of Grb2 SH3 domain binding to HPK1 proline-rich motifs revealed the first mechanism for receptor-proximal recruitment of HPK1.

    Evidence Dominant-negative epistasis placing TAK1 between HPK1 and MKK4; in vitro SH3 binding and co-IP after EGF stimulation

    PMID:9278437 PMID:9346925

    Open questions at the time
    • Whether TAK1 is a direct HPK1 substrate not shown
    • Functional relevance in hematopoietic cells not yet tested
  3. 1999 High

    Discovery that caspase-3 cleaves HPK1 at Asp385 during apoptosis, generating a constitutively active kinase fragment and an adaptor-binding-deficient C-terminal fragment, revealed a proteolytic switch that bifurcates HPK1 signaling into pro-apoptotic JNK and anti-NF-κB outputs.

    Evidence In vitro cleavage by recombinant caspase-3, D385A mutagenesis, co-IP loss of Grb2/Crk binding

    PMID:10602493

    Open questions at the time
    • In vivo physiological consequence of cleavage not yet demonstrated
    • Whether cleavage occurs during normal T cell activation unknown
  4. 2000 High

    Establishing that HPK1 is activated by TCR/BCR engagement via Src/Syk kinases and adaptors SLP-76/BLNK/LAT, and that kinase-dead HPK1 potentiates TCR signaling, defined HPK1 as a negative feedback regulator of antigen receptor responses.

    Evidence HPK1 kinase activity assays after receptor engagement, kinase-dead dominant-negative effects on AP-1/ERK, co-IP with adaptors

    PMID:10795738

    Open questions at the time
    • Substrates mediating negative regulation not identified
    • In vivo consequence in knockout animals not yet shown
  5. 2001 High

    Mechanistic dissection showed that full-length HPK1 activates NF-κB through IKKβ independently of JNK, while the caspase-generated C-terminal fragment dominantly inhibits NF-κB by sequestering the IKK complex, establishing dual roles for intact versus cleaved HPK1.

    Evidence Dominant-negative IKKβ and SEK1 epistasis, truncation analysis, NF-κB reporter assays; endogenous IKK co-IP, siRNA, HPK1-C transgenic mice (2005 follow-up)

    PMID:11278403 PMID:16341093

    Open questions at the time
    • Direct HPK1 phosphorylation of IKK subunits not demonstrated
    • Stoichiometry of HPK1-C sequestration in vivo unclear
  6. 2001 Medium

    Identification of additional SH3-containing adaptors Grap2/MONA/Gads and Clnk as HPK1-binding partners expanded the upstream receptor-proximal signaling network connecting immunoreceptors to HPK1 activation.

    Evidence Co-IP from Jurkat cells (Grap2), yeast two-hybrid plus co-IP (Clnk), kinase-dead epistasis on IL-2 promoter

    PMID:11313918 PMID:11509653

    Open questions at the time
    • Relative contribution of each adaptor not dissected in primary cells
    • Whether adaptors are redundant or pathway-specific unknown
  7. 2007 High

    Identification of PKA-mediated phosphorylation of Ser171 as the mechanism for PGE2-induced HPK1 activation defined a tyrosine-kinase-independent activation route, linking prostaglandin/cAMP signaling to HPK1 in immunosuppressive contexts.

    Evidence S171A mutagenesis abolishing PGE2-induced activation, PKA-deficient S49 cell validation, pharmacological dissection

    PMID:17895239

    Open questions at the time
    • Whether PKA directly phosphorylates S171 in vitro not shown with purified components
    • In vivo relevance to tumor microenvironment PGE2 not tested
  8. 2009 High

    Identification of CARMA1 as a direct HPK1 substrate (phosphorylated at S549/S551/S552) required for TCR-induced NF-κB activation provided the first substrate-level mechanism for HPK1's role in NF-κB signaling.

    Evidence In vitro kinase assay with CARMA1 linker, site-directed mutagenesis, rescue in CARMA1-deficient T cells

    PMID:19706536

    Open questions at the time
    • Whether CARMA1 phosphorylation is activating or priming for negative regulation not fully resolved
    • Relationship to HPK1's overall negative regulatory role on T cells needs clarification
  9. 2010 High

    Discovery that HPK1 competes with ADAP for SLP-76 binding to dampen Rap1 activation and LFA-1-mediated integrin adhesion in both T and B cells established HPK1 as a negative regulator of inside-out integrin signaling.

    Evidence HPK1-deficient mouse T and B cells, competitive co-IP, Rap1-GTP pulldown, ICAM-1 adhesion assays

    PMID:20824186 PMID:20957749

    Open questions at the time
    • Whether HPK1 kinase activity or scaffolding is required for this competition not resolved
    • Relative importance in vivo during immune responses not established
  10. 2012 High

    Demonstration that HPK1 phosphorylates BLNK at T152, triggering 14-3-3 binding and K48-linked ubiquitination/degradation of BLNK, provided the molecular mechanism for HPK1-mediated attenuation of BCR signaling.

    Evidence In vitro kinase assay, HPK1-KO B cells, mass spectrometry of ubiquitination sites, site-directed mutagenesis

    PMID:22334673

    Open questions at the time
    • E3 ligase responsible for BLNK ubiquitination not identified
    • Whether analogous phosphodegron mechanism operates for SLP-76 in T cells unknown
  11. 2019 High

    Crystal structures of the HPK1 kinase domain in non-phosphorylated, phosphorylated, and phosphomimetic states revealed that inactive HPK1 forms a dimer with activation loops blocking partner active sites, and activation-loop phosphorylation disrupts this dimer, establishing the structural basis for trans-regulatory autoinhibition.

    Evidence X-ray crystallography at 2.17–3.00 Å resolution in multiple phosphorylation states

    PMID:31018963

    Open questions at the time
    • Full-length HPK1 structure not determined
    • How C-terminal domains modulate dimerization unknown at this point
  12. 2020 High

    Genetic ablation and pharmacological inhibition/PROTAC degradation of HPK1 enhanced anti-tumor T cell responses via the NF-κB–Blimp1 axis, validating HPK1 as an immune checkpoint whose loss prevents T cell exhaustion in tumor models.

    Evidence MAP4K1 KO mice, CAR-T cell tumor models, PROTAC degradation, pharmacological inhibition

    PMID:32860752

    Open questions at the time
    • Optimal therapeutic window and potential autoimmune consequences not addressed
    • Whether kinase activity or scaffolding drives exhaustion not resolved
  13. 2021 High

    HPK1 was shown to negatively regulate innate antiviral signaling by recruiting E3 ligase DTX4 to promote K48-linked ubiquitination and proteasomal degradation of TBK1/IKKε, extending HPK1's negative regulatory role beyond adaptive to innate immunity.

    Evidence Yeast two-hybrid, co-IP, ubiquitination assay with K48-linkage specificity, DTX4 knockdown epistasis, KO cells

    PMID:34908452

    Open questions at the time
    • Direct biochemical reconstitution of HPK1-DTX4-TBK1 trimeric complex not performed
    • Whether HPK1 kinase activity is required for DTX4 recruitment not tested
  14. 2024 High

    Structural determination of the citron homology domain (CHD) as a β-propeller that binds the kinase domain to restrain activity and dock SLP-76 resolved how the C-terminal region autoinhibits HPK1 and mediates substrate engagement, complementing earlier kinase domain structures.

    Evidence X-ray crystallography of CHD, HDX-MS for KD-CHD interaction, mutagenesis, cellular stability assays

    PMID:38697971

    Open questions at the time
    • Full-length HPK1 structure with CHD–KD interaction at atomic resolution still lacking
    • Whether allosteric inhibitors target the CHD-KD interface not determined
  15. 2024 High

    HPK1 was identified as a negative regulator of NK cell cytotoxicity; conditional overexpression exacerbated melanoma metastasis while KO conferred resistance, broadening HPK1's immune checkpoint role beyond T and B cells to NK cells, with TGF-β1 identified as an upstream inducer.

    Evidence NK cell-specific conditional HPK1 overexpression and KO mice, tumor metastasis models, NK cytotoxicity assays

    PMID:38828677

    Open questions at the time
    • Substrates mediating NK cell suppression not identified
    • Whether HPK1 operates through same SLP-76/integrin axis in NK cells unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full-length HPK1 structure capturing CHD-KD intramolecular regulation, identification of the E3 ligase for BLNK degradation, whether kinase activity versus scaffolding drives T cell exhaustion, and whether HPK1 inhibition triggers autoimmunity in therapeutic settings.
  • Full-length HPK1 atomic structure not solved
  • Kinase-dependent vs. scaffolding-dependent functions not genetically separated in vivo
  • In vivo autoimmune consequences of chronic HPK1 inhibition not systematically evaluated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 6 GO:0140096 catalytic activity, acting on a protein 4 GO:0060090 molecular adaptor activity 3
Localization
GO:0005829 cytosol 3
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-168256 Immune System 6 R-HSA-5357801 Programmed Cell Death 3
Partners
BLNKCARMA1CRKDTX4GRB2MEKK1SLP76TBK1
Complex memberships
IKK complex (via HPK1-C sequestration)

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 HPK1 (MAP4K1) is a novel Ste20-related serine/threonine kinase that activates the JNK/SAPK pathway; it directly binds and phosphorylates MEKK1, and JNK1 activation by HPK1 is blocked by dominant-negative MEKK1 or MKK4/SEK1 mutants, placing HPK1 upstream of MEKK1 and MKK4 in the JNK cascade. Unlike PAK65, HPK1 does not bind Rac1/Cdc42, indicating Rac1/Cdc42-independent activation. Transfection/overexpression in vivo kinase assays, direct binding/phosphorylation of MEKK1 in vitro, dominant-negative epistasis Genes & development High 8824585
1996 HPK1 specifically activates the SAPK/JNK pathway (but not p38/RK or ERK) and signals via the SH3-containing mixed lineage kinase MLK-3 and SEK1; a functional HPK1 kinase domain is required for SAPK activation. Transfection into COS1 cells, dominant-negative epistasis with SEK1 and MLK-3 The EMBO journal High 9003777
1997 TAK1 acts as an intermediate in the HPK1→TAK1→MKK4/SEK1→JNK kinase cascade: kinase-defective TAK1 suppresses HPK1-induced JNK activity; dominant-negative MEKK1 and MLK3 do not inhibit TAK1-induced JNK, placing TAK1 specifically between HPK1 and MKK4. Transient transfection, dominant-negative epistasis, kinase-dead mutants The Journal of biological chemistry High 9278437
1997 Grb2 SH3 domains bind directly to specific proline-rich motifs in the HPK1 C-terminal tail; EGF stimulation recruits the Grb2·HPK1 complex to the autophosphorylated EGF receptor and Shc; activated receptor and cytoplasmic tyrosine kinases (including EGFR) induce tyrosine phosphorylation of HPK1. In vitro SH3-binding assay, co-immunoprecipitation from transfected Cos1 cells, EGF stimulation The Journal of biological chemistry High 9346925
1998 HPK1 binds selectively to the first SH3 domains of c-Crk and CRKL via proline-rich motifs in its C-terminal non-catalytic region; HPK1 also binds both SH3 domains of Grb2 and weakly to Nck; c-Crk II and CRKL are substrates phosphorylated by HPK1 in vitro. In vitro SH3-binding assay with >25 SH3 domains, co-immunoprecipitation of endogenous proteins, in vitro kinase assay Oncogene High 9788432
1999 HPK1 is cleaved by caspase-3 during apoptosis at the conserved DDVD motif (Asp385); cleavage separates the N-terminal kinase domain from the C-terminal regulatory domain, enhances HPK1 kinase activity, and abolishes binding to adaptor proteins Grb2 and Crk. In vitro cleavage by recombinant caspase-3, peptide inhibitor blockade, mutational analysis (D385A), in vivo/in vitro cleavage assays, co-immunoprecipitation Oncogene High 10602493
1999 HPK1 activates both IKK-α and IKK-β, linking the HPK1-MEKK1 stress response pathway to NF-κB activation; IKK-β phosphorylates IκB constitutively while IKK-α requires stimulation. Overexpression/co-transfection, kinase activity assays Oncogene Medium 10523828
2000 HPK1 is activated by TCR and BCR engagement; Src and Syk/ZAP-70 tyrosine kinases and adaptor proteins LAT, SLP-76, BLNK, Grb2, and Grap are required for HPK1 activation; overexpressed HPK1 inhibits TCR-induced AP-1 and ERK2 activation (negative regulation), while kinase-inactive HPK1 potentiates these responses. HPK1 kinase activity assays after receptor engagement, dominant-negative and kinase-dead HPK1 overexpression, co-immunoprecipitation Immunity High 10795738
2001 HPK1 activates NF-κB through a pathway independent of SAPK/JNK; full-length kinase-active HPK1 is required for NF-κB activation while the isolated kinase domain suffices for SAPK/JNK; dominant-negative IKKβ blocks HPK1-mediated NF-κB activation; caspase cleavage releases the HPK1-C fragment which dominantly inhibits NF-κB (including NIK- and TNFα-induced) by impairing the IKK complex. Dominant-negative SEK1 and IKKβ epistasis, overexpression of full-length vs. kinase domain and C-terminal fragment, NF-κB reporter assays The Journal of biological chemistry High 11278403
2001 Grap2 (MONA/GADS-related adaptor) interacts with HPK1 in vitro and in Jurkat T cells via its C-terminal SH3 domain binding to the second proline-rich motif of HPK1; co-expression of Grap2 with HPK1 increases HPK1 kinase activity and additively enhances JNK activation and IL-2 promoter activity. Co-immunoprecipitation from Jurkat cells, kinase activity assay, luciferase reporter Oncogene Medium 11313918
2001 Clnk (SLP-76 family adaptor) physically associates with HPK1 in hematopoietic cells (identified by yeast two-hybrid and co-transfection), with interaction augmented by immunoreceptor stimulation; kinase-defective HPK1 blocks Clnk-stimulated IL-2 promoter activity, indicating Clnk signals through HPK1. Yeast two-hybrid, co-transfection co-immunoprecipitation in Cos-1 cells, Jurkat transfection luciferase assay, kinase-dead epistasis Molecular and cellular biology Medium 11509653
2003 PGE2 positively activates HPK1 catalytic activity in hematopoietic cells; ectopic HPK1 negatively regulates PGE2-induced fos gene transcription, identifying HPK1 as a negative regulator of PGE2-GPCR signaling. HPK1 kinase activity assay after PGE2 treatment, ectopic expression/reporter assay Blood Medium 12522005
2004 The Mona/Gads C-terminal SH3 domain (SH3C) binds to an HPK1 proline-rich motif combining an atypical RXXK motif (essential for binding via charge interactions) with a PXXP motif; crystal structure of the complex reveals SH3 domain versatility and a binding mode distinct from SLP-76. Isothermal titration calorimetry, X-ray crystallography, mutagenesis The Journal of biological chemistry High 15100220
2005 HPK1 is a functional component of the endogenous IKK complex in T cells; full-length HPK1 enhances IKKβ phosphorylation and is required for TCR-mediated NF-κB activation; siRNA knockdown of HPK1 blunts NF-κB activation; caspase-cleaved HPK1-C sequesters the inactive IKK complex by binding to IKKα and IKKβ, suppressing NF-κB and sensitizing T cells to AICD. Co-immunoprecipitation with endogenous IKK complex, siRNA knockdown, HPK1-C transgenic mice, NF-κB reporter assays The EMBO journal High 16341093
2006 During monocytic differentiation, caspase-3 cleaves HPK1 into the N-terminal HPK1-N fragment (kinase domain), which is constitutively active, sustains JNK activation, phosphorylates Bad, and promotes IL-3-independent progenitor survival and monocytic lineage differentiation. Primary mouse progenitor cell culture, caspase inhibitor treatment, JNK activity assay, Bad phosphorylation assay Cell death and differentiation Medium 17024227
2007 PGE2 activates HPK1 via a cAMP/PKA-dependent pathway that is independent of phosphotyrosine-based signaling (Lck, ZAP-70, SLP-76, LAT) and SH3-mediated adaptor interactions; Ser171 within the activation loop is the PKA phosphorylation site required for this response, as S171A mutation completely abrogates PGE2-induced HPK1 activation; HPK1 fails to respond to PGE2 in PKA-deficient S49 cells. Kinase activity assay, site-directed mutagenesis (S171A), PKA-deficient S49 cell line, pharmacological dissection The Journal of biological chemistry High 17895239
2007 Caspase-cleaved HPK1-C selectively blocks NF-κB-dependent antiapoptotic Bcl-2 family member induction but not proapoptotic Bim; T and B lymphocytes from HPK1-C transgenic mice undergo AICD independently of CD95/CD95L via caspase-9; siRNA knockdown of HPK1/HPK1-C reduces AICD. HPK1-C transgenic mice, siRNA knockdown, Bcl-2 family protein western blotting, flow cytometric apoptosis assays Blood High 17712048
2008 After cerebral ischemia, activated Src tyrosine-phosphorylates HPK1 (via NMDA receptor activation), which then activates the MLK3-MKK7-JNK3 pathway promoting neuronal death; PP2 (Src inhibitor) or MK801 (NMDA antagonist) reduced HPK1, MLK3, JNK3, and c-Jun activation and protected neurons. Immunoprecipitation, immunoblot in rat ischemia/reperfusion model, pharmacological inhibition (PP2, MK801), histology/TUNEL FEBS letters Medium 18498770
2009 HPK1 directly phosphorylates the linker region of CARMA1 at residues S549, S551, and S552 (distinct from PKCθ sites) in a TCR stimulation-dependent manner; CARMA1 S551A or S549A/S551A mutants fail to restore NF-κB activation and IL-2 expression; HPK1 interaction with CARMA1 is TCR-stimulation-dependent. In vitro kinase assay with CARMA1 linker constructs, site-directed mutagenesis, co-immunoprecipitation, NF-κB reporter in CARMA1-deficient T cells Proceedings of the National Academy of Sciences of the United States of America High 19706536
2010 HPK1 competes with ADAP for SLP-76 binding; HPK1 dampens Rap1 activation downstream of TCR, reducing LFA-1 activity; HPK1-deficient T cells show increased ADAP recruitment to SLP-76, elevated Rap1 activation, and increased adhesion to ICAM-1 and spreading. HPK1-deficient mouse T cells, co-immunoprecipitation, Rap1 activation assay (RalGDS pulldown), ICAM-1 adhesion assay European journal of immunology High 20957749
2010 HPK1 associates with SKAP-HOM in B cells and negatively regulates Rap1-mediated LFA-1 integrin activity; HPK1 knockdown in Wehi 231 B cells elevates Rap1-GTP, increases LFA-1-dependent aggregation and ICAM-1 adhesion, and constitutively phosphorylates FAK, via a PI3K/PLC-independent module involving RIAM. shRNA knockdown in Wehi 231 cells, HPK1-/- mouse B cell analysis, Rap1 activation assay, adhesion assay, co-immunoprecipitation, FAK phosphorylation PloS one Medium 20824186
2012 HPK1 phosphorylates BLNK at threonine 152 after BCR activation, which mediates BLNK/14-3-3 binding; T152-phosphorylated BLNK is ubiquitinated at K37, K38, and K42, leading to BLNK degradation and attenuation of MAPK and IKK activation; HPK1-deficient B cells show hyper-proliferation and hyper-activation of these kinases upon BCR ligation. HPK1-deficient B cells, co-immunoprecipitation, in vitro kinase assay, mass spectrometry identification of ubiquitination sites, site-directed mutagenesis The Journal of biological chemistry High 22334673
2013 HPK1 is required for CXCL1-induced LFA-1-mediated neutrophil adhesion to ICAM-1 under flow; HPK1 is enriched at the lamellipodium of polarized neutrophil-like cells and colocalizes with mAbp1 and actin; HPK1 constitutively co-immunoprecipitates with mAbp1; Mac-1 affinity regulation is independent of HPK1; HPK1-deficient mice show defective PMN adhesion and extravasation in vivo. HPK1-deficient mouse neutrophils, intravital microscopy, adhesion assay under flow, co-immunoprecipitation, LFA-1 affinity assay, confocal microscopy Blood High 23460610
2019 PDIA6 interacts with MAP4K1 (HPK1) by co-immunoprecipitation and inhibits MAP4K1 phosphorylation, thereby suppressing the MAP4K1/JNK/c-Jun signaling pathway and reducing cisplatin-induced apoptosis and autophagy in NSCLC cells. Co-immunoprecipitation, phospho-kinase array, gain/loss-of-function in vitro and in vivo EBioMedicine Medium 30922965
2019 Crystal structures of the native HPK1 kinase domain reveal it forms an inactive dimer in the non-phosphorylated state (activation loop of each monomer occupying partner's ATP/substrate-binding site); doubly phosphorylated activation loop adopts an active conformation with reduced dimer interface; phosphomimetic mutant (T165E/S171E) shows an alternative domain-swapped configuration; revealing trans-regulation via dimer formation and remodeling of the activation segment. X-ray crystallography of HPK1 kinase domain in non-phosphorylated, doubly phosphorylated, and phosphomimetic states complexed with sunitinib (2.17-3.00 Å resolution) The Journal of biological chemistry High 31018963
2020 HPK1 mediates T cell dysfunction via the HPK1-NFκB-Blimp1 axis; MAP4K1 knockout mice show slower tumor growth and less exhausted, more proliferative tumor-infiltrating T cells; HPK1 depletion, pharmacological inhibition, or PROTAC-mediated degradation improves CAR-T cell efficacy in preclinical models. MAP4K1 KO mice, CAR-T cell tumor models, PROTAC degradation, pharmacological inhibition Cancer cell High 32860752
2021 MAP4K1 (HPK1) negatively regulates RLR antiviral signaling by interacting with TBK1 (identified by yeast two-hybrid) and promoting K48-linked ubiquitination and proteasomal degradation of TBK1/IKKε via the E3 ubiquitin ligase DTX4; MAP4K1 overexpression inhibits IFN-β production after RNA virus infection, while knockdown/knockout has the opposite effect; DTX4 knockdown abrogates TBK1 ubiquitination. Yeast two-hybrid, co-immunoprecipitation, overexpression and knockdown/knockout, ubiquitination assay (K48-linkage), proteasome inhibitor treatment Microbiology spectrum High 34908452
2021 An allosteric HPK1 inhibitor binds preferentially to unphosphorylated (inactive) full-length HPK1 (>24-fold vs. active HPK1), is non-competitive with ATP, requires domains outside the isolated kinase domain, and attenuates kinase autophosphorylation, revealing an allosteric pocket encompassing residues within and outside the kinase domain. Kinase cascade assay, ATP-competition assay, isolated kinase domain binding assay, biochemical binding assays Biochemistry High 34608799
2024 The HPK1 citron homology domain (CHD) adopts a seven-bladed β-propellor fold that directly binds to the kinase domain (KD); CHD-KD interaction negatively regulates kinase activity; CHD provides protein stability in cells and contributes to docking of the substrate SLP76. X-ray crystallography (CHD structure), hydrogen-deuterium exchange mass spectrometry, mutagenesis, biochemical binding assays, functional kinase assays, cellular stability assays Nature communications High 38697971
2024 HPK1 is aberrantly overexpressed in dysfunctional NK cells; conditional HPK1 overexpression in NK cells exacerbates melanoma lung metastasis; MAP4K1-deficient mice are resistant to metastasis; mechanistically HPK1 restrains NK cell cytotoxicity and expansion via activating receptors; TGF-β1 upregulates HPK1 in NK cells. Conditional NK cell-specific HPK1 overexpression mouse model, MAP4K1-deficient mice, tumor metastasis assays, NK cytotoxicity assays, activating receptor signaling assays Advanced science High 38828677
2024 In glioblastoma cells, MAP4K1 loss down-regulates membrane-bound IL-18R and IL-6R by inhibiting the PI3K-AKT pathway; MAP4K1 restoration rescues IL-18R/IL-6R expression and proliferative responses to IL-18, revealing a cancer cell-intrinsic oncogenic role via the IL-18/IL-18R/PI3K-AKT pathway. MAP4K1 siRNA knockdown, MAP4K1 restoration rescue, transcriptome analysis, PI3K-AKT pathway western blotting, IL-18 stimulation assays Life science alliance Medium 37734869
2025 HPK1 enhances NF-κB/STAT3/p38-MAPK pathways and gasdermin D cleavage in neutrophils, promoting neutrophil hyperactivation; HPK1 promotes mobilization of CXCR2high bone marrow neutrophils after ischemic stroke; HPK1 loss or pharmacological inhibition reduces neutrophil hyperactivation, NET aggregation, and post-stroke lung/neurological injury. HPK1-deficient mice, pharmacological HPK1 inhibition, neutrophil activation assays, LPS-stimulated pathway analysis, mouse AIS model EMBO molecular medicine Medium 40169896

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Human HPK1, a novel human hematopoietic progenitor kinase that activates the JNK/SAPK kinase cascade. Genes & development 220 8824585
1996 HPK1, a hematopoietic protein kinase activating the SAPK/JNK pathway. The EMBO journal 205 9003777
1997 Activation of the hematopoietic progenitor kinase-1 (HPK1)-dependent, stress-activated c-Jun N-terminal kinase (JNK) pathway by transforming growth factor beta (TGF-beta)-activated kinase (TAK1), a kinase mediator of TGF beta signal transduction. The Journal of biological chemistry 169 9278437
2020 Hematopoietic Progenitor Kinase1 (HPK1) Mediates T Cell Dysfunction and Is a Druggable Target for T Cell-Based Immunotherapies. Cancer cell 158 32860752
2000 HPK1 is activated by lymphocyte antigen receptors and negatively regulates AP-1. Immunity 115 10795738
2019 PDIA6 modulates apoptosis and autophagy of non-small cell lung cancer cells via the MAP4K1/JNK signaling pathway. EBioMedicine 84 30922965
1997 SH2/SH3 adaptor proteins can link tyrosine kinases to a Ste20-related protein kinase, HPK1. The Journal of biological chemistry 74 9346925
2021 Enhanced antitumor immunity by a novel small molecule HPK1 inhibitor. Journal for immunotherapy of cancer 71 33408094
1999 Caspase-mediated cleavage and functional changes of hematopoietic progenitor kinase 1 (HPK1). Oncogene 70 10602493
2001 Caspase-mediated cleavage of hematopoietic progenitor kinase 1 (HPK1) converts an activator of NFkappaB into an inhibitor of NFkappaB. The Journal of biological chemistry 66 11278403
2005 Activation or suppression of NFkappaB by HPK1 determines sensitivity to activation-induced cell death. The EMBO journal 64 16341093
2004 Mona/Gads SH3C binding to hematopoietic progenitor kinase 1 (HPK1) combines an atypical SH3 binding motif, R/KXXK, with a classical PXXP motif embedded in a polyproline type II (PPII) helix. The Journal of biological chemistry 61 15100220
2020 A perspective on HPK1 as a novel immuno-oncology drug target. eLife 58 32896273
2012 Down-regulation of B cell receptor signaling by hematopoietic progenitor kinase 1 (HPK1)-mediated phosphorylation and ubiquitination of activated B cell linker protein (BLNK). The Journal of biological chemistry 52 22334673
2009 Phosphorylation of CARMA1 by HPK1 is critical for NF-kappaB activation in T cells. Proceedings of the National Academy of Sciences of the United States of America 52 19706536
2011 hsa-miR-96 up-regulates MAP4K1 and IRS1 and may function as a promising diagnostic marker in human bladder urothelial carcinomas. Molecular medicine reports 51 21993544
1998 The germinal center kinase (GCK)-related protein kinases HPK1 and KHS are candidates for highly selective signal transducers of Crk family adapter proteins. Oncogene 51 9788432
2022 The development of small-molecule inhibitors targeting HPK1. European journal of medicinal chemistry 50 36209628
2012 HPK1 as a novel target for cancer immunotherapy. Immunologic research 50 22477524
2001 Leukocyte-specific adaptor protein Grap2 interacts with hematopoietic progenitor kinase 1 (HPK1) to activate JNK signaling pathway in T lymphocytes. Oncogene 49 11313918
2005 Functional interactions of HPK1 with adaptor proteins. Journal of cellular biochemistry 46 15770651
2021 Inhibitors of immuno-oncology target HPK1 - a patent review (2016 to 2020). Expert opinion on therapeutic patents 43 33956554
2021 Discovery of Diaminopyrimidine Carboxamide HPK1 Inhibitors as Preclinical Immunotherapy Tool Compounds. ACS medicinal chemistry letters 42 33859804
2001 Synergistic regulation of immunoreceptor signaling by SLP-76-related adaptor Clnk and serine/threonine protein kinase HPK-1. Molecular and cellular biology 42 11509653
2022 Discovery of Macrocycle-Based HPK1 Inhibitors for T-Cell-Based Immunotherapy. Journal of medicinal chemistry 40 36542759
2007 Caspase-cleaved HPK1 induces CD95L-independent activation-induced cell death in T and B lymphocytes. Blood 40 17712048
1999 Hematopoietic progenitor kinase-1 (HPK1) stress response signaling pathway activates IkappaB kinases (IKK-alpha/beta) and IKK-beta is a developmentally regulated protein kinase. Oncogene 40 10523828
2021 Discovery of Spiro-azaindoline Inhibitors of Hematopoietic Progenitor Kinase 1 (HPK1). ACS medicinal chemistry letters 38 35059127
2022 The HPK1 Inhibitor A-745 Verifies the Potential of Modulating T Cell Kinase Signaling for Immunotherapy. ACS chemical biology 35 35188729
2017 The homeodomain-interacting protein kinase HPK-1 preserves protein homeostasis and longevity through master regulatory control of the HSF-1 chaperone network and TORC1-restricted autophagy in Caenorhabditis elegans. PLoS genetics 35 29036198
2007 Prostaglandin E2 activates HPK1 kinase activity via a PKA-dependent pathway. The Journal of biological chemistry 35 17895239
2021 Identification of Potent Reverse Indazole Inhibitors for HPK1. ACS medicinal chemistry letters 33 33738073
2012 Pdcd4 knockdown up-regulates MAP4K1 expression and activation of AP-1 dependent transcription through c-Myc. Biochimica et biophysica acta 33 22801218
2006 Sustained JNK signaling by proteolytically processed HPK1 mediates IL-3 independent survival during monocytic differentiation. Cell death and differentiation 33 17024227
2021 SPIB acts as a tumor suppressor by activating the NFkB and JNK signaling pathways through MAP4K1 in colorectal cancer cells. Cellular signalling 31 34530056
2003 Hematopoietic progenitor kinase 1 (HPK1) negatively regulates prostaglandin E2-induced fos gene transcription. Blood 31 12522005
2019 DLX6-AS1 promotes cell proliferation, migration and EMT of gastric cancer through FUS-regulated MAP4K1. Cancer biology & therapy 30 31591939
2019 Multiple conformational states of the HPK1 kinase domain in complex with sunitinib reveal the structural changes accompanying HPK1 trans-regulation. The Journal of biological chemistry 26 31018963
2013 Hematopoietic progenitor kinase 1 (HPK1) is required for LFA-1-mediated neutrophil recruitment during the acute inflammatory response. Blood 25 23460610
2019 Long noncoding RNA CDKN2B-AS1 interacts with transcription factor BCL11A to regulate progression of cerebral infarction through mediating MAP4K1 transcription. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 22 30870006
2024 Discovery of Pyridine-2-Carboxamides Derivatives as Potent and Selective HPK1 Inhibitors for the Treatment of Cancer. Journal of medicinal chemistry 21 39585942
2023 Design, Synthesis, and Pharmacological Evaluation of Isoindoline Analogues as New HPK1 Inhibitors. Journal of medicinal chemistry 21 37990878
2024 Discovery of an Exceptionally Orally Bioavailable and Potent HPK1 PROTAC with Enhancement of Antitumor Efficacy of Anti-PD-L1 Therapy. Journal of medicinal chemistry 20 39084610
2022 Development of a series of quinazoline-2,5-diamine derivatives as potent hematopoietic progenitor kinase 1 (HPK1) inhibitors. European journal of medicinal chemistry 20 36621137
2010 HPK1 competes with ADAP for SLP-76 binding and via Rap1 negatively affects T-cell adhesion. European journal of immunology 20 20957749
2023 Discovery of 7H-Pyrrolo[2,3-d]pyrimidine Derivatives as potent hematopoietic progenitor kinase 1 (HPK1) inhibitors. European journal of medicinal chemistry 19 37062169
2023 Discovery of highly efficient CRBN-recruiting HPK1-PROTAC as a potential chemical tool for investigation of scaffolding roles in TCR signaling. Bioorganic chemistry 19 38086239
2020 HPK1 Influences Regulatory T Cell Functions. ImmunoHorizons 19 32631900
2019 The Structure of HPK1 Kinase Domain: To Boldly Go Where No Immuno-Oncology Drugs Have Gone Before. Structure (London, England : 1993) 19 30605659
2010 HPK1 associates with SKAP-HOM to negatively regulate Rap1-mediated B-lymphocyte adhesion. PloS one 19 20824186
2024 Discovery of novel, potent, selective and orally bioavailable HPK1 inhibitor for enhancing the efficacy of anti-PD-L1 antibody. European journal of medicinal chemistry 17 38350360
2024 Current strategies for targeting HPK1 in cancer and the barriers to preclinical progress. Expert opinion on therapeutic targets 17 38650383
2024 Discovery of PF-07265028, A Selective Small Molecule Inhibitor of Hematopoietic Progenitor Kinase 1 (HPK1) for the Treatment of Cancer. Journal of medicinal chemistry 16 39651809
2023 Highly potent, orally active novel small-molecule HPK1 inhibitor DS21150768 induces anti-tumor responses in multiple syngeneic tumor mouse models. European journal of pharmacology 16 37944847
2021 Discovery of an Allosteric, Inactive Conformation-Selective Inhibitor of Full-Length HPK1 Utilizing a Kinase Cascade Assay. Biochemistry 16 34608799
2016 Homeodomain-Interacting Protein Kinase (HPK-1) regulates stress responses and ageing in C. elegans. Scientific reports 16 26791749
2021 MAP4K1 functions as a tumor promotor and drug mediator for AML via modulation of DNA damage/repair system and MAPK pathway. EBioMedicine 15 34166980
2021 The Kinase MAP4K1 Inhibits Cytosolic RNA-Induced Antiviral Signaling by Promoting Proteasomal Degradation of TBK1/IKKε. Microbiology spectrum 15 34908452
2025 Discovery and Optimization of Pyrazine Carboxamide AZ3246, a Selective HPK1 Inhibitor. Journal of medicinal chemistry 14 39928839
2023 Discovery of potent and selective HPK1 inhibitors based on the 2,4-disubstituted pyrimidine scaffold with immune modulatory properties for ameliorating T cell exhaustion. Bioorganic chemistry 14 37536217
2024 Discovery of BAY-405: An Azaindole-Based MAP4K1 Inhibitor for the Enhancement of T-Cell Immunity against Cancer. Journal of medicinal chemistry 13 39331123
2024 Discovery of Novel PROTAC-Based HPK1 Degraders with High Potency and Selectivity for Cancer Immunotherapy. Journal of medicinal chemistry 13 39446986
2022 Discovery of Novel HPK1 Inhibitors Through Structure-Based Virtual Screening. Frontiers in pharmacology 13 35370676
2012 The pan-caspase inhibitor Q-VD-OPh has anti-leukemia effects and can interact with vitamin D analogs to increase HPK1 signaling in AML cells. Leukemia research 13 22541691
2024 HPK1 Dysregulation-Associated NK Cell Dysfunction and Defective Expansion Promotes Metastatic Melanoma Progression. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 12 38828677
2023 An HPK1 inhibitor enhanced the tumour response to anti-PD-1 immunotherapy in non-Hodgkin's lymphoma. Clinical and experimental medicine 12 37106265
2023 Discovery of quinazoline HPK1 inhibitors with high cellular potency. Bioorganic & medicinal chemistry 12 37531921
2020 Using yeast surface display to engineer a soluble and crystallizable construct of hematopoietic progenitor kinase 1 (HPK1). Acta crystallographica. Section F, Structural biology communications 12 33439152
2024 HPK1 citron homology domain regulates phosphorylation of SLP76 and modulates kinase domain interaction dynamics. Nature communications 11 38697971
2024 Discovery of GNE-6893, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of HPK1. ACS medicinal chemistry letters 11 39291002
2023 Design and synthesis of 1H-pyrazolo[3,4-d]pyrimidine derivatives as hematopoietic progenitor kinase 1 (HPK1) inhibitors. Bioorganic chemistry 11 37659145
2022 Discovery of Pyrazolopyridine Derivatives as HPK1 Inhibitors. ACS medicinal chemistry letters 11 36655125
2013 Homeodomain interacting protein kinase (HPK-1) is required in the soma for robust germline proliferation in C. elegans. Developmental dynamics : an official publication of the American Association of Anatomists 11 23904186
2012 Dual role of hematopoietic progenitor kinase 1 (HPK1) as a positive regulator of 1α,25-dihydroxyvitamin D-induced differentiation and cell cycle arrest of AML cells and as a mediator of vitamin D resistance. Cell cycle (Georgetown, Tex.) 11 22421156
2024 Design, Synthesis, and Biological Evaluation of a Series of Spiro Analogues as Novel HPK1 Inhibitors. ACS medicinal chemistry letters 10 39563821
2023 Glioblastoma cellular MAP4K1 facilitates tumor growth and disrupts T effector cell infiltration. Life science alliance 10 37734869
2022 Potent and Selective Biaryl Amide Inhibitors of Hematopoietic Progenitor Kinase 1 (HPK1). ACS medicinal chemistry letters 10 36655134
2024 Design, synthesis, and biological evaluation of 2,4-diaminopyrimidine derivatives as potent Hematopoietic Progenitor Kinase 1 (HPK1) inhibitors. Bioorganic chemistry 9 38795581
2024 Opportunities and challenges for targeting HPK1 in cancer immunotherapy. Bioorganic chemistry 9 39369461
2024 Discovery of 5-aminopyrido[2,3-d]pyrimidin-7(8H)-one derivatives as new hematopoietic progenitor kinase 1 (HPK1) inhibitors. European journal of medicinal chemistry 8 38479166
2024 Discovery of 1(2H)-phthalazinone and 1(2H)-isoquinolinone derivatives as potent hematopoietic progenitor kinase 1 (HPK1) inhibitors. European journal of medicinal chemistry 8 39303515
2025 Discovery of 1,2,4-benzotriazine derivatives as new hematopoietic progenitor kinase 1 (HPK1) inhibitors. Bioorganic chemistry 7 39826501
2025 Design, Synthesis, and biological evaluation of 7H-Pyrrolo[2,3-d]pyrimidines as potent HPK1 kinase inhibitors. Bioorganic & medicinal chemistry 6 39874881
2018 Identification of proteins regulated by acid adaptation related two component system HPK1/RR1 in Lactobacillus delbrueckii subsp. bulgaricus. Archives of microbiology 6 30022229
2024 Pharmacological inhibition of HPK1 synergizes with PD-L1 blockade to provoke antitumor immunity against tumors with low antigenicity. Biochemical and biophysical research communications 5 38685185
2024 Design, synthesis, and biological evaluation of novel HPK1 inhibitors possessing 3-cyano-quinoline moiety. Bioorganic chemistry 5 39299176
2024 An updated review of small-molecule HPK1 kinase inhibitors (2016-present). Future medicinal chemistry 5 39582317
2025 HPK1 kinase inhibitor: a sufficient approach to target HPK1 to modulate T cell activation in cancer immunotherapy compared with degraders. Frontiers in immunology 4 39981246
2025 Discovery of a Novel Potent and Orally Efficacious PROTAC Degrader of HPK1 for Tumor Immunotherapy. Journal of medicinal chemistry 4 40738757
2008 Tyrosine phosphorylation of HPK1 by activated Src promotes ischemic brain injury in rat hippocampal CA1 region. FEBS letters 4 18498770
2025 Updated patent review for hematopoietic progenitor kinase (HPK1) inhibitors and degraders (2021-present). Expert opinion on therapeutic patents 3 39950624
2025 Highly selective HPK1 inhibitor NDI-101150 mediates immune cell activation and robust antitumor responses, distinct from immune checkpoint blockade. Journal for immunotherapy of cancer 3 40738502
2015 [Interactions between MAP4K1 and adaptor proteins]. Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences 3 25832533
2025 Design, synthesis and structure-activity relationship studies of novel macrocyclic 2,4-diaminopyrimidines as HPK1 inhibitors. Bioorganic & medicinal chemistry 2 40494219
2025 Design, synthesis, and biological evaluation of 2-substituted-pyridin-4-yl macrocyclic derivatives as new selective HPK1 inhibitors. Bioorganic chemistry 2 40902512
2023 Theoretical Studies on Selectivity of HPK1/JAK1 Inhibitors by Molecular Dynamics Simulations and Free Energy Calculations. International journal of molecular sciences 2 36768974
2022 Decoding the signaling profile of hematopoietic progenitor kinase 1 (HPK1) in innate immunity: A proteomic approach. European journal of immunology 2 35099066
2013 Gimme a brake: HPK1 regulates LFA-1 and neutrophil traction. Blood 2 23682030
2025 Targeting HPK1 inhibits neutrophil responses to mitigate post-stroke lung and cerebral injuries. EMBO molecular medicine 1 40169896
2025 MAP4K1 and MAP4K2 regulate ABA-induced and Ca2+-mediated stomatal closure in Arabidopsis. Science advances 1 41417897