Affinage

KALRN

Kalirin · UniProt O60229

Length
2986 aa
Mass
340.3 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KALRN (Kalirin) is a multidomain Rho-family guanine nucleotide exchange factor that drives actin cytoskeletal remodeling underlying dendritic spine formation, axon and dendrite outgrowth, and synaptic plasticity (PMID:10692441, PMID:12177196, PMID:25146373). Its first GEF domain (GEF1) catalyzes GDP/GTP exchange on Rac1 and RhoG, and this activity is the core engine of its neuronal functions: GEF1-driven RhoG activation initiates axon outgrowth (PMID:12177196), while GEF1-driven Rac1 activation produces lamellipodia, spines, and downstream PAK signaling (PMID:10692441, PMID:11182094). The synaptic isoform Kalirin-7 is enriched in the postsynaptic density, where its C-terminal PDZ-binding motif tethers it to PSD-95 and its overexpression increases spine number and size in a manner requiring both GEF activity and PDZ binding (PMID:10692441, PMID:11182094, PMID:18199770). Kalirin-7 is a postsynaptic signaling hub whose GEF activity is gated by phosphorylation: CaMKII phosphorylates Kalirin-7 at Thr95 downstream of NMDA receptor activation to enhance GEF activity and spine enlargement, and Cdk5 phosphorylates Thr1590 to permit protrusion formation (PMID:18031682, PMID:18628310, PMID:21488700). Through direct binding to the NR2B subunit of the NMDA receptor and to AMPA receptors, Kalirin-7 couples synaptic activity to AMPAR surface upregulation, and it is required for NMDA-receptor-dependent LTP and LTD (PMID:18031682, PMID:21880917, PMID:22182308). Genetic and pharmacological work establishes Kalirin/Trio as the CaMKII effectors responsible for AMPAR up-regulation during LTP (PMID:26858404). Kalirin is recruited and contextualized by upstream partners: GDP-bound Arf6 recruits it to the plasma membrane to control Rac activation (PMID:17640372), N-cadherin/AF-6 recruits Kalirin-7 to synapses (PMID:18550750), it binds and potentiates TrkA neurotrophin signaling via its N-terminal PH domain (PMID:15923627), and it acts in the BDNF-TrkB pathway to enable Rac1-dependent neurite outgrowth (PMID:27036892). Beyond the synapse, Kalirin functions outside neurons: as a Rac1 GEF in arterial smooth muscle cells driving migration and neointimal hyperplasia (PMID:23288169), in FSTL-1-induced GLUT4 translocation and glucose uptake in muscle (PMID:27989699), in bone homeostasis via RANKL/OPG balance (PMID:24380811), and in regulated secretory granule maturation through its interactions with iNOS and PAM (PMID:9873042, PMID:9915831, PMID:17881726). A rare GEF-domain variant (D1338N) that impairs Rac1 activation reduces spine size and correlates with reduced cortical volume, and a schizophrenia-linked GEF2 variant (P2255T) shifts activity toward RhoA, linking Kalirin dysfunction to altered neuronal morphology (PMID:25224588, PMID:29241584).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1999 High

    Established that Kalirin functions outside its GEF role by binding regulators of secretion, defining an early non-cytoskeletal interaction landscape.

    Evidence Yeast two-hybrid and co-association assays identified iNOS and the PAM cytosolic domain as Kalirin partners; cell-based ACTH secretion assays linked it to regulated exocytosis

    PMID:9873042 PMID:9915831

    Open questions at the time
    • Structural basis of iNOS homodimer inhibition not resolved
    • How PAM binding relates to GEF activity unclear
    • In vivo relevance of secretory roles not yet tested by knockout
  2. 2000 High

    Defined the core molecular activity of Kalirin-7 as a postsynaptically enriched Rac1 GEF and revealed its multi-isoform domain architecture, framing how distinct isoforms could serve distinct compartments.

    Evidence Subcellular fractionation, in vitro GEF exchange assay on Rac1, fibroblast morphology, molecular cloning, and isoform-specific antisera

    PMID:10692441 PMID:10777487

    Open questions at the time
    • Functional differences between isoforms not yet assigned
    • RhoG and RhoA specificity of GEF domains not addressed here
    • Endogenous substrate selectivity in neurons not established
  3. 2001 High

    Connected Kalirin-7's GEF activity to dendritic spine morphogenesis and showed PSD-95 anchoring is required for proper synaptic localization and function.

    Evidence Co-IP with PSD-95, GEF-dead and PDZ-binding-deficient mutants, and spine imaging in primary neurons

    PMID:11182094

    Open questions at the time
    • Upstream activators triggering Rac1 activation at spines unknown
    • Whether endogenous loss phenocopies overexpression not yet tested
  4. 2002 High

    Resolved the GTPase specificity of the GEF1 domain in axon initiation, showing RhoG rather than Rac1/RhoA/Cdc42 drives new axon outgrowth.

    Evidence Microinjection of sympathetic neurons with antisense, dominant-negative, and constitutively active Rho GTPase constructs

    PMID:12177196

    Open questions at the time
    • RhoG-to-Rac1 hierarchy in spine vs axon contexts not unified
    • Endogenous upstream signals not identified
  5. 2005 High

    Placed Kalirin upstream and downstream of neurotrophin signaling by showing it binds TrkA via its N-terminal PH domain and amplifies NGF responses.

    Evidence Co-IP, antisense knockdown in PC12 cells, in vitro kinase assay, domain mapping, neurite outgrowth

    PMID:15923627

    Open questions at the time
    • Mechanism of TrkA autophosphorylation potentiation unresolved
    • Whether interaction is direct not fully established
  6. 2007 High

    Identified CaMKII phosphorylation at Thr95 and Arf6-dependent membrane recruitment as activity-coupled regulatory inputs that gate Kalirin's GEF output, linking NMDAR activity to spine enlargement and AMPAR control.

    Evidence Phospho-specific antibodies, CaMKII co-expression, electrophysiology, Co-IP, Arf6 mutant binding and Rac1 GTP-loading assays, and GEF1-dependent secretion assays

    PMID:17640372 PMID:17881726 PMID:18031682

    Open questions at the time
    • Whether T95 phosphorylation directly alters GEF catalysis or localization not resolved
    • Structural mechanism of Arf6 spectrin-repeat binding undefined
  7. 2008 High

    Established Kalirin-7 as essential in vivo for spine density, LTP, and learning, and dissected the regulatory and recruitment machinery (Cdk5 Thr1590 phosphorylation, N-cadherin/AF-6, Sec14p lipid binding, interneuron synaptogenesis).

    Evidence Kal7 knockout mice with morphology/electrophysiology/behavior, Cdk5 in vitro kinase assay and mutants, N-cadherin clustering with reciprocal Co-IP, Sec14p lipid-binding assays, and shRNA in interneurons

    PMID:18199770 PMID:18550750 PMID:18585704 PMID:18628310 PMID:19020030

    Open questions at the time
    • How distinct phospho-inputs are integrated at single spines unclear
    • Lipid binding's contribution to in vivo function untested
    • Compensation by larger isoforms complicates interpretation
  8. 2011 High

    Defined direct Kalirin-7–NR2B binding via the PH domain and showed selectivity for NMDA-receptor-dependent plasticity, linking the interaction to receptor surface expression and behavior.

    Evidence In vitro binding/domain mapping, KO electrophysiology distinguishing NMDAR-dependent vs -independent LTP/LTD, surface biotinylation, behavioral pharmacology, and PSD phosphoproteomics

    PMID:21488700 PMID:21880917 PMID:22182308

    Open questions at the time
    • How NR2B binding couples mechanistically to GEF activation unclear
    • Which phospho-sites dominate in vivo not resolved
  9. 2013 High

    Extended Kalirin's role beyond neurons—into smooth muscle migration, bone homeostasis, and pain signaling—while in the brain linking Kalirin-7 to cocaine-induced AMPAR upregulation.

    Evidence Smooth-muscle conditional KO and carotid injury model with Rac1/PAK readouts, global KO bone histomorphometry, NAc lentiviral shRNA with behavior, and spinal nerve ligation siRNA with Co-IP epistasis

    PMID:23288169 PMID:23516288 PMID:23825406 PMID:24380811

    Open questions at the time
    • Isoform identity in non-neuronal tissues incompletely mapped (Kal9 in SMC vs others)
    • Pain and bone mechanisms rest on single-lab studies
    • GEF substrate selectivity across tissues not uniformly defined
  10. 2016 High

    Identified Kalirin (with redundant paralog Trio) as the long-sought CaMKII effector driving AMPAR up-regulation during LTP, and showed GEF1–Rac1 signaling mediates BDNF-TrkB-driven neurite outgrowth.

    Evidence Constructs blocking CaMKII–Kalirin interaction with LTP/AMPAR readouts, and Kalrn KO neurons with GEF1 inhibition, Rac1 GTP-loading, and Kalirin-7 rescue under BDNF stimulation

    PMID:26858404 PMID:27036892 PMID:27989699

    Open questions at the time
    • Degree of Kalirin/Trio redundancy across synapse types unquantified
    • Coupling of CaMKII signal to GEF1 catalysis mechanistically incomplete
  11. 2017 High

    Linked disease-associated coding variants to specific GEF defects—loss of Rac1 activation (D1338N) and a gain of RhoA activation (P2255T)—connecting Kalirin GTPase output to neuronal morphology and brain structure.

    Evidence In vitro Rho GTPase pulldowns with variant constructs, primary neuron spine/dendrite morphology, mRNA stability assays, and human neuroimaging

    PMID:25224588 PMID:29241584 PMID:31801062

    Open questions at the time
    • Causal link between variants and clinical phenotypes not established by family genetics in this corpus
    • NLGN1 interaction's structural and functional detail limited

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many phosphorylation inputs, adhesion-molecule recruiters, and GTPase substrates are integrated to produce isoform- and context-specific outputs across tissues remains unresolved.
  • No unified structural model of full-length Kalirin autoregulation
  • Mechanism switching GEF1 between Rac1 and RhoG substrates undefined
  • How GEF2-RhoA vs GEF1-Rac1 outputs are balanced in long isoforms unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0008092 cytoskeletal protein binding 2 GO:0098772 molecular function regulator activity 2 GO:0008289 lipid binding 1
Localization
GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 3
Partners
ARF6CDH2GRIN2BNLGN1NOS2NTRK1PAMPSD-95
Complex memberships
N-cadherin/AF-6/Kalirin-7 adhesion complexPSD-95 postsynaptic density complexpSGK1-kalirin-PSD-95-pNR2B complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Kalirin-7, an isoform of the neuronal GDP/GTP exchange factor Kalirin, is highly enriched in the postsynaptic density fraction of rat cerebral cortex. Its Dbl homology-pleckstrin homology (DH-PH) domain catalyzes in vitro exchange of GDP for GTP on Rac1, and expression in fibroblasts induces lamellipodia and membrane ruffling indicative of Rac1 activation. Subcellular fractionation, in vitro GEF exchange assay, transient expression in fibroblasts The Journal of biological chemistry High 10692441
2001 Kalirin-7 interacts with PDZ domain-containing proteins, including PSD-95, co-localizing at synapses of cultured hippocampal neurons. Overexpression increases spine number and size; a PDZ-binding-deficient mutant mislocalizes to soma inducing aberrant filopodia; a GEF-inactive mutant reduces spine number below controls. Kalirin-7 regulates dendritic morphogenesis through Rac1 signaling to the actin cytoskeleton. Co-immunoprecipitation, heterologous expression, loss-of-function with GEF-dead and PDZ-binding mutants, primary cortical neuron imaging Neuron High 11182094
1999 Kalirin associates with iNOS both in vitro and in vivo (identified via yeast two-hybrid screen of hippocampal cDNA library and confirmed by co-association assays). Kalirin inhibits iNOS enzymatic activity by preventing formation of iNOS homodimers. Expression of exogenous Kalirin in pituitary cells dramatically reduces iNOS inhibition of ACTH secretion. Yeast two-hybrid screen, in vitro binding, iNOS activity assay, cell-based ACTH secretion assay The Journal of biological chemistry High 9873042
1999 Kalirin, identified through its interaction with the cytosolic domain of PAM (peptidylglycine alpha-amidating monooxygenase), alters cytoskeletal organization in CHO and AtT-20 cells expressing membrane PAM. Expression of Kalirin in AtT-20 cells restores stimulated (regulated) secretion of ACTH that is eliminated by membrane PAM overexpression alone, implicating Kalirin in regulated exocytosis. Co-expression in CHO and AtT-20 cells, cytoskeletal fractionation, ACTH secretion assay The Journal of biological chemistry Medium 9915831
2000 The Kalirin gene generates multiple isoforms through alternative 5'- and 3'-ends and an internal translational initiation site. Different isoforms (Kal7, Kal8, Kal9, Kal12) contain distinct C-terminal domains including a PDZ-binding motif, SH3 domain, second DH-PH GEF domain, and a putative Ser/Thr kinase. Form-specific antisera demonstrated different Kalirin isoforms localize to distinct subcellular compartments of cultured neurons. Molecular cloning, isoform-specific antisera, immunocytochemistry of cultured neurons, Western blot The Journal of biological chemistry High 10777487
2002 The first GEF domain of Kalirin (KalGEF1) initiates new axon outgrowth from sympathetic neurons via RhoG-mediated mechanisms. Kalirin antisense blocked axon extension; Kalirin overexpression induced axonal sprouting dependent on GEF1 activity. The KalGEF1 phenotype was mimicked by constitutively active RhoG and blocked by RhoG inhibitors; constitutively active Rac1, RhoA, and Cdc42 could not initiate new axons. Microinjection of sympathetic neurons with expression vectors and antisense oligonucleotides, dominant-negative and constitutively active Rho GTPase constructs, actin cytoskeleton imaging The Journal of neuroscience High 12177196
2005 Kalirin binds to and colocalizes with the TrkA neurotrophin receptor in neurons. Inhibition of Kalirin decreases NGF-induced TrkA autophosphorylation and process extension; Kalirin overexpression potentiates TrkA autophosphorylation and neurite outgrowth. Domain mapping showed that the N-terminal pleckstrin homology (PH) domain of Kalirin mediates the interaction with TrkA. Elevated Kalirin expression increases NGF-stimulated cellular activation of Rac, Mek, and CREB. Co-immunoprecipitation, antisense knockdown in PC12 cells, in vitro kinase assay, domain mapping, neurite outgrowth assay Molecular and cellular biology High 15923627
2007 NMDA receptor activation in pyramidal neurons causes CaMKII-dependent phosphorylation of Kalirin-7 at threonine 95 (T95), regulating its GEF activity and leading to Rac1 activation and rapid enlargement of existing dendritic spines. Kalirin-7 also interacts with AMPA receptors and controls their synaptic expression. Kalirin expression and spine localization are required for activity-dependent spine enlargement and enhancement of AMPAR-mediated synaptic transmission. Phospho-specific antibodies, CaMKII co-expression, dominant-negative constructs, spine imaging, electrophysiology, Co-IP in cortical neurons Neuron High 18031682
2007 GDP-bound Arf6 binds to the spectrin repeat region of Kalirin5 (demonstrated by binding assays and co-immunoprecipitation). Wild-type Arf6 expression recruits Kalirin to the plasma membrane and enhances Kalirin5-induced membrane ruffling and Rac1 activation; an activation-deficient Arf6 mutant (T27N) recruits Kalirin to membranes but inhibits Kalirin5-induced Rac1 activation and ruffling. Thus Arf6 regulates Rac activation through its GTPase cycle by controlling Kalirin membrane recruitment. In vitro binding assay, co-immunoprecipitation, cell morphology imaging, Rac1 activation (GTP-pull-down), dominant-negative and constitutively active Arf6 mutants BMC cell biology High 17640372
2007 Kalirin and its homolog Trio, acting through their N-terminal GEF1 domain and downstream substrates Rac1 and RhoG, regulate cargo secretion from immature secretory granules. GEF1 overexpression enhances constitutive-like secretion from immature granules, depleting secretory cargo; pharmacological inhibition of endogenous GEF1 activity decreases this secretion and accumulates mature product peptide. Overexpression and pharmacological inhibition of GEF1, secretion assays in neuroendocrine cells, subcellular colocalization with immature granule markers Molecular biology of the cell Medium 17881726
2008 Kalirin-7 knockout mice (lacking Kal7-specific terminal exon) display decreased hippocampal spine density, deficient hippocampal LTP, impaired passive avoidance learning, and reduced Cdk5 levels in purified PSDs. In vitro, Kal7(KO) neurons show decreased excitatory synapses only after 21 DIV, rescued by exogenous Kal7 expression. Compensatory increases in larger Kalirin isoforms occur. Conditional knockout mouse, Golgi impregnation, electron microscopy, electrophysiology (LTP), Western blot, behavioral testing, primary neuron culture The Journal of neuroscience High 19020030
2008 N-cadherin-dependent adhesion recruits the Rac1 GEF Kalirin-7 to synapses through the scaffolding protein AF-6/afadin. N-cadherin, AF-6, and Kalirin-7 colocalize at synapses and form multiprotein complexes in rat cortical pyramidal neurons. N-cadherin clustering promotes reciprocal recruitment of all three proteins, increases Rac1 at spines, and activates PAK. N-cadherin-dependent spine enlargement requires AF-6 and Kalirin-7 function. Co-immunoprecipitation, confocal colocalization, dominant-negative constructs, N-cadherin clustering assay, spine morphology imaging, PAK phosphorylation assay The Journal of neuroscience High 18550750
2008 Kalirin-7 is localized to the postsynaptic side of excitatory synapses (shaft and spine) of hippocampal interneurons, overlapping with PSD-95 and NMDA receptor subunit NR1. Reducing Kal7 decreases PSD-95-positive, bassoon-positive clusters on dendritic shafts of interneurons. Kal7 overexpression induces spine-like structures on aspiny interneurons that recruit excitatory (not inhibitory) presynaptic endings; this requires Kal7's PDZ binding motif. Immunofluorescence, shRNA knockdown, overexpression, confocal imaging in hippocampal neuron cultures The Journal of neuroscience High 18199770
2008 Cdk5 phosphorylates Kalirin-7 at Thr1590 (the only Cdk5 site in Kal7, immediately following the first GEF domain). Phosphorylation at Thr1590 slightly increases GEF activity and Kalirin-7 solubility. Ala1590 mutant retains GEF activity but cannot cause extension of cytoplasmic protrusions or normal spine formation; Asp1590 (phosphomimetic) mutant has slightly increased GEF activity and dominant-negative Cdk5 fails to block its protrusion-inducing effect. In vitro Cdk5 kinase assay, site-directed mutagenesis, PC12 cell morphology assay, GEF activity assay, dendritic spine imaging in cortical neurons Journal of cell science High 18628310
2008 The Sec14p domain of Kalirin binds PI(3,5)P2 and PI3P in vitro. The intact N-terminal Sec14p and spectrin-like repeat region together (not separated) are required for the unique cell morphology (compact round cells with cortical actin) induced by full-length Kal7, distinguishing it from Delta-Kal7 (which lacks these domains and induces lamellipodia). Kal7 and DeltaKal7 have equivalent GEF activity in vitro. Lipid-binding in vitro assay, truncation and deletion constructs expressed in cells lacking endogenous Kalirin, in vitro GEF assay, cell morphology imaging Experimental cell research Medium 18585704
2011 Kalirin-7 directly interacts with the NR2B subunit of the NMDA receptor via its pleckstrin homology (PH) domain binding to the juxtamembrane region of NR2B (preceding the cytosolic C-terminal domain). Kal7(KO) mice show decreased NR2B-dependent NMDA receptor currents in cortical pyramidal neurons and specific deficit in NR2B cell surface expression. Genotypic differences in conditioned place preference and passive avoidance in Kal7(KO) mice are abrogated by NR2B-specific antagonist treatment. In vitro pulldown/binding assay, domain mapping, whole-cell electrophysiology, surface biotinylation, behavioral pharmacology in KO mice The Journal of neuroscience High 21880917
2007 Kalirin-7 protein is significantly diminished at mRNA and protein levels in AD hippocampus. In cultured cells, Kalirin-7 associates with iNOS and down-regulates iNOS enzyme activity. The down-regulation maps to a highly conserved 33-amino-acid sequence (K617–H649) within Kalirin-7. Kalirin-7 complexes with iNOS less in AD hippocampus than controls, correlating with elevated iNOS activity in AD tissue. Co-immunoprecipitation, iNOS activity assay, deletion mapping, qRT-PCR, Western blot of human postmortem tissue Journal of Alzheimer's disease Medium 18057561
2011 Kalirin-7 was identified as a post-synaptic density signaling hub through phosphoproteomic analysis. Six PSD-localized kinases (CaMKII, PKA, PKC, Cdk5, and others) phosphorylate Kal7 at multiple sites. A site in the Sec14p domain is phosphorylated by CaMKII, PKA, and PKC in mouse brain but not in non-neuronal cells. Sites in the PH domain and GEF-PDZ linker region affect GEF activity when phosphorylated. LC-MS/MS phosphoproteomics of recombinant Kal7 and mouse brain Kal7, in vitro kinase assays, site-directed mutagenesis with GEF activity assay Journal of proteome research Medium 21488700
2013 Kalirin-9 is the predominant Kalirin isoform expressed in arterial smooth muscle cells (SMCs). In SMCs, Kalirin activates Rac1 (not RhoA). Reduced Kalirin function (heterozygous Kalrn deletion, Kalirin RNAi, or GEF1-specific inhibitor) diminishes Rac1-GTP levels, PAK autophosphorylation, and SMC migration. Kalrn(-/+) and SMC-specific Kalrn(-/+) mice show ~60% reduction in carotid endothelial denudation-induced neointimal hyperplasia. Heterozygous Kalrn knockout, RNAi, pharmacological GEF1 inhibition, Rac1-GTP pulldown, PAK autophosphorylation, migration assay, SMC-specific conditional knockout, in vivo carotid injury model Arteriosclerosis, thrombosis, and vascular biology High 23288169
2013 Kalirin-7 mediates cocaine-induced AMPA receptor (GluA1) surface upregulation and dendritic spine density increases in the nucleus accumbens (NAc). Kalirin-7 knockdown in NAc core via lentiviral shRNA abolished cocaine-withdrawal-associated AMPAR surface expression and spine density increases without blocking locomotor sensitization, but severely impaired incentive sensitization (cocaine self-administration). Downstream effectors Rac1 and PAK were activated in cocaine-sensitized rats with elevated Kal-7. Lentiviral shRNA knockdown in rat NAc, surface biotinylation (AMPAR), spine density analysis, locomotor and self-administration behavioral assays, Rac1-GTP pulldown, PAK phosphorylation The Journal of neuroscience High 23825406
2013 Spinal SGK1 phosphorylation following nerve injury interacts with and upregulates kalirin expression; kalirin then participates in a pSGK1–kalirin–PSD-95–pNR2B complex. Kalirin-specific siRNA reduces spinal nerve ligation-induced allodynia, NR2B phosphorylation, kalirin–PSD-95 coupling, and PSD-95–pNR2B coupling without affecting SGK1 phosphorylation. Spinal nerve ligation model in rats, siRNA knockdown, co-immunoprecipitation, co-immunofluorescence, behavioral allodynia testing, SGK1 pharmacological inhibition The Journal of neuroscience Medium 23516288
2014 Kalirin-9 and Kalirin-12 (isoforms expressed before synaptogenesis) are required for dendritic outgrowth and branching. shRNA-mediated knockdown of Kal9 or Kal12 in hippocampal cultures results in stunted dendritic outgrowth and branching without affecting axonal polarity. Pharmacological inhibition of the GEF1 domain (ITX3, Z62954982) replicates the phenotype. The active kinase domain unique to Kal12 increases neurite number and length; inactive kinase decreases growth. isoform-specific shRNA in hippocampal cultures, GEF1 pharmacological inhibitors, kinase domain overexpression, total Kalrn knockout mouse neurons, neurite morphology quantification Cerebral cortex High 25146373
2014 A rare coding variant D1338N in the catalytic domain of Kalirin-7 significantly diminishes its ability to catalyze Rac1 activation. Unlike wild-type Kalirin-7, Kalirin-7-D1338N fails to increase dendritic spine size and density in primary neurons. Subjects carrying this variant display reduced cortical volume in the superior temporal sulcus; mice with reduced kalirin expression show reduced neuropil volume in the rodent STS homologue. In vitro GEF assay (Rac1 activation), primary neuron spine morphology imaging, human neuroimaging, mouse neuropil volumetry Nature communications High 25224588
2016 CaMKII phosphorylation of Kalirin is sufficient to enhance synaptic AMPA receptor expression. Kalirin and its paralog Trio play critical and redundant roles in excitatory synapse structure and function. Preventing CaMKII signaling through Kalirin and Trio together prevents LTP induction, identifying Kalirin/Trio as key targets of CaMKII responsible for AMPAR up-regulation during LTP. Molecular constructs blocking CaMKII-Kalirin interaction, electrophysiology (LTP recording), spine imaging, AMPAR surface expression assay PNAS High 26858404
2016 Kalirin's GEF1 domain and Rac1 activation are required for BDNF-TrkB-stimulated neurite outgrowth and branching. Neurons from Kalrn knockout mice cannot activate Rac1 in response to BDNF. BDNF-stimulated neurite outgrowth was abolished by GEF1-specific inhibition or Kalrn shRNA and rescued in KO neurons by Kalirin-7 (GEF1 only, no GEF2). Prolonged TrkB activation and altered ERK/CREB/Akt signaling kinetics occur in Kalrn KO neurons. Kalrn knockout neurons, shRNA knockdown, GEF1-specific pharmacological inhibitor (ITX3), Rac1 GTP-loading assay, neurite outgrowth quantification, Kalirin-7 rescue expression Neuropharmacology High 27036892
2017 A schizophrenia-linked coding variant KALRN-P2255T in the second GEF domain of Kalirin-9 increases RhoA GTPase activation (but not Rac1 activation) in HEK293 cells. The variant reduces dendritic branching and spine size in primary cortical neurons. It also increases mRNA stability, elevating Kal9 protein levels, so that net RhoA activation is further enhanced. Together, these alterations negatively impact neuronal morphology. Kal9 overexpression in cortical neurons and HEK293 cells, Rho GTPase activation assays (RhoA and Rac1 pulldown), mRNA stability assay, dendritic morphology quantification Biological psychiatry High 29241584
2016 Kalirin acts as a GEF for Rac1 in skeletal muscle cells and is induced by FSTL-1 (follistatin-like 1). Kalirin knockdown by siRNA blocks FSTL-1-induced PAK1 phosphorylation, Rac1-GTP loading, GLUT4 translocation to the plasma membrane, and glucose uptake in L6 muscle cells. siRNA knockdown, Rac1-GTP pulldown, PAK1 phosphorylation, GLUT4 translocation assay, glucose uptake assay in L6 cells and primary myoblasts Cellular signalling Medium 27989699
2019 Unbiased proteomics identified the Kalirin-7 interactome, revealing association with synaptic adhesion molecules. Specifically, Kalirin-7 was identified as an interactor of neuroligin-1 (NLGN1), and NLGN1-dependent synaptic function is mediated through Kalirin-7 in an interaction-dependent manner. Unbiased proteomics (interactome), co-immunoprecipitation, electrophysiology to assess NLGN1-dependent synaptic function with Kalirin-7 interaction mutants Cell reports Medium 31801062
2013 Global Kalirin knockout (Kal-KO) mice exhibit reduced trabecular and cortical bone mass, decreased bone formation rate, decreased osteoblast number, and increased osteoclast surface. In vitro, Kal-KO osteoclasts show increased resorbing activity and differentiation; Kal-KO osteoblasts show decreased mineralization and decreased OPG secretion inversely correlated with ERK activity, suggesting Kalirin regulates RANKL/OPG balance. Global Kalrn knockout mice, micro-CT, histomorphometry, in vitro osteoclast and osteoblast differentiation assays, OPG/ERK biochemistry Bone Medium 24380811
2018 Spinal protein kinase Mζ (PKMζ) regulates AMPA receptor (GluA1) trafficking and spine plasticity via Kalirin-7 overexpression in remifentanil-induced postincisional hyperalgesia. PKMζ inhibitor reduced remifentanil-induced hyperalgesia, Kalirin-7 expression, and GluA1 trafficking. Kalirin-7 knockdown by shRNA impaired remifentanil-caused hyperalgesia, postsynaptic GluA1 insertion, and spine plasticity. Rat plantar incision model, shRNA knockdown, PKMζ inhibitor, whole-cell patch-clamp, AMPAR trafficking assay, spine morphology quantification Anesthesiology Medium 29578864
2012 KalSR(KO/KO) mice (lacking spectrin-repeat exon) show profound decreases in neuromuscular function and pre- and postsynaptic deficits at the neuromuscular junction, as well as alterations in sarcomere length. Pituitary secretion of growth hormone and prolactin were deficient. These deficits were less marked when Kalrn loss was restricted to the nervous system, implicating non-neuronal Kalirin expression in muscle and secretory function. Spectrin-repeat exon knockout mouse, rotarod and wire hang tests, NMJ morphology (electron microscopy), pituitary hormone secretion assay, neuron-specific conditional KO comparison BMC neuroscience Medium 23116210
2011 Loss of Kalirin-7 in KO mice results in impaired NMDA receptor-dependent LTP and long-term depression (LTD) in hippocampus, whereas NMDA receptor-independent LTP is normal, demonstrating that Kal7 is a selective and essential modulator of NMDA receptor-dependent synaptic plasticity. Kal7 knockout mice, electrophysiology (LTP and LTD induction with different protocols including NMDAR-dependent and -independent forms) BMC neuroscience High 22182308
2010 Estradiol increases Kalirin-7 protein levels at postsynaptic densities of excitatory synapses in hippocampal neurons via estrogen receptor α (ERα). ERα-selective (not ERβ-selective) agonist increases Kal7 and excitatory synapse number; when Kal7 is reduced by shRNA, estradiol can no longer increase synapse formation. GABAergic transmission blockade (bicuculline) robustly increases Kal7 expression. Ovariectomized rat model, selective ER agonists, shRNA knockdown, immunofluorescence, synapse density quantification Hippocampus Medium 20333733

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Tight junction pore and leak pathways: a dynamic duo. Annual review of physiology 684 20936941
2008 Contextual regulation of inflammation: a duet by transforming growth factor-beta and interleukin-10. Immunity 401 18400189
2007 Kalirin-7 controls activity-dependent structural and functional plasticity of dendritic spines. Neuron 313 18031682
2001 The neuronal Rho-GEF Kalirin-7 interacts with PDZ domain-containing proteins and regulates dendritic morphogenesis. Neuron 311 11182094
2018 The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood 294 30287523
2010 Stem cells and the niche: a dynamic duo. Cell stem cell 286 20144784
2011 Epithelial-mesenchymal transition and cancer stem cells: a dangerously dynamic duo in breast cancer progression. Breast cancer research : BCR 266 21392411
2021 GSK-3 and Tau: A Key Duet in Alzheimer's Disease. Cells 231 33804962
2020 Oncolytic Viruses and the Immune System: The Dynamic Duo. Molecular therapy. Methods & clinical development 200 32071927
2020 Microglia and Astrocytes in Disease: Dynamic Duo or Partners in Crime? Trends in immunology 193 32819809
2012 Adipose tissue and breast epithelial cells: a dangerous dynamic duo in breast cancer. Cancer letters 175 22643115
2018 DUET: A Phase 2 Study Evaluating the Efficacy and Safety of Sparsentan in Patients with FSGS. Journal of the American Society of Nephrology : JASN 153 30361325
2015 Regulation of plant growth and development by the GROWTH-REGULATING FACTOR and GRF-INTERACTING FACTOR duo. Journal of experimental botany 146 26160584
2014 The serotonin-BDNF duo: developmental implications for the vulnerability to psychopathology. Neuroscience and biobehavioral reviews 135 24704572
2008 Kalirin-7 is required for synaptic structure and function. The Journal of neuroscience : the official journal of the Society for Neuroscience 133 19020030
2007 The integrin-growth factor receptor duet. Journal of cellular physiology 132 17886260
2008 ERBB3/HER3 and ERBB2/HER2 duet in mammary development and breast cancer. Journal of mammary gland biology and neoplasia 121 18454306
2000 An isoform of kalirin, a brain-specific GDP/GTP exchange factor, is enriched in the postsynaptic density fraction. The Journal of biological chemistry 119 10692441
2013 Adult neural stem cells and their niche: a dynamic duo during homeostasis, regeneration, and aging. Current opinion in neurobiology 118 24090877
2019 N-hydroxypipecolic acid and salicylic acid: a metabolic duo for systemic acquired resistance. Current opinion in plant biology 106 30927665
2007 Peakwide mapping on chromosome 3q13 identifies the kalirin gene as a novel candidate gene for coronary artery disease. American journal of human genetics 100 17357071
1999 Kalirin inhibition of inducible nitric-oxide synthase. The Journal of biological chemistry 99 9873042
2010 Fractalkine/CX3CR1: why a single chemokine-receptor duo bears a major and unique therapeutic potential. Expert opinion on therapeutic targets 93 20055718
2000 Isoforms of kalirin, a neuronal Dbl family member, generated through use of different 5'- and 3'-ends along with an internal translational initiation site. The Journal of biological chemistry 86 10777487
2016 Kalirin and Trio proteins serve critical roles in excitatory synaptic transmission and LTP. Proceedings of the National Academy of Sciences of the United States of America 85 26858404
2008 Kalirin-7 is an essential component of both shaft and spine excitatory synapses in hippocampal interneurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 83 18199770
2008 Coordination of synaptic adhesion with dendritic spine remodeling by AF-6 and kalirin-7. The Journal of neuroscience : the official journal of the Society for Neuroscience 81 18550750
2002 Kalirin Dbl-homology guanine nucleotide exchange factor 1 domain initiates new axon outgrowths via RhoG-mediated mechanisms. The Journal of neuroscience : the official journal of the Society for Neuroscience 80 12177196
2021 Crosstalk between endoplasmic reticulum stress and oxidative stress: a dynamic duo in multiple myeloma. Cellular and molecular life sciences : CMLS 72 33599798
2017 Lipoprotein(a) and inflammation: A dangerous duet leading to endothelial loss of integrity. Pharmacological research 72 28185944
2014 Lysosomes and α-synuclein form a dangerous duet leading to neuronal cell death. Frontiers in neuroanatomy 71 25177278
2010 Resequencing and association analysis of the KALRN and EPHB1 genes and their contribution to schizophrenia susceptibility. Schizophrenia bulletin 70 21041834
2020 The Signaling Duo CXCL12 and CXCR4: Chemokine Fuel for Breast Cancer Tumorigenesis. Cancers 69 33096815
2018 Interplay between the unfolded protein response and reactive oxygen species: a dynamic duo. Journal of experimental botany 67 29415271
2007 Kalirin is under-expressed in Alzheimer's disease hippocampus. Journal of Alzheimer's disease : JAD 66 17851188
2002 Genomic organization and differential expression of Kalirin isoforms. Gene 62 11891045
2007 Arf6 recruits the Rac GEF Kalirin to the plasma membrane facilitating Rac activation. BMC cell biology 61 17640372
2011 Kalirin binds the NR2B subunit of the NMDA receptor, altering its synaptic localization and function. The Journal of neuroscience : the official journal of the Society for Neuroscience 60 21880917
2017 CDPKs and 14-3-3 Proteins: Emerging Duo in Signaling. Trends in plant science 58 28065409
2005 Kalirin: a dual Rho guanine nucleotide exchange factor that is so much more than the sum of its many parts. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry 57 15746383
1999 Kalirin, a multifunctional PAM COOH-terminal domain interactor protein, affects cytoskeletal organization and ACTH secretion from AtT-20 cells. The Journal of biological chemistry 57 9915831
2019 Neurons and Microglia; A Sickly-Sweet Duo in Diabetic Pain Neuropathy. Frontiers in neuroscience 53 30766472
2020 IL-23 and PSMA-targeted duo-CAR T cells in Prostate Cancer Eradication in a preclinical model. Journal of translational medicine 52 31937346
2012 Kalirin, a key player in synapse formation, is implicated in human diseases. Neural plasticity 51 22548195
2001 Expression of kalirin, a neuronal GDP/GTP exchange factor of the trio family, in the central nervous system of the adult rat. The Journal of comparative neurology 51 11116227
2010 Kalirin: a novel genetic risk factor for ischemic stroke. Human genetics 50 20107840
2019 α-Synuclein and Glia in Parkinson's Disease: A Beneficial or a Detrimental Duet for the Endo-Lysosomal System? Cellular and molecular neurobiology 44 30637614
2013 Kalirin promotes neointimal hyperplasia by activating Rac in smooth muscle cells. Arteriosclerosis, thrombosis, and vascular biology 43 23288169
2007 Under-expression of Kalirin-7 Increases iNOS activity in cultured cells and correlates to elevated iNOS activity in Alzheimer's disease hippocampus. Journal of Alzheimer's disease : JAD 43 18057561
2005 Critical role for Kalirin in nerve growth factor signaling through TrkA. Molecular and cellular biology 43 15923627
2016 The entangled ER-mitochondrial axis as a potential therapeutic strategy in neurodegeneration: A tangled duo unchained. Cell calcium 42 27212603
2014 The dynamic duo: combining NMR and small angle scattering in structural biology. Protein science : a publication of the Protein Society 42 24687405
2013 Kalirin-7 mediates cocaine-induced AMPA receptor and spine plasticity, enabling incentive sensitization. The Journal of neuroscience : the official journal of the Society for Neuroscience 42 23825406
2007 Kalirin/Trio Rho guanine nucleotide exchange factors regulate a novel step in secretory granule maturation. Molecular biology of the cell 42 17881726
2020 tRNA 2'-O-methylation by a duo of TRM7/FTSJ1 proteins modulates small RNA silencing in Drosophila. Nucleic acids research 39 31943105
2013 Spinal serum-inducible and glucocorticoid-inducible kinase 1 mediates neuropathic pain via kalirin and downstream PSD-95-dependent NR2B phosphorylation in rats. The Journal of neuroscience : the official journal of the Society for Neuroscience 39 23516288
2012 β-Amyloid 42/40 ratio and kalirin expression in Alzheimer disease with psychosis. Neurobiology of aging 39 22429885
2020 KALRN: A central regulator of synaptic function and synaptopathies. Gene 38 33189799
2014 Kalirin-9 and Kalirin-12 Play Essential Roles in Dendritic Outgrowth and Branching. Cerebral cortex (New York, N.Y. : 1991) 38 25146373
2012 Kalrn plays key roles within and outside of the nervous system. BMC neuroscience 38 23116210
2020 Multi-peptide presentation and hydrogel mechanics jointly enhance therapeutic duo-potential of entrapped stromal cells. Biomaterials 37 32244091
2011 Kalirin-7 is necessary for normal NMDA receptor-dependent synaptic plasticity. BMC neuroscience 37 22182308
2010 Kalirin-7, an important component of excitatory synapses, is regulated by estradiol in hippocampal neurons. Hippocampus 36 20333733
2008 Regulation of Kalirin by Cdk5. Journal of cell science 35 18628310
2004 Hypertension and microalbuminuria: the new detrimental duo. Blood pressure 35 15581333
2011 Kalrn promoter usage and isoform expression respond to chronic cocaine exposure. BMC neuroscience 33 21329509
2018 Spinal Protein Kinase Mζ Regulates α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor Trafficking and Dendritic Spine Plasticity via Kalirin-7 in the Pathogenesis of Remifentanil-induced Postincisional Hyperalgesia in Rats. Anesthesiology 32 29578864
2017 A Schizophrenia-Linked KALRN Coding Variant Alters Neuron Morphology, Protein Function, and Transcript Stability. Biological psychiatry 32 29241584
2014 A sequence variant in human KALRN impairs protein function and coincides with reduced cortical thickness. Nature communications 31 25224588
2023 Neutrophil Extracellular Traps and NLRP3 Inflammasome: A Disturbing Duo in Atherosclerosis, Inflammation and Atherothrombosis. Vaccines 30 36851139
2017 Fractalkine and placental growth factor: A duet of inflammation and angiogenesis in cardiovascular disorders. Cytokine & growth factor reviews 30 29290570
2008 Autonomous functions for the Sec14p/spectrin-repeat region of Kalirin. Experimental cell research 30 18585704
2016 Kalirin is required for BDNF-TrkB stimulated neurite outgrowth and branching. Neuropharmacology 29 27036892
2015 The Dynamic Duo: Niche/Stem Cell Interdependency. Stem cell reports 29 26028534
2013 Pulmonary hypertension and idiopathic pulmonary fibrosis: a dastardly duo. The American journal of the medical sciences 29 23313949
2021 The Duo of Osteogenic and Angiogenic Differentiation in ADSC-Derived Spheroids. Frontiers in cell and developmental biology 28 33898413
2018 Cancer Chemoradiotherapy Duo: Nano-Enabled Targeting of DNA Lesion Formation and DNA Damage Response. ACS applied materials & interfaces 27 30255704
2008 Kalirin-7, a protein enriched in postsynaptic density, is involved in ischemic signal transduction. Neurochemical research 27 18338255
2024 Immunogenicity of third dose COVID-19 vaccine strategies in patients who are immunocompromised with suboptimal immunity following two doses (OCTAVE-DUO): an open-label, multicentre, randomised, controlled, phase 3 trial. The Lancet. Rheumatology 26 38734019
2019 Synaptic Kalirin-7 and Trio Interactomes Reveal a GEF Protein-Dependent Neuroligin-1 Mechanism of Action. Cell reports 26 31801062
2016 Kalirin, a GEF for Rac1, plays an important role in FSTL-1-mediated glucose uptake in skeletal muscle cells. Cellular signalling 25 27989699
2013 The Rho-GEF Kalirin regulates bone mass and the function of osteoblasts and osteoclasts. Bone 25 24380811
2001 Kalirin, a GDP/GTP exchange factor of the Dbl family, is localized to nerve, muscle, and endocrine tissue during embryonic rat development. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 25 11410608
2012 Chromosome instability and deregulated proliferation: an unavoidable duo. Cellular and molecular life sciences : CMLS 24 22223110
2004 Kalirin expression is regulated by multiple promoters. Journal of molecular neuroscience : MN 24 14742910
2020 KALRN mutations promote antitumor immunity and immunotherapy response in cancer. Journal for immunotherapy of cancer 23 33037113
2024 Overlaps and divergences between tauopathies and synucleinopathies: a duet of neurodegeneration. Translational neurodegeneration 22 38528629
2023 Quercetin and AMPK: A Dynamic Duo in Alleviating MG-Induced Inflammation via the AMPK/SIRT1/NF-κB Pathway. Molecules (Basel, Switzerland) 22 37959807
2011 Identification of kalirin-7 as a potential post-synaptic density signaling hub. Journal of proteome research 21 21488700
2019 The Role of (Modified) Lipoproteins in Vascular Function: A Duet Between Monocytes and the Endothelium. Current medicinal chemistry 20 29546830
2014 A dangerous duo in adipose tissue: high-mobility group box 1 protein and macrophages. The Yale journal of biology and medicine 19 24910558
2010 CLIC4 and Schnurri-2: a dynamic duo in TGF-beta signaling with broader implications in cellular homeostasis and disease. Nucleus (Austin, Tex.) 19 20617112
2022 Dangerous dynamic duo: Lactic acid and PD-1 blockade. Cancer cell 18 35093211
2023 Restoration of energy homeostasis under oxidative stress: Duo synergistic AMPK pathways regulating arginine kinases. PLoS genetics 17 37535699
2022 Effect of Nystatin on Candida albicans - Streptococcus mutans duo-species biofilms. Archives of oral biology 17 36395564
2020 Spinal NR2B phosphorylation at Tyr1472 regulates IRE(-)DMT1-mediated iron accumulation and spine morphogenesis via kalirin-7 in tibial fracture-associated postoperative pain after orthopedic surgery in female mice. Regional anesthesia and pain medicine 17 33443215
2018 A Talented Duo: IFIT1 and IFIT3 Patrol Viral RNA Caps. Immunity 17 29562196
2017 A Novel Long Non-coding RNA, durga Modulates Dendrite Density and Expression of kalirin in Zebrafish. Frontiers in molecular neuroscience 17 28442991
2016 Association of KALRN, ADIPOQ, and FTO gene polymorphism in type 2 diabetic patients with coronary artery disease: possible predisposing markers. Coronary artery disease 17 27218147
2016 Exome sequencing discloses KALRN homozygous variant as likely cause of intellectual disability and short stature in a consanguineous pedigree. Human genomics 17 27421267

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