Affinage

APLP2

Amyloid beta precursor like protein 2 · UniProt Q06481

Length
763 aa
Mass
87.0 kDa
Annotated
2026-06-09
68 papers in source corpus 38 papers cited in narrative 37 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

APLP2 is a type I transmembrane glycoprotein of the APP family that functions in synaptic transmission, neural development, and diverse cell-surface signaling processes, acting largely redundantly with APP (PMID:9461064). Like APP, APLP2 undergoes sequential proteolytic processing by alpha- and beta-secretases—with BACE modulating its cleavage in vivo (PMID:14970212, PMID:15080893)—and by the metalloproteinases ADAM10 and TACE to shed a soluble neurotrophic ectodomain (PMID:16279945, PMID:9923612), followed by gamma-/epsilon-secretase cleavage that liberates an intracellular domain (AICD2) (PMID:14970212, PMID:15080893); ectodomain shedding is controlled by MAPK/PKC-epsilon signaling (PMID:11443060). APLP2 and APP are functionally redundant during postnatal development, with double knockout causing early lethality (PMID:9461064), and together they sustain neuromuscular and central synaptic transmission: they bind the presynaptic release machinery via the N-terminus of their intracellular domains in a complex with Mint2/Munc18 to support quantal glutamate release (PMID:21522131, PMID:26551565), interact with NMDA receptor GluN1 to promote receptor surface expression (PMID:25683482), control VGLUT2 expression through the intracellular domain (PMID:18535156), and maintain neuronal Ca2+ homeostasis through SERCA-ATPase and Stim1/2 (PMID:34172567). APP family loss in GABAergic interneurons impairs LTP, spatial learning, and excitation/inhibition balance (PMID:32219307), and APLP2 at GABAergic terminals engages microglial CD11b in trans to restrain pain sensitization (PMID:36442651). APLP2 forms homo- and heterotypic cis complexes with APP, reducing Abeta42 generation (PMID:19126676), and is subject to post-translational regulation including chondroitin-sulfate modification at Ser-614 governed by alternative splicing (PMID:8071334, PMID:7622456) and Bat3-mediated stabilization against proteasomal degradation (PMID:22641691). APLP2 also modulates copper homeostasis (PMID:10526140), inhibits plasma clotting through its Kunitz-type protease inhibitor domain (PMID:19403832), and regulates glypican-1 heparan sulfate catabolism (PMID:15677459). Outside the nervous system, APLP2 promotes pancreatic cancer cell migration via actin reorganization (PMID:25576918), inhibits TGF-beta signaling by destabilizing TGFBR2 through competition with Hsp90 (PMID:37479189), suppresses MHC class I surface expression (PMID:24353913), and its AICD2 fragment activates NF-kB via p65 to drive antimicrobial macrophage responses (PMID:37844466); endothelial APLP2sα promotes postischemic angiogenesis through allosteric activation of the KIT receptor (PMID:42172320).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1994 High

    Established the first defined post-translational modification of APLP2, pinpointing a single chondroitin-sulfate attachment site that would distinguish APLP2 proteoglycan forms.

    Evidence Site-directed mutagenesis (Ser614Ala) and chondroitinase digestion in transfected CHO/COS cells

    PMID:8071334

    Open questions at the time
    • Functional consequence of CS-GAG modification not addressed
    • Does not connect modification to a downstream signaling or trafficking event
  2. 1995 High

    Showed that CS-GAG modification of APLP2 is switched by alternative splicing, defining a regulated mechanism for generating proteoglycan versus non-proteoglycan APLP2 isoforms.

    Evidence Isoform expression and chondroitinase analysis of APLP2-751 vs APLP2-763 in transfected cells

    PMID:7622456

    Open questions at the time
    • Physiological role of each isoform unresolved
    • Tissue-specific splicing regulation not mapped
  3. 1997 High

    Resolved whether APLP2 has an essential individual function by revealing functional redundancy with APP, a foundational genetic insight for the family.

    Evidence APLP2 single KO and APP/APLP2 double KO mouse phenotyping

    PMID:9461064

    Open questions at the time
    • Molecular basis of redundancy not defined
    • Specific lethal process in double KO not identified
  4. 1999 Medium

    Connected APLP2 to metal handling and to neurotrophic ectodomain activity, broadening its role beyond development.

    Evidence Tissue copper measurement in KO mice and neurite outgrowth assay with recombinant sAPLP2

    PMID:10526140 PMID:9923612

    Open questions at the time
    • Direct copper-binding mechanism of APLP2 not shown
    • Receptor mediating sAPLP2 neurite outgrowth unknown
  5. 2005 High

    Defined the proteolytic machinery acting on APLP2, establishing that it is processed analogously to APP by BACE, ADAM10/TACE, and gamma/epsilon-secretases.

    Evidence Tagged constructs in neuroblastoma cells, secretase overexpression, pharmacological inhibition, and BACE/ADAM10 KO and transgenic mice

    PMID:14970212 PMID:15080893 PMID:16279945

    Open questions at the time
    • Physiological signaling output of each fragment not fully resolved
    • Regulation of cleavage site choice in vivo not detailed
  6. 2005 High

    Distinguished APP from APLP2 in heparan sulfate metabolism, showing APLP2 regulates copper/NO-catalyzed glypican-1 autodegradation.

    Evidence Cell-free copper-form assays, imaging, and KO neurons and fibroblasts

    PMID:15677459

    Open questions at the time
    • In vivo relevance of glypican-1 regulation unclear
    • Link between this activity and synaptic/developmental roles not made
  7. 2009 High

    Demonstrated APLP2 forms cis homo- and heteromeric complexes with APP and exerts anticoagulant activity, two distinct mechanistic roles for the protein.

    Evidence FRET, Co-IP, deletion mutants for complex formation; recombinant KPI assays and thrombosis/hemorrhage KO models for anticoagulation

    PMID:19126676 PMID:19403832

    Open questions at the time
    • Stoichiometry and physiological abundance of heteromers unknown
    • Protease target of the KPI domain in vivo not identified
  8. 2011 High

    Identified the synaptic mechanism by which APLP2/APP support neurotransmission, linking the intracellular domain to the Mint2/Munc18 release machinery.

    Evidence APPsalpha knock-in on APLP2-null background, electrophysiology, Co-IP of APP/Mint2/Munc18 complex

    PMID:21522131

    Open questions at the time
    • Whether APLP2 intracellular domain binds the complex identically to APP not separated
    • Direct versus adaptor-mediated binding not dissected
  9. 2015 High

    Refined the synaptic mechanism by mapping the presynaptic-binding region of the intracellular domain and demonstrating its requirement for glutamate release, while linking APLP2 to NMDA receptor surface expression.

    Evidence Domain mapping with JCasp interference peptide and glutamate release in hippocampal slices; Co-IP and surface assays with GluN1/GluN2

    PMID:25683482 PMID:26551565

    Open questions at the time
    • Direct binding partner within the release machinery not fully defined
    • NMDA receptor surface effect not tested in vivo for APLP2 specifically
  10. 2021 High

    Established a molecular pathway for APP/APLP2 in synaptic plasticity through neuronal calcium homeostasis and identified the secreted ectodomain as the functional rescue species.

    Evidence Conditional double KO neurons, Ca2+ imaging, SERCA/Stim1/2 analysis, AAV-APPsalpha rescue and LTP

    PMID:34172567

    Open questions at the time
    • Receptor transducing the chronic APPsalpha rescue signal not identified
    • APLP2-specific contribution versus APP not separated
  11. 2023 Medium

    Extended APLP2 signaling beyond the nervous system, defining AICD2-driven NF-kB activation and APLP2-mediated TGFBR2 destabilization as distinct effector mechanisms.

    Evidence Co-IP of AICD2 with p65 and NF-kB reporters in macrophages; Co-IP with TGFBR2/Hsp90 plus ubiquitination and gain/loss-of-function for TGF-beta signaling

    PMID:37479189 PMID:37844466

    Open questions at the time
    • Single-lab Co-IP evidence without reciprocal structural validation
    • Whether AICD2 directly binds p65 or acts via cofactors unresolved
  12. 2026 Medium

    Identified a receptor target for the APLP2 ectodomain, showing endothelial APLP2sα drives angiogenesis by allosteric modulation of KIT.

    Evidence Endothelial-specific KO mice, myocardial infarction model, secretase assays, KIT signaling, AAV-APPsalpha rescue

    PMID:42172320

    Open questions at the time
    • Direct biophysical binding of APLP2sα to KIT not shown
    • Whether neuronal ectodomain roles also use KIT not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How APLP2's many context-specific activities (synaptic, vascular, immune, oncogenic) are coordinated by a common proteolytic and trafficking logic, and which receptors transduce the soluble ectodomain in each setting, remains unresolved.
  • No unifying receptor for sAPLP2 across tissues established
  • APLP2-specific versus APP-shared functions not systematically separated
  • Structural basis of intracellular-domain partner selection unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 2 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 2 GO:0005886 plasma membrane 2 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 2
Partners
APPBAT3CD11BGLUN1MINT2MUNC18PCSK9TGFBR2
Complex memberships
APP-APLP2 cis heteromerAPP/Mint2/Munc18 presynaptic complex

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 APLP2 contains a cytoplasmic domain predicted to couple with the GTP-binding protein G(o), suggesting it may function as a cell surface activator of this G protein, similar to APP. Sequence analysis and structural prediction of cloned APLP2 gene Nature genetics Low 8220435
1994 APLP2 is modified by chondroitin sulfate (CS) glycosaminoglycan addition at a single site (Ser-614); a serine-to-alanine substitution at position 614 abolishes CS GAG modification, identifying this as the sole modification site. Stable transfection of CHO and COS-1 cells, chondroitinase AC digestion, site-directed mutagenesis The Journal of biological chemistry High 8071334
1995 CS GAG modification of APLP2 is regulated by alternative splicing: the APLP2-763 isoform, containing a 12 amino acid insertion N-terminal to Ser-614, is not modified by CS GAG, whereas APLP2-751 is. Similarly, APP isoforms lacking exon 15 sequences (L-APP) are CS GAG-modified, whereas those containing exon 15 are not. Expression of alternatively spliced isoforms in transfected cells, chondroitinase digestion, biochemical analysis The Journal of biological chemistry High 7622456
1995 APLP2 is enriched in postsynaptic compartments in cortex and hippocampus, and is abundant in olfactory sensory axons and axon terminals in glomeruli; CS GAG-modified APLP2 forms are enriched in olfactory epithelium and accumulate in the olfactory bulb, consistent with a role in axonal pathfinding and/or synaptogenesis. Immunocytochemistry with APLP2-specific antibodies, confocal microscopy, biochemical fractionation The Journal of neuroscience Medium 7472397
1997 APLP2 and APP are functionally redundant in vivo: APLP2 single KO mice are viable and fertile, but APP/APLP2 double KO mice exhibit ~80% early postnatal lethality, demonstrating that APLP2 and APP can substitute for each other functionally. Generation of APLP2 KO and APP/APLP2 double KO mice, phenotypic analysis Neurobiology of aging High 9461064
1998 APLP2 is required for correct genomic segregation in dividing cells: homozygous APLP2 deletion embryos arrest before the blastocyst stage with abnormal nuclear DNA content (departing from normal 2-4C values), and antisense suppression in fibroblasts produces daughter cells with abnormal DNA contents, indicating a role in mitotic genome segregation. Generation of large genomic deletion in mice, DNA content analysis, antisense RNA transfection in fibroblasts The EMBO journal Medium 9707424
1999 APP and APLP2 expression specifically modulates copper homeostasis in the liver and cerebral cortex; APP(-/-) and APLP2(-/-) mice show significantly elevated copper levels in cerebral cortex (40% and 16%, respectively) and liver (80% and 36%, respectively) compared to wild-type, with no significant differences in zinc or iron. Atomic absorption spectrophotometry of tissue from APP(-/-) and APLP2(-/-) knockout mice Brain research Medium 10526140
1999 Recombinant soluble APLP2 ectodomain (sAPLP2) promotes neurite outgrowth in chick sympathetic neurons with activity similar to APP isoforms sAPP695 and sAPP751. Expression of recombinant sAPLP2 in Pichia pastoris, neurite outgrowth assay on chick sympathetic neurons FEBS letters Medium 9923612
2001 APLP2 ectodomain shedding in corneal epithelial cells is regulated by MAP kinase (MAPK): basal shedding and that induced by PKC activator PMA or EGF is blocked by the MEK inhibitor U-0126; PKC-epsilon is involved in PMA- and EGF-induced shedding. Western blotting, flow cytometry, indirect immunofluorescence, pharmacological inhibition with U-0126 and PKC-epsilon inhibitor in human corneal epithelial cells American journal of physiology. Cell physiology Medium 11443060
2004 APLP2 is processed by alpha-, beta-, gamma-, and epsilon-secretase-like cleavages, producing C-terminal fragments, intracellular domains (AICD-like), and p3-like and Abeta-like fragments. BACE (beta-secretase) modulates APLP2 processing in vivo: APLP2 proteolytic products are decreased in BACE KO mice and increased in BACE transgenic mice; overexpression of BACE in cultured cells increases APLP2 processing. C-terminally tagged constructs in stably transfected SH-SY5Y cells, pharmacological inhibitors, BACE KO and transgenic mice, Western blot The Journal of biological chemistry; Molecular and cellular neurosciences High 14970212 15080893
2005 APLP2 is a substrate for the disintegrin-metalloproteinases ADAM10 and TACE (ADAM17): overexpression of either proteinase in HEK293 cells increases shedding of soluble APLP2 severalfold; ADAM10-preferring inhibitor most strongly reduces shedding in neuroblastoma cells; ADAM10 transgenic mice show significantly increased soluble APLP2 and its C-terminal fragments. Overexpression of ADAM10/TACE in HEK293 cells, pharmacological inhibition in neuroblastoma cells, ADAM10 transgenic mice, Western blot The FEBS journal High 16279945
2005 APP and APLP2 modulate Cu/Zn-nitric oxide-catalyzed degradation of glypican-1 heparan sulfate: in cell-free experiments, the Cu(I) form of APP and both Cu(II) and Cu(I) forms of APLP2 inhibit glypican-1 autodegradation; in primary cortical neurons from APP or APLP2 KO mice, nitric oxide-catalyzed heparan sulfate degradation is increased; in APLP2 KO (but not APP KO) fibroblasts, heparan sulfate degradation is also increased. Cell-free biochemical experiments, confocal immunofluorescence microscopy, flow cytometry, primary neurons and fibroblasts from KO mice The Journal of biological chemistry High 15677459
2006 PAT1a binds directly to APP, APLP1, and APLP2 in vivo and co-localizes with them in trans-Golgi network vesicles or endosomes in primary neurons; PAT1a interacts with the basolateral sorting signal of APP/APLPs; overexpression or RNAi knockdown of PAT1a modulates APP/APLP surface levels and promotes their processing, resulting in increased Abeta secretion. Co-immunoprecipitation, co-localization in primary neurons, overexpression and RNAi knockdown, cell surface assays The Journal of biological chemistry High 17050537
2006 APP and APLP2 are required for keratinocyte proliferation, migration, and adhesion: keratinocytes from APP/APLP2 double KO mice show ~40% reduced proliferation in vivo and in vitro, reduced migration velocity, and compromised cell-substrate adhesion; double KO keratinocytes die within the first week of culture. Proliferation deficits are rescued by exogenous recombinant sAPPalpha. KO mouse keratinocyte isolation, proliferation assays, migration assays, rescue with recombinant sAPPalpha Experimental cell research Medium 16584729
2008 APP and APLP2 are required for normal glucose and insulin homeostasis: APP/APLP2 double KO mice show 66% lower plasma glucose and hyperinsulinemia compared to wild-type at postnatal day, identifying a role for APP/APLP2 in modulating plasma insulin and glucose concentrations. Plasma analysis from double KO mice at E17 and postnatal, glucose and insulin measurements The Journal of pathology Medium 18393365
2008 Loss of APP and APLP2 in neurons leads to decreased expression of vesicular glutamate transporter 2 (VGLUT2) and reduced glutamate uptake/release; blocking gamma-secretase in wild-type neurons similarly decreases VGLUT2; VGLUT2 levels can be restored in double KO neurons by a construct encoding the C-terminal intracellular domain of APP, indicating the intracellular domain mediates this function. ESC-derived neurons from APP/APLP2 double KO mice, VGLUT2 mRNA and protein quantification, gamma-secretase inhibition, APP intracellular domain rescue construct, electrophysiology in hippocampal slices Stem cells High 18535156
2009 APLP2 and APP share overlapping anticoagulant functions: recombinant KPI domains of both proteins inhibit plasma clotting in vitro; APLP2(-/-) and APP(-/-) mice both exhibit significantly shorter times to carotid artery occlusion and produce smaller hematomas in intracerebral hemorrhage models, indicating a prothrombotic phenotype when APLP2 is absent. Recombinant KPI domain inhibition assays, carotid artery thrombosis model, intracerebral hemorrhage model in KO mice The Journal of neuroscience High 19403832
2009 Live cell imaging shows that APLP2 localizes predominantly to intracellular compartments (unlike APLP1 which is mainly at the cell surface); APLP2 forms homo- and heterotypic cis interactions with APP family members detectable by FRET and co-immunoprecipitation; interactions occur in a modular mode with the N-terminal half of the ectodomain crucial for APP-APLP2 interactions; coexpression of APP with APLP2 leads to diminished Abeta42 generation, attributed to heteromeric complex formation. Live cell imaging, FRET, co-immunoprecipitation, deletion mutant analysis Journal of cell science High 19126676
2011 APLP2 and APP are synergistically required for neuromuscular transmission: APPsα-DM mice (expressing only secreted APPsα on APLP2-null background) show impaired neuromuscular transmission with reductions in quantal content, readily releasable pool, and vesicle release sustainability, resulting in muscular weakness; defects are associated with loss of an APP/Mint2/Munc18 complex; APPsα-DM muscle shows fragmented postsynaptic specializations. APPsα knock-in mice crossed onto APLP2-deficient background, electrophysiology, co-immunoprecipitation of APP/Mint2/Munc18 complex, morphological analysis The EMBO journal High 21522131
2011 APLP2 mediates signaling via formation of transcriptionally active triple protein complexes with adaptor protein Mint3 and transcriptional co-activators Taz and Yap; complex formation is regulated by gamma-secretase cleavage of APLP2; Mint1 (instead of Mint3) prevents nuclear translocation of the complex. Co-immunoprecipitation, transactivation assays, gamma-secretase inhibition Journal of Alzheimer's disease Medium 21178287
2013 APLP2 is required for proper cell cycle exit of cortical neuronal progenitors: silencing APLP2 in vivo in an APP/APLP1 double KO background causes cortical progenitors to remain undifferentiated longer with a higher number of mitotic cells; neuron-specific APLP2 downregulation does not affect the speed or position of migrating excitatory cortical neurons. shRNA-mediated APLP2 silencing in vivo in APP/APLP1 double KO mice, analysis of mitotic cells and neuronal differentiation Journal of cell science Medium 23345401
2013 PCSK9 interacts directly with APLP2 (but not APP) via its C-terminal domain in a pH-dependent manner; APLP2 (but not APP) mediates postendocytic delivery of PCSK9 to lysosomes, making it required for PCSK9 function in LDLR degradation. Co-immunoprecipitation, pH-dependent binding assays, cell-based PCSK9 trafficking assays The Journal of biological chemistry Medium 23430252
2013 APLP2 co-immunoprecipitates with MHC class I molecules in Ewing's sarcoma cells; irradiation redistributes APLP2 and MHC class I on the cell surface; APLP2 siRNA knockdown increases MHC class I surface expression, indicating APLP2 inhibits MHC class I surface expression. Co-immunoprecipitation, flow cytometry, siRNA knockdown Oncoimmunology Medium 24353913
2014 APP/APLP2 expression is required for transport of anhydromannose-containing heparan sulfate from endosomes to the nucleus and subsequently to autophagosomes: nuclear HS translocation is seen in WT but not APP(-/-) or APLP2(-/-) MEFs; transfection of APP restores nuclear import; beta- and gamma-secretase inhibitors block nuclear transport, implicating APP/APLP2 degradation products. Deconvolution immunofluorescence microscopy with anMan-specific antibody, 35S-labeling, secretase inhibitor treatment, APP(-/-) and APLP2(-/-) MEFs, transfection rescue The Journal of biological chemistry Medium 24898256
2015 APP and APLP2 interact with the synaptic release machinery via the NH2-terminal region of their intracellular domains; a peptide (JCasp) naturally produced by gamma-secretase/caspase double-cut of APP interferes with APP-presynaptic protein interactions and reduces glutamate release in hippocampal slices from wild-type but not APP-deficient mice; deletion of APP and APLP2 produces synaptic deficits similar to those caused by JCasp. Mapping of binding domain, JCasp cell-penetrating peptide treatment, glutamate release assay in acute hippocampal slices, APP/APLP2 double KO comparison eLife High 26551565
2015 APLP2 co-immunoprecipitates with NMDA receptor subunits GluN1/GluN2A and GluN1/GluN2B in mammalian cells and in adult brain; interaction is via GluN1 subunit; APLP2 enhances GluN1/GluN2A and GluN1/GluN2B cell surface expression. Co-immunoprecipitation from transfected cells and adult brain lysates, cell surface expression assays Journal of neurochemistry Medium 25683482
2015 APLP2 knockdown in pancreatic cancer cells reduces migration and invasion, decreases cortical actin, and increases intracellular actin filaments; APLP2 knockdown reduces tumor weight and metastasis in orthotopic mouse models, indicating APLP2 affects actin cytoskeleton organization to promote cancer cell migration. Inducible shRNA knockdown, migration/invasion assays, actin cytoskeleton imaging, orthotopic tumor transplantation in mice Oncotarget Medium 25576918
2015 Aplp2 knockout mice develop high degrees of hyperopia and exhibit dose-dependent reduction in susceptibility to environmentally induced myopia; the phenotype is associated with reduced contrast sensitivity and changes in electrophysiological properties of retinal amacrine cells, which express Aplp2. Aplp2 KO mice, refraction measurement, contrast sensitivity testing, retinal electrophysiology PLoS genetics Medium 26313004
2017 APP, APLP2, and LRP1 all interact with PCSK9, but none is required for PCSK9-mediated LDLR degradation in vivo: infusion of PCSK9 into App(-/-), Aplp2(-/-), Aplp2-depleted App(-/-), or liver-specific Lrp1(-/-) mice results in similar reductions in hepatic LDLR as in wild-type mice. Co-immunoprecipitation, PCSK9 infusion into multiple KO mouse lines, hepatic LDLR measurement Biochimica et biophysica acta Medium 28495363
2018 APLP2 promotes cell migration in Drosophila via JNK signaling: ectopic APLP2 expression activates JNK by phosphorylation, which triggers MMP1 expression required for basement membrane degradation and cell migration; loss of JNK suppresses APLP2-induced migration while gain of JNK enhances it. Drosophila ectopic expression, JNK loss- and gain-of-function epistasis, phosphorylation assays, MMP1 expression analysis BioMed research international Medium 30155482
2020 Loss of APP and APLP2 specifically in GABAergic forebrain neurons (DlxCre cDKO) impairs synaptic plasticity (LTP), spatial learning, and excitation/inhibition balance; reduced action potential firing of CA1 pyramidal cells and altered excitatory/inhibitory synaptic currents indicate APP family proteins in inhibitory interneurons maintain functional network activity. Conditional double KO using DlxCre, electrophysiology (LTP, synaptic currents), behavioral testing, morphological analysis Cerebral cortex High 32219307
2021 APP and APLP2 together control neuronal Ca2+ homeostasis; loss of both (but not APLP2 alone) impairs Ca2+ handling, ER Ca2+ store refill, and synaptic plasticity via altered SERCA-ATPase function and expression of store-operated Ca2+ channel-associated proteins Stim1 and Stim2; long-term AAV-mediated expression of APPsα (but not acute application) restores Ca2+ homeostasis and LTP in APP/APLP2 cDKO neurons. APP/APLP2 conditional double KO neurons, Ca2+ imaging, SERCA-ATPase and Stim1/Stim2 expression analysis, AAV-mediated APPsα rescue, LTP recordings PNAS High 34172567
2022 Peripheral nerve injury reduces APLP2 expression specifically in spinal GABAergic inhibitory interneurons; targeted knockdown of APLP2 in GAD2-positive neurons evokes pain hypersensitivity via microglial activation; APLP2 at GABAergic terminals interacts with microglia-specific integrin CD11b in a trans-cellular manner, and disruption of this interaction leads to microglia-dependent pain sensitization. Nerve injury model, conditional APLP2 knockdown in GAD2-Cre mice, co-immunoprecipitation of APLP2 with CD11b, pain behavioral testing, microglial activation assays Neuropharmacology Medium 36442651
2023 APLP2 (as YWK-II/APLP2) inhibits TGF-β signaling by promoting degradation of TGFBR2: APLP2 associates with TGFBR2 in a TGF-β activity-dependent manner, binds Hsp90 to interfere with the TGFBR2-Hsp90 stabilizing interaction, and leads to enhanced ubiquitination and degradation of TGFBR2; knockdown of APLP2 increases TGFBR2 protein level and sensitizes cells to TGF-β, while overexpression destabilizes TGFBR2. Co-immunoprecipitation, knockdown and overexpression experiments, ubiquitination assays, TGF-β signaling readouts Biochimica et biophysica acta. Molecular cell research Medium 37479189
2023 The APLP2 cleaved intracellular domain product (AICD2), generated by gamma-secretase, translocates to the nucleus where it interacts with p65, enhancing NF-κB transcriptional activity to upregulate IL-1β and iNOS expression; APLP2 mutation/knockdown reduces macrophage-mediated killing of Mycobacterium tuberculosis. Aplp2 mutant/knockdown macrophages, nuclear translocation assay, co-immunoprecipitation with p65, NF-κB reporter assays, iNOS and IL-1β measurement, M.tb infection in KO mice International immunopharmacology Medium 37844466
2012 Bat3 interacts with APLP2 (YWK-II/APLP2) and enhances its stability by reducing ubiquitylation and proteasomal degradation; the proline-rich domain of Bat3 is required for binding to APLP2; nuclear export of Bat3 under apoptotic stimulation elevates APLP2 protein levels. Co-immunoprecipitation, domain deletion analysis, ubiquitylation assays, apoptosis stimulation Journal of cell science Medium 22641691
2026 Endothelial APLP2 is required for postischemia angiogenesis after myocardial infarction; hypoxia induces alpha-secretase-mediated processing of APLP2 into soluble APLP2sα; APPsα and APLP2sα exert proangiogenic effects by positive allosteric modulation of the endothelial receptor tyrosine kinase KIT, promoting neovascularization. Endothelial-specific APP/APLP2 knockout mice, myocardial infarction model, secretase activity assays, KIT receptor signaling assays, AAV rescue with APPsα Science advances Medium 42172320

Source papers

Stage 0 corpus · 68 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 Isolation and characterization of APLP2 encoding a homologue of the Alzheimer's associated amyloid beta protein precursor. Nature genetics 337 8220435
1997 Generation of APLP2 KO mice and early postnatal lethality in APLP2/APP double KO mice. Neurobiology of aging 275 9461064
1999 Copper levels are increased in the cerebral cortex and liver of APP and APLP2 knockout mice. Brain research 222 10526140
2004 The proteolytic processing of the amyloid precursor protein gene family members APLP-1 and APLP-2 involves alpha-, beta-, gamma-, and epsilon-like cleavages: modulation of APLP-1 processing by n-glycosylation. The Journal of biological chemistry 181 14970212
2011 APP and APLP2 are essential at PNS and CNS synapses for transmission, spatial learning and LTP. The EMBO journal 153 21522131
2004 BACE (beta-secretase) modulates the processing of APLP2 in vivo. Molecular and cellular neurosciences 96 15080893
2015 APLP2 Regulates Refractive Error and Myopia Development in Mice and Humans. PLoS genetics 79 26313004
2009 Subcellular localization and dimerization of APLP1 are strikingly different from APP and APLP2. Journal of cell science 79 19126676
1995 Distribution of an APP homolog, APLP2, in the mouse olfactory system: a potential role for APLP2 in axogenesis. The Journal of neuroscience : the official journal of the Society for Neuroscience 77 7472397
2005 Shedding of the amyloid precursor protein-like protein APLP2 by disintegrin-metalloproteinases. The FEBS journal 74 16279945
2015 APP and APLP2 interact with the synaptic release machinery and facilitate transmitter release at hippocampal synapses. eLife 71 26551565
1994 Amyloid precursor-like protein 2 (APLP2) is modified by the addition of chondroitin sulfate glycosaminoglycan at a single site. The Journal of biological chemistry 66 8071334
2005 Increased processing of APLP2 and APP with concomitant formation of APP intracellular domains in BDNF and retinoic acid-differentiated human neuroblastoma cells. Journal of neurochemistry 60 16150056
2013 Characterization of proprotein convertase subtilisin/kexin type 9 (PCSK9) trafficking reveals a novel lysosomal targeting mechanism via amyloid precursor-like protein 2 (APLP2). The Journal of biological chemistry 53 23430252
1999 Recombinant human amyloid precursor-like protein 2 (APLP2) expressed in the yeast Pichia pastoris can stimulate neurite outgrowth. FEBS letters 52 9923612
2008 Identification of the Alzheimer's disease amyloid precursor protein (APP) and its homologue APLP2 as essential modulators of glucose and insulin homeostasis and growth. The Journal of pathology 49 18393365
2005 The amyloid precursor protein (APP) of Alzheimer disease and its paralog, APLP2, modulate the Cu/Zn-Nitric Oxide-catalyzed degradation of glypican-1 heparan sulfate in vivo. The Journal of biological chemistry 45 15677459
1995 Novel regulation of chondroitin sulfate glycosaminoglycan modification of amyloid precursor protein and its homologue, APLP2. The Journal of biological chemistry 44 7622456
2013 APLP2 regulates neuronal stem cell differentiation during cortical development. Journal of cell science 42 23345401
2009 AbetaPP/APLP2 family of Kunitz serine proteinase inhibitors regulate cerebral thrombosis. The Journal of neuroscience : the official journal of the Society for Neuroscience 40 19403832
2008 Embryonic stem cell-derived neurons as a cellular system to study gene function: lack of amyloid precursor proteins APP and APLP2 leads to defective synaptic transmission. Stem cells (Dayton, Ohio) 40 18535156
2010 Neurons generated from APP/APLP1/APLP2 triple knockout embryonic stem cells behave normally in vitro and in vivo: lack of evidence for a cell autonomous role of the amyloid precursor protein in neuronal differentiation. Stem cells (Dayton, Ohio) 33 20049903
2006 PAT1a modulates intracellular transport and processing of amyloid precursor protein (APP), APLP1, and APLP2. The Journal of biological chemistry 33 17050537
2006 Keratinocytes from APP/APLP2-deficient mice are impaired in proliferation, adhesion and migration in vitro. Experimental cell research 32 16584729
1998 APLP2, a member of the Alzheimer precursor protein family, is required for correct genomic segregation in dividing mouse cells. The EMBO journal 32 9707424
1994 Complete nucleotide and deduced amino acid sequence of rat amyloid protein precursor-like protein 2 (APLP2/APPH): two amino acids length difference to human and murine homologues. Biochimica et biophysica acta 32 8086458
2012 Deletion of the amyloid precursor-like protein 2 (APLP2) does not affect hippocampal neuron morphology or function. Molecular and cellular neurosciences 29 22353605
2015 APLP1 and APLP2, members of the APP family of proteins, behave similarly to APP in that they associate with NMDA receptors and enhance NMDA receptor surface expression. Journal of neurochemistry 27 25683482
1996 Quantification of APP and APLP2 mRNA in APOE genotyped Alzheimer's disease brains. Brain research. Molecular brain research 27 9037522
2014 Amyloid precursor protein (APP)/APP-like protein 2 (APLP2) expression is required to initiate endosome-nucleus-autophagosome trafficking of glypican-1-derived heparan sulfate. The Journal of biological chemistry 26 24898256
2010 Generation of conditional null alleles for APP and APLP2. Genesis (New York, N.Y. : 2000) 26 20140888
2017 APP, APLP2 and LRP1 interact with PCSK9 but are not required for PCSK9-mediated degradation of the LDLR in vivo. Biochimica et biophysica acta. Molecular and cell biology of lipids 25 28495363
2015 Amyloid precursor-like protein 2 (APLP2) affects the actin cytoskeleton and increases pancreatic cancer growth and metastasis. Oncotarget 25 25576918
2011 Signaling via amyloid precursor-like proteins APLP1 and APLP2. Journal of Alzheimer's disease : JAD 25 21178287
2003 Accumulation of the amyloid precursor-like protein APLP2 and reduction of APLP1 in retinoic acid-differentiated human neuroblastoma cells upon curcumin-induced neurite retraction. Brain research. Molecular brain research 25 14597230
2001 A role for MAP kinase in regulating ectodomain shedding of APLP2 in corneal epithelial cells. American journal of physiology. Cell physiology 24 11443060
2020 Lack of APP and APLP2 in GABAergic Forebrain Neurons Impairs Synaptic Plasticity and Cognition. Cerebral cortex (New York, N.Y. : 1991) 23 32219307
2012 Regulation of apoptosis by Bat3-enhanced YWK-II/APLP2 protein stability. Journal of cell science 22 22641691
1994 The gene for the amyloid precursor-like protein APLP2 is assigned to human chromosome 11q23-q25. Genomics 21 8020984
2016 Amyloid precursor-like protein 1 (APLP1) exhibits stronger zinc-dependent neuronal adhesion than amyloid precursor protein and APLP2. Journal of neurochemistry 20 26801522
2013 APLP2 regulates the expression of MHC class I molecules on irradiated Ewing's sarcoma cells. Oncoimmunology 18 24353913
2013 Hippocampal network oscillations in APP/APLP2-deficient mice. PloS one 17 23585881
1995 The mouse APLP2 gene. Chromosomal localization and promoter characterization. The Journal of biological chemistry 17 7592716
2012 Tol2 gene trap integrations in the zebrafish amyloid precursor protein genes appa and aplp2 reveal accumulation of secreted APP at the embryonic veins. Developmental dynamics : an official publication of the American Association of Anatomists 16 22275008
2014 Quantitation and localization of intracellular redox active metals by X-ray fluorescence microscopy in cortical neurons derived from APP and APLP2 knockout tissue. Metallomics : integrated biometal science 15 25098278
2021 APPsα rescues impaired Ca2+ homeostasis in APP- and APLP2-deficient hippocampal neurons. Proceedings of the National Academy of Sciences of the United States of America 12 34172567
1996 Studies on the metabolism and biological function of APLP2. Annals of the New York Academy of Sciences 11 8624130
1996 A new quantitative solution hybridisation-RNase protection assay for APP and APLP2 mRNA. Brain research. Molecular brain research 10 9037521
2009 PAT1 induces cell death signal and SET mislocalization into the cytoplasm by increasing APP/APLP2 at the cell surface. Neurobiology of aging 9 19570594
2023 Comparative binding analysis of WGX50 and Alpha-M with APP family proteins APLP1 and APLP2 using structural-dynamics and free energy calculation approaches. Physical chemistry chemical physics : PCCP 8 37199163
2023 Comprehensive intratumoral heterogeneity landscaping of liver hepatocellular carcinoma and discerning of APLP2 in cancer progression. Environmental toxicology 8 37515494
2016 APLP2, RRM2, and PRC1: New Putative Markers for the Differential Diagnosis of Thyroid Follicular Lesions. Thyroid : official journal of the American Thyroid Association 8 27796194
2006 YWK-II protein/APLP2 in mouse gametes: potential role in fertilization. Molecular reproduction and development 8 16177981
2004 Identification and expression of the first nonmammalian amyloid-beta precursor-like protein APLP2 in the amphibian Xenopus laevis. European journal of biochemistry 8 15128300
1996 Genomic structure and chromosomal localization of the mouse CDEI-binding protein CDEBP (APLP2) gene and promoter sequences. Genomics 7 8661100
2022 Reduced expression of APLP2 in spinal GABAergic inhibitory neurons contributed to nerve injury-induced microglial activation and pain sensitization. Neuropharmacology 6 36442651
2017 Amyloid-precursor Like Proteins APLP1 and APLP2 Are Dispensable for Normal Development of the Neonatal Respiratory Network. Frontiers in molecular neuroscience 6 28690498
2018 Oral administration of alcalase potato protein hydrolysate-APPH attenuates high fat diet-induced cardiac complications via TGF-β/GSN axis in aging rats. Environmental toxicology 5 30240538
2023 Mycobacterium tuberculosis suppresses APLP2 expression to enhance its survival in macrophage. International immunopharmacology 4 37844466
2018 APLP2 Modulates JNK-Dependent Cell Migration in Drosophila. BioMed research international 4 30155482
2023 YWK-II/APLP2 inhibits TGF-β signaling by interfering with the TGFBR2-Hsp90 interaction. Biochimica et biophysica acta. Molecular cell research 3 37479189
2023 APLP2 is predominantly cleaved by β-secretase and γ-secretase in the human brain. Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society 2 36691315
2020 APLP2 gene polymorphisms are associated with high TC and LDL-C levels in Chinese population in Xinjiang, China. Bioscience reports 2 32716039
2006 Delineation of the functional domains of the extracellular region of YWK-II Protein/APLP2 of sperm membrane. Frontiers in bioscience : a journal and virtual library 1 16720320
2005 The amyloid-beta precursor-like protein APLP2 and its relative APP are differentially regulated during neuroendocrine cell activation. Molecular and cellular neurosciences 1 16154762
2003 Crystallization and preliminary crystallographic analysis of extracellular fragment X3 of YWK-II/APPH: a human sperm membrane protein related to the Alzheimer betaA4-amyloid precursor protein. Acta crystallographica. Section D, Biological crystallography 1 12595709
2002 Crystallization and preliminary crystallographic analysis of a partial extracellular fragment of a sperm membrane protein YWK-II/APPH related to the Alzheimer betaA4-amyloid precursor protein. Acta crystallographica. Section D, Biological crystallography 1 12499552
2026 Endothelial soluble APP/APLP2 promote heart repair through KIT-mediated angiogenesis. Science advances 0 42172320

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