LPXN (leupaxin) is a paxillin-family LD/LIM adaptor enriched in hematopoietic cells and vascular smooth muscle. It cycles among the cytoplasm, focal adhesions or podosomes, and the nucleus. At adhesion structures, its LD motifs bind focal-adhesion-family tyrosine kinases including PYK2/PTK2B and FAK1/PTK2, while regulated contacts with Src-family kinases, PTP-PEST, and p95PKL connect integrin-associated signaling to cytoskeletal organization. LIM3 directs focal-adhesion targeting, and adhesion-site recruitment precedes stimulus-dependent LPXN tyrosine phosphorylation. In murine osteoclasts, podosomal LPXN promotes adhesion and bone-resorptive activity. B-cell-receptor stimulation recruits LPXN to the plasma membrane and induces Lyn binding in human BJAB lymphoma cells; gain-of-function experiments in mouse A20 cells show selective inhibition of B-cell-receptor outputs. Nuclear LPXN acts as a transcriptional coactivator with androgen receptor in prostate-cancer cells and as a serum-response-factor cofactor in vascular smooth-muscle systems; beta-catenin coactivation has also been observed in hepatocellular-carcinoma models. These transcriptional and migration effects depend on cell state and experimental context. Two human isoforms differ at their extreme N termini, but no isoform-specific activity has been established.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003712 transcription coregulator activity | IBA GO_REF:0000033 | MODIFY | Summary: LPXN positively coactivates transcription with androgen receptor, SRF, and beta-catenin in defined cellular contexts. Reason: The transferred parent term is direction-neutral, whereas direct LPXN experiments consistently show increased target transcription; GO:0003713 transcription coactivator activity captures that positive direction. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:2147677 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. PANTHER:PTN000655374 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. UniProtKB:O60711 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. Proposed replacements: transcription coactivator activity |
| GO:0002102 podosome | IBA GO_REF:0000033 | ACCEPT | Summary: LPXN localizes to podosomes. Reason: PMID:12674328 identifies leupaxin in the osteoclast podosomal complex. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:2147677 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. PANTHER:PTN000655374 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. UniProtKB:O60711 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: LPXN localizes to the nucleus. Reason: PMID:18451096 and PMID:18497331 connect nuclear entry to transcriptional coregulation. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:2147677 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. PANTHER:PTN000655374 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. UniProtKB:O60711 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. |
| GO:0005911 cell-cell junction | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Cell-cell-junction localization is transferred from paxillin-family sources but is not established for human LPXN. Reason: Direct LPXN evidence supports focal adhesions and podosomes, not cell-cell junctions; junctional localization should not be transferred across paxillin-family paralogs without target evidence. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN000655348 SUPPORTS SOURCE BUT NOT TARGET Source localization does not establish cell-cell-junction residence for human LPXN. UniProtKB:P49023 SUPPORTS SOURCE BUT NOT TARGET Source localization does not establish cell-cell-junction residence for human LPXN. WB:WBGene00016197 SUPPORTS SOURCE BUT NOT TARGET Source localization does not establish cell-cell-junction residence for human LPXN. |
| GO:0005925 focal adhesion | IBA GO_REF:0000033 | ACCEPT | Summary: LPXN localizes to focal adhesions. Reason: Multiple direct studies establish focal-adhesion recruitment and function. Propagation Review Root cause: NO FAILURE CORE Sources checked: FB:FBgn0041789 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. MGI:MGI:102784 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. MGI:MGI:108295 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. MGI:MGI:2147677 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. PANTHER:PTN000655348 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. RGD:1305759 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. UniProtKB:O43294 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. UniProtKB:O60711 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. UniProtKB:P49023 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. UniProtKB:P49024 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. |
| GO:0050859 negative regulation of B cell receptor signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: LPXN has a context-bounded inhibitory effect on B-cell-receptor signaling. Reason: Human BJAB cells directly establish BCR-induced LPXN phosphorylation, plasma-membrane recruitment, and Lyn binding, but the negative pathway outputs were demonstrated by LPXN overexpression in mouse A20 lymphoma cells. Retain this positive evidence as contextual rather than a core human LPXN process. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: MGI:MGI:2147677 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. PANTHER:PTN000655374 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. UniProtKB:O60711 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. |
| GO:0002102 podosome | IEA GO_REF:0000120 | ACCEPT | Summary: LPXN localizes to podosomes. Reason: PMID:12674328 identifies leupaxin in the osteoclast podosomal complex. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q99N69 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. ensembl:ENSMUSP00000025601 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. UniProtKB-SubCell:SL-0295 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: LPXN localizes to the nucleus. Reason: PMID:18451096 and PMID:18497331 connect nuclear entry to transcriptional coregulation. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q99N69 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. ensembl:ENSMUSP00000025601 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. UniProtKB-SubCell:SL-0191 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: LPXN localizes in the cytoplasm. Reason: Direct studies establish cytoplasmic localization and regulated redistribution. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0086 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: LPXN can localize to the plasma membrane. Reason: PMID:17640867 directly reports BCR-induced plasma-membrane recruitment. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0039 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. |
| GO:0005925 focal adhesion | IEA GO_REF:0000120 | ACCEPT | Summary: LPXN localizes to focal adhesions. Reason: Multiple direct studies establish focal-adhesion recruitment and function. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00028361 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. UniProtKB:Q99N69 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. ensembl:ENSMUSP00000025601 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. UniProtKB-SubCell:SL-0118 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Perinuclear cytoplasmic localization is plausible but is a secondary spatial detail. Reason: The reviewed subcellular record supports this location, but it is not central to the directly established adhesion-site and nuclear-cofactor functions. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0198 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. |
| GO:0005515 protein binding | IPI PMID:21900206 A directed protein interaction network for investigating int... | MODIFY | Summary: A directed interaction assay detected LPXN with Q05397, PTK2/FAK1. Reason: The partner identity supports GO:1990782 protein tyrosine kinase binding, which is more informative than generic protein binding. Proposed replacements: protein tyrosine kinase binding |
| GO:0005515 protein binding | IPI PMID:23088713 Protein interactions of the transcription factor Hoxa1. | MARK AS OVER ANNOTATED | Summary: A Hoxa1 interactome screen reported LPXN binding with occurs_in cytoplasm and occurs_in vesicle extensions. Reason: Retain the exact screen provenance, but generic protein binding and screen compartments do not establish a defining LPXN function. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Proteome-scale binary-interactome screening produced six merged candidate LPXN partners. Reason: The heterogeneous screen contacts cannot be represented by one precise binding function; generic protein binding is not informative. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MODIFY | Summary: An interactome map reported merged PTK2/FAK1 and PLEKHH2 candidate contacts. Reason: GO:1990782 precisely captures the Q05397 PTK2/FAK1 interaction. Q8IVE3 is PLEKHH2, not PYK2/PTK2B or a protein tyrosine phosphatase, and no domain-resolved evidence identifies an informative current binding term for that screen contact. In particular, GO:0030274 would assert that LPXN binds a LIM domain on PLEKHH2 and is not supported. The PLEKHH2 IPI is retained in the machine provenance without inventing a second replacement. Proposed replacements: protein tyrosine kinase binding |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | MARK AS OVER ANNOTATED | Summary: A proteome-scale screen reported an LPXN–HOXC9 candidate interaction. Reason: A screen contact does not establish a mechanistic LPXN role, and generic protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: A reference interactome map produced eleven merged candidate LPXN partners. Reason: The partners span unrelated protein classes, so the generic term cannot be refined faithfully or treated as core. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: A neurodegeneration interactome map reported an LPXN–OPTN candidate contact. Reason: No direct LPXN mechanism follows from this screen hit; generic protein binding is over-annotation. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: A cell-specific interactome map reported merged PTK2/FAK1 and PLEKHH2 contacts. Reason: GO:1990782 precisely captures binding to Q05397 PTK2/FAK1. Q8IVE3 is PLEKHH2 and the screen does not resolve an LPXN binding activity more informative than generic protein binding for that partner; LIM-domain binding would have the wrong participant direction. Proposed replacements: protein tyrosine kinase binding |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MARK AS OVER ANNOTATED | Summary: Fragment-scale screening produced twenty merged candidate PDZ and other partners. Reason: The heterogeneous screen partners lack direct mechanistic validation and cannot be captured by one precise molecular-function term. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MODIFY | Summary: A multimodal interactome map reported merged PTK2/FAK1 and PLEKHH2 contacts. Reason: GO:1990782 captures the Q05397 PTK2/FAK1 interaction. The Q8IVE3 PLEKHH2 screen contact has no verified partner- or domain-specific GO binding term; it remains represented by the exact supporting-entity provenance rather than an unsupported LIM- or phosphatase-binding replacement. Proposed replacements: protein tyrosine kinase binding |
| GO:0003712 transcription coregulator activity | IEA GO_REF:0000107 | MODIFY | Summary: LPXN positively coactivates transcription with androgen receptor, SRF, and beta-catenin in defined contexts. Reason: Direct human and multi-species cellular studies consistently establish a positive transcriptional effect, so GO:0003713 is more informative than the direction-neutral transferred parent term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q99N69 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. ensembl:ENSMUSP00000025601 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. Proposed replacements: transcription coactivator activity |
| GO:0033628 regulation of cell adhesion mediated by integrin | IEA GO_REF:0000107 | ACCEPT | Summary: LPXN regulates integrin-mediated cell adhesion, with direction determined by cellular and extracellular-matrix context. Reason: The direction-neutral orthology transfer is appropriate: direct human MDA-MB-231 experiments show negative regulation of collagen-I adhesion, whereas murine osteoclast gain- and loss-of-function studies support a positive contribution to adhesion and resorptive organization. The parent term preserves the shared integrin-adhesion role without generalizing one context-specific direction. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q99N69 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. ensembl:ENSMUSP00000025601 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. |
| GO:0050859 negative regulation of B cell receptor signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: LPXN has a context-bounded inhibitory effect on B-cell-receptor signaling. Reason: The negative signaling outputs derive from LPXN overexpression in mouse A20 lymphoma cells, while the human BJAB evidence establishes recruitment and Lyn binding. The transfer is biologically defensible but contextual rather than a core human LPXN process. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q99N69 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. ensembl:ENSMUSP00000025601 SUPPORTS TRANSFER Source provenance supports this conservative transfer to human LPXN. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: LPXN localizes to the cytosol. Reason: This agrees with its directly observed cytoplasmic pool and regulated redistribution. |
| GO:0005925 focal adhesion | IDA GO_REF:0000052 | ACCEPT | Summary: LPXN localizes to focal adhesions. Reason: Multiple direct studies establish focal-adhesion recruitment and function. |
| GO:0016607 nuclear speck | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Human Protein Atlas data localize LPXN to nuclear specks. Reason: Retain as secondary localization: mechanistic studies establish nuclear shuttling but not a core nuclear-speck role. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | KEEP AS NON CORE | Summary: LPXN was detected in an NK-cell membrane proteome. Reason: This HDA location is valid contextually but less informative than regulated focal-adhesion and BCR-induced plasma-membrane recruitment. |
| GO:0003712 transcription coregulator activity | IDA PMID:18451096 Leupaxin, a novel coactivator of the androgen receptor, is e... | MODIFY | Summary: Direct experiments establish LPXN as an androgen-receptor transcriptional coactivator. Reason: Ligand-dependent activation of androgen-receptor transcription establishes positive coactivator activity, which GO:0003713 captures more precisely than the direction-neutral parent term. Proposed replacements: transcription coactivator activity |
| GO:0003712 transcription coregulator activity | IDA PMID:18497331 The LIM protein leupaxin is enriched in smooth muscle and fu... | MODIFY | Summary: Direct experiments establish nuclear LPXN as an SRF cofactor. Reason: LPXN increases SRF-dependent smooth-muscle marker transcription, supporting the positive child term GO:0003713 transcription coactivator activity. Proposed replacements: transcription coactivator activity Supporting Evidence: PMID:18497331 We found that leupaxin forms a complex with serum response factor and associates with CArG-containing regions of smooth muscle promoters and that ectopic expression of leupaxin induces smooth muscle marker gene expression in both 10T1/2 cells and rat aortic smooth muscle cells. |
| GO:0005515 protein binding | IPI PMID:18451096 Leupaxin, a novel coactivator of the androgen receptor, is e... | MODIFY | Summary: LPXN directly interacts with androgen receptor in a ligand-dependent manner. Reason: GO:0050681 nuclear androgen receptor binding precisely captures the experimentally identified interaction. Proposed replacements: nuclear androgen receptor binding |
| GO:0005515 protein binding | IPI PMID:18497331 The LIM protein leupaxin is enriched in smooth muscle and fu... | MODIFY | Summary: Direct experiments identify SRF and Q05397 PTK2/FAK1 interactions. Reason: GO:0008134 captures transcription-factor binding to SRF and GO:1990782 captures PTK2/FAK1 binding more precisely than GO:0005515. Proposed replacements: transcription factor binding protein tyrosine kinase binding |
| GO:0005634 nucleus | IDA PMID:18451096 Leupaxin, a novel coactivator of the androgen receptor, is e... | ACCEPT | Summary: LPXN undergoes nuclear localization during nucleocytoplasmic shuttling. Reason: PMID:18451096 directly demonstrates the location. |
| GO:0005634 nucleus | IDA PMID:18497331 The LIM protein leupaxin is enriched in smooth muscle and fu... | ACCEPT | Summary: Nuclear LPXN supports SRF-dependent transcription. Reason: PMID:18497331 directly demonstrates the location. Supporting Evidence: PMID:18497331 In addition, our studies reveal that leupaxin can undergo cytoplasmic/nuclear shuttling and functions as an serum response factor cofactor in the nucleus. |
| GO:0005737 cytoplasm | IDA PMID:18451096 Leupaxin, a novel coactivator of the androgen receptor, is e... | ACCEPT | Summary: LPXN localizes in the cytoplasm during regulated shuttling and adhesion-site recruitment. Reason: PMID:18451096 directly demonstrates the location. |
| GO:0005737 cytoplasm | IDA PMID:18497331 The LIM protein leupaxin is enriched in smooth muscle and fu... | ACCEPT | Summary: LPXN localizes in the cytoplasm and redistributes in response to FAK activity. Reason: PMID:18497331 directly demonstrates the location. Supporting Evidence: PMID:18497331 In addition, our studies reveal that leupaxin can undergo cytoplasmic/nuclear shuttling and functions as an serum response factor cofactor in the nucleus. |
| GO:0005925 focal adhesion | IDA PMID:18451096 Leupaxin, a novel coactivator of the androgen receptor, is e... | ACCEPT | Summary: LPXN localizes to focal adhesions in prostate-cancer cells. Reason: PMID:18451096 directly demonstrates this central adhesion-site location. |
| GO:0005925 focal adhesion | IDA PMID:18497331 The LIM protein leupaxin is enriched in smooth muscle and fu... | ACCEPT | Summary: LPXN localizes to focal adhesions in smooth-muscle cells. Reason: PMID:18497331 directly demonstrates the location and its link to FAK-dependent localization control. Supporting Evidence: PMID:18497331 Leupaxin localizes within focal adhesions and co-localizes with FAK in these cells ( Fig 2A and Supplemental Fig 2A ). |
| GO:0005925 focal adhesion | IDA PMID:20543562 Leupaxin is similar to paxillin in focal adhesion targeting ... | ACCEPT | Summary: Stimulated LPXN translocates to focal adhesions through its LIM3 targeting domain. Reason: PMID:20543562 directly tests stimulus-dependent targeting. |
| GO:0007162 negative regulation of cell adhesion | IDA PMID:20543562 Leupaxin is similar to paxillin in focal adhesion targeting ... | MODIFY | Summary: LPXN negatively regulates collagen-I adhesion in human MDA-MB-231 cells. Reason: LPXN knockdown increases adhesion to collagen I, an integrin-dependent extracellular-matrix substrate; GO:0033629 captures both the negative regulatory direction and integrin-mediated adhesion more precisely than GO:0007162. Proposed replacements: negative regulation of cell adhesion mediated by integrin |
| GO:0002102 podosome | IDA PMID:12674328 Leupaxin is a critical adaptor protein in the adhesion zone ... | ACCEPT | Summary: LPXN is a component of the osteoclast podosomal adhesion complex. Reason: PMID:12674328 directly localizes LPXN at or near podosomes. |
| GO:0005515 protein binding | IPI PMID:17640867 Leupaxin negatively regulates B cell receptor signaling. | MODIFY | Summary: BCR stimulation induces direct LPXN interaction with the Src-family kinase LYN. Reason: GO:1990782 protein tyrosine kinase binding precisely captures the activation-dependent LYN interaction. Proposed replacements: protein tyrosine kinase binding |
| GO:0005737 cytoplasm | IDA PMID:17640867 Leupaxin negatively regulates B cell receptor signaling. | ACCEPT | Summary: B-cell experiments observe cytoplasmic LPXN before activation-dependent redistribution. Reason: PMID:17640867 directly supports the location. |
| GO:0005886 plasma membrane | IDA PMID:17640867 Leupaxin negatively regulates B cell receptor signaling. | ACCEPT | Summary: BCR cross-linking recruits LPXN to the plasma membrane in human BJAB cells. Reason: PMID:17640867 directly supports the location. |
| GO:0050859 negative regulation of B cell receptor signaling pathway | IDA PMID:17640867 Leupaxin negatively regulates B cell receptor signaling. | KEEP AS NON CORE | Summary: LPXN suppresses selected BCR-induced kinase and IL-2 outputs. Reason: The inhibitory JNK, p38, Akt, and IL-2 results were obtained after LPXN overexpression in mouse A20 B-lymphoma cells. Human BJAB cells directly establish BCR-induced recruitment and Lyn binding, but not endogenous loss of human pathway inhibition; retain the process as contextual non-core biology. |
| GO:0007155 cell adhesion | NAS PMID:9565592 Leupaxin is a novel LIM domain protein that forms a complex ... | KEEP AS NON CORE | Summary: The broad cell-adhesion annotation is compatible with LPXN's adhesion-site adaptor role. Reason: Retain as non-core because later direct work provides more informative direction and context for adhesion regulation. |
| GO:0007165 signal transduction | TAS PMID:9565592 Leupaxin is a novel LIM domain protein that forms a complex ... | KEEP AS NON CORE | Summary: The original PYK2/PTK2B-association study supports participation in leukocyte signaling. Reason: Retain as non-core because signal transduction is too broad; specific annotations capture BCR inhibition, adhesion regulation, and transcriptional coregulation. |
| GO:0065003 protein-containing complex assembly | TAS PMID:9565592 Leupaxin is a novel LIM domain protein that forms a complex ... | MARK AS OVER ANNOTATED | Summary: LPXN associates with PYK2/PTK2B in a signaling complex. Reason: Complex association does not directly establish that LPXN executes protein-containing complex assembly, so the process claim is over-annotated. |
| GO:0030674 protein-macromolecule adaptor activity | IDA PMID:17329398 Interaction of Pyk2 and PTP-PEST with leupaxin in prostate c... | NEW | Summary: In human PC-3 prostate-cancer cells, LPXN associates with PYK2/PTK2B, c-Src, and PTP-PEST in a migration-regulating signaling complex. Reason: Direct human cellular evidence places LPXN with both protein tyrosine kinases and a protein tyrosine phosphatase in a signaling assembly whose perturbation changes migration. This supports an adaptor activity more informatively than generic protein binding, without asserting that the assembly is obligate or constitutive. Murine podosome evidence and purified LPXN-PYK2/PTK2B structural biochemistry provide additional, explicitly bounded support for the interaction architecture. Supporting Evidence: PMID:17329398 In conclusion, our data demonstrate that LPXN forms a signaling complex with Pyk2, c-Src, and PTP-PEST to regulate migration of prostate cancer cells. |
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Download this section (compressed HTML)Q: Does endogenous LPXN simultaneously bridge PYK2/PTK2B or FAK1/PTK2, Src, PTP-PEST, and p95PKL at adhesion structures, or do these partners exchange in distinct signaling states?
Q: Is the murine osteoclast requirement for LPXN conserved in primary human osteoclast podosome organization and bone resorption?
Q: Which endogenous B-cell contexts require LPXN for inhibition of B-cell-receptor signaling, independently of the mouse A20 overexpression paradigm?
Q: What controls LPXN nuclear entry and determines selection of androgen receptor, SRF, or beta-catenin transcriptional programs?
Q: Do LPXN isoforms 1 and 2 differ in expression, adhesion-site targeting, partner binding, or nuclear coactivation?
Experiment: Endogenously tag LPXN in human macrophages and vascular smooth-muscle cells, then combine time-resolved proximity labeling, cross-linking quantitative proteomics, and single-particle focal-adhesion imaging before and after integrin or inflammatory stimulation. Compare wild-type LPXN with LD1-, LD3-, and LIM3-contact mutants introduced at the endogenous locus.
Hypothesis: LPXN organizes a stimulus-dependent sequence of kinase, phosphatase, and cytoskeletal-regulator contacts rather than a constitutive multiprotein complex.
Type: cell biology and proteomics
Experiment: Use CRISPR knockout or an acute degron in primary human monocyte-derived osteoclasts, quantify podosome-belt architecture, traction, and mineral resorption, and rescue with wild-type LPXN or PYK2/PTK2B-binding- and focal-adhesion-targeting mutants.
Hypothesis: LPXN is required cell-autonomously for human osteoclast podosome organization and mineral resorption.
Type: functional cell biology
Experiment: Introduce an acute LPXN degron into human B-cell models, measure time-resolved JNK, p38, Akt, ERK, NF-kappaB, calcium, and cytokine responses after BCR cross-linking, and rescue from the endogenous locus with wild-type, LD3-mutant, and Y72F LPXN.
Hypothesis: Endogenous LPXN restrains a defined subset of B-cell-receptor outputs through activation-dependent LD3-Lyn binding and Tyr72 phosphorylation.
Type: signal transduction
Experiment: Couple endogenous LPXN live-cell tracking and acute FAK perturbation to LPXN/SRF/androgen-receptor/beta-catenin CUT&RUN and nascent-RNA sequencing in primary vascular smooth-muscle cells and matched disease-cell models.
Hypothesis: FAK-regulated nuclear accumulation selects distinct LPXN transcriptional programs according to lineage and transcription-factor availability.
Type: cell biology and functional genomics
Experiment: Quantify isoform-specific transcripts and N-terminal peptides across LPXN-rich tissues, then compare endogenous-locus isoform-1 and isoform-2 rescue for half-life, focal-adhesion targeting, partner proteomes, and nuclear coactivation.
Hypothesis: The alternative N terminus of LPXN isoform 2 changes protein stability or partner selection without altering the shared LD/LIM interaction core.
Type: isoform-resolved proteomics
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The endogenous composition, stoichiometry, and temporal order of LPXN-bound PYK2/PTK2B or FAK1/PTK2, Src-family kinases, PTP-PEST, and p95PKL at adhesion structures are unresolved.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Pairwise cellular associations and a purified 1:1 LPXN-PYK2/PTK2B-FAT interaction are established, but they do not show that all partners bind simultaneously or define a single constitutive complex.
Significance: Resolving the assembly sequence is necessary to distinguish LPXN-mediated bridging from mutually exclusive partner exchange and to explain how the adaptor changes adhesion signaling.
What would resolve it: Endogenous time-resolved proximity labeling, quantitative co-complex analysis, and interaction-motif rescue experiments at focal adhesions and podosomes would establish partner occupancy and dependence.
Gap: Whether LPXN is required for podosome organization and bone resorption in human osteoclasts is unknown.
OPEN BIOLOGY BP_DARK
What is known: Localization, gain- and loss-of-function phenotypes, and kinase associations are established in murine osteoclasts, but direct human osteoclast evidence is lacking.
Significance: Human evidence would determine whether the mouse resorption phenotype is a conserved physiological role of LPXN rather than a species- or assay-specific effect.
What would resolve it: Endogenous LPXN loss and rescue in primary human monocyte-derived osteoclasts, coupled to podosome-belt imaging and mineral-resorption assays, would close this gap.
Gap: The relative abundance, localization, partner selection, and activity of the two human LPXN protein isoforms have not been established.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: UniProt records an alternative extreme N terminus for isoform 2, while the functional literature does not distinguish LPXN isoforms.
Significance: Isoform-resolved evidence is needed before any adhesion, signaling, or nuclear coactivation function can be called isoform-specific.
What would resolve it: Isoform-selective transcript and proteomic measurements followed by endogenous-locus isoform-specific rescue would determine whether the short N-terminal difference changes LPXN behavior.
Gap: The mechanism and physiological scope of LPXN nuclear import and its choice among androgen receptor, SRF, and beta-catenin transcriptional programs are unresolved.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Nucleocytoplasmic shuttling, nuclear coactivator activity, and FAK-dependent control of nuclear accumulation are established in selected smooth-muscle and cancer-cell systems, but no universal import determinant or target program has been demonstrated.
Significance: This distinction is required to separate a normal adhesion-to-nucleus signal from lineage- or disease-specific coactivation.
What would resolve it: Endogenous trafficking perturbations combined with partner-resolved chromatin occupancy and transcriptional profiling across primary hematopoietic and smooth-muscle cells would define the mechanism and scope.
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