LPP encodes lipoma-preferred partner, a zyxin-family adhesion adaptor with a proline-rich N-terminal region and three C-terminal LIM domains. Intact LPP localizes to focal adhesions, stress fibers, and cell-cell contacts, where it connects cytoskeletal and junctional proteins through several mapped interaction surfaces. Its partners include VASP, the central rod of ACTN1, the N terminus of palladin, and the PDZ domains of SCRIB; the SCRIB interaction is mediated by the extreme LPP C terminus and is not required to target either protein to cell-cell contacts. Cooperative action of the three LIM domains, including the linker between LIM domains 1 and 2, supports robust focal- adhesion targeting. LPP also undergoes regulated nucleocytoplasmic shuttling. Nuclear export depends on an N-terminal leucine-rich export signal, whereas the mechanism of nuclear import is unresolved. LPP can activate a heterologous GAL4 reporter, but an endogenous transcriptional target or sequence-specific DNA-binding activity has not been established. In rat aortic smooth-muscle cells, human endothelial/smooth-muscle co-culture, rat vascular injury, ApoE-null mouse atherosclerosis, and human or mouse cancer-model contexts, mechanical cues, TGFΞ², and adhesion signaling alter LPP abundance or localization and influence adhesion turnover, spreading, migration, or invasion in context-specific ways. Chromosomal rearrangements can produce HMGA2-LPP or KMT2A-LPP fusion proteins that retain two or three LPP LIM domains joined to regions of the respective nuclear partner proteins; these chimeras show predominantly nuclear behavior.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001725 stress fiber | IBA GO_REF:0000033 | ACCEPT | Summary: LPP is retained at actin-associated adhesion structures, including stress fibers. Reason: Stress-fiber localization is coherent with LPP's zyxin-family architecture, its established recruitment to actin-linked adhesion sites, and the reviewed phylogenetic transfer. It represents a core site of action for this adhesion scaffold. Propagation Review Root cause: NO FAILURE CORE Sources checked: FB:FBgn0011642 SUPPORTS TRANSFER Exact WITH/FROM donor supports conserved stress-fiber localization in the zyxin-family context. PANTHER:PTN000654183 SUPPORTS TRANSFER Exact PANTHER family node supports the reviewed phylogenetic transfer. UniProtKB:Q8WUP2 SUPPORTS TRANSFER Exact human LIM-protein donor supports transfer of actin-associated adhesion-site localization. |
| GO:0005925 focal adhesion | IBA GO_REF:0000033 | ACCEPT | Summary: LPP acts at focal adhesions, a defining localization for this zyxin-family scaffold. Reason: The IBA is consistent with direct human localization and proteomic evidence placing LPP at focal adhesions, where its LIM domains mediate targeting. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000654183 SUPPORTS TRANSFER Exact PANTHER family node supports the reviewed focal-adhesion transfer. UniProtKB:Q8WUP2 SUPPORTS TRANSFER Exact human LIM-protein donor is consistent with conserved focal-adhesion localization. Supporting Evidence: PMID:15649318 Whereas LPP is also localized in focal adhesions and in the nucleus, Scrib could not be detected at these locations in MDCKII and CV-1 cells. |
| GO:0098609 cell-cell adhesion | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The phylogenetic cell-cell-adhesion assertion is retained as a positive but non-core transfer. Reason: The IBA donors support a conserved adhesion context, but direct human evidence in this review establishes LPP localization and partner binding at cell-cell contacts rather than a required role in the cell-cell adhesion process. The SCRIB interaction does not establish that process and is not used as positive process evidence. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000654183 SUPPORTS TRANSFER Exact PANTHER family node supports the reviewed cell-cell-adhesion transfer. UniProtKB:Q8WUP2 SUPPORTS TRANSFER Exact human LIM-protein donor supports a conserved adhesion role. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Nuclear localization is retained as a regulated, secondary compartment for LPP. Reason: LPP shuttles from adhesion sites through the cytoplasm to the nucleus and has reporter transcriptional activity there, but this transient regulatory pool is secondary to its defining adhesion-site scaffold role. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0191 SUPPORTS TRANSFER Exact UniProt subcellular-location mapping agrees with experimentally described nuclear shuttling of LPP. Supporting Evidence: PMID:15649318 Previously, we found that the Lipoma Preferred Partner (LPP) protein is localized at sites of cell adhesion such as focal adhesions and cell-cell contacts, and shuttles to the nucleus where it has transcriptional activation capacity. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Cytoplasmic localization is valid but is a broad trafficking and scaffold context. Reason: LPP has an established cytoplasmic pool and undergoes nucleocytoplasmic shuttling, but the generic cytoplasm term is less informative than its focal- adhesion, junctional, and stress-fiber sites of action. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0086 SUPPORTS TRANSFER Exact UniProt subcellular-location mapping is consistent with the documented cytoplasmic LPP pool. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: The broad plasma-membrane mapping is retained as a secondary localization. Reason: LPP is recruited to cell-cell contacts and focal adhesions at the cell periphery, but generic plasma membrane is less informative than the focal- adhesion and junction terms that identify its functional sites. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0039 SUPPORTS TRANSFER Exact UniProt subcellular-location mapping agrees with LPP at membrane-associated adhesion sites. |
| GO:0070161 anchoring junction | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Anchoring-junction localization is valid but less informative than focal adhesion. Reason: The term appropriately represents the focal-adhesion context of LPP, where its LIM domains target the protein to actin-linked membrane attachment sites. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0038 SUPPORTS TRANSFER Exact UniProt cell-junction mapping is consistent with LPP's established focal-adhesion localization. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA immunofluorescence supports a cytosolic pool, retained as non-core. Reason: A cytosolic pool is expected for a shuttling, soluble adhesion scaffold, but this broad localization does not identify the specialized adhesion structures where LPP's core activity is organized. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA immunofluorescence supports a broad plasma-membrane pool, retained as non-core. Reason: This experimental localization agrees with LPP recruitment to membrane- associated focal adhesions and cell-cell contacts, but the generic membrane term does not identify the specialized adhesion structures where LPP acts. |
| GO:0030054 cell junction | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence supports LPP localization at cell junctions. Reason: Although broader than cell-cell contact, the term is the available source localization that directly supports the junctional site of LPP's PDZ-domain- binding activity and agrees with independent cell-cell-contact evidence. |
| GO:0005925 focal adhesion | HDA PMID:21423176 Analysis of the myosin-II-responsive focal adhesion proteome... | ACCEPT | Summary: High-throughput focal-adhesion proteomics supports LPP occurrence in fibroblast focal adhesions. Reason: The HDA assertion is consistent with extensive independent human LPP localization evidence. The source is a high-throughput focal-adhesion proteome, so the exact fibroblast extension is retained and no additional mechanistic role is inferred from detection alone. |
| GO:0005515 protein binding | IPI PMID:15649318 The tumor suppressor Scrib interacts with the zyxin-related ... | MODIFY | Summary: The generic binding annotation should be replaced by PDZ domain binding. Reason: PMID:15649318 directly maps the interaction to the C-terminal tail of LPP and the PDZ domains of SCRIB. GO:0030165 captures the demonstrated molecular activity more informatively than generic protein binding. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:15649318 The binding between Scrib and LPP is mediated by the PDZ domains of Scrib and the carboxy-terminus of LPP. |
| GO:0051393 alpha-actinin binding | IPI PMID:12615977 The lipoma preferred partner LPP interacts with alpha-actini... | NEW | Summary: Direct interaction assays establish alpha-actinin binding by LPP. Reason: PMID:12615977 maps the alpha-actinin interaction to its central rod and to a conserved N-terminal determinant in LPP. GO:0051393 precisely represents this direct partner-binding activity without asserting broader cytoskeletal bridging. Supporting Evidence: PMID:12615977 This site was mapped to the central rod of alpha-actinin, which contains spectrin-like repeats 2 and 3. In the case of LPP, a conserved motif present at the N-terminus was shown to be responsible for the interaction. |
| GO:0030335 positive regulation of cell migration | IMP PMID:23447672 A complex containing LPP and Ξ±-actinin mediates TGFΞ²-induced... | NEW | Summary: LPP positively regulates TGFΞ²-induced migration in human HER2-positive HCC1954 breast-cancer cells. Reason: Transient LPP knockdown abolished the TGFΞ²-induced increase in HCC1954 cell migration. The assignment is restricted to this HER2-positive human breast- cancer context and does not generalize the phenotype to all human cells. Supporting Evidence: PMID:23447672 Transient knockdown of LPP was sufficient to ablate the TGFΞ²-induced increase in migration (Fig. 1D) and invasion (Fig. 1E) seen in HCC1954 cells transfected with control siRNAs. |
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Download this section (compressed HTML)Q: Which LPP partner combinations occupy focal adhesions, stress fibers, and cell-cell junctions in unperturbed human cells?
Q: What molecular mechanism imports intact LPP into the nucleus, and which physiological stimuli control its import-export balance?
Q: Does nuclear LPP regulate endogenous transcription or chromatin-associated processes independently of the reporter transactivation seen in GAL4 assays?
Q: How do force and matrix stiffness alter LPP conformation, modification, and selection among VASP, ACTN1, palladin, and SCRIB?
Q: Do smooth-muscle-enriched transcripts initiated from the intronic promoter produce a distinguishable LPP protein species or only change abundance?
Experiment: Perform endogenous LPP proximity labeling and quantitative cross-linking mass spectrometry in human epithelial and vascular smooth-muscle cells under low and high tension, with interaction-motif mutants analyzed in parallel.
Hypothesis: Mechanical context reorganizes LPP partner occupancy, and distinct mapped motifs recruit separable VASP-, ACTN1-, palladin-, and SCRIB-containing modules.
Experiment: Use single-molecule imaging and fluorescence recovery measurements of endogenously tagged LPP at focal adhesions, stress fibers, and cell-cell junctions while selectively disrupting each interaction determinant.
Hypothesis: LPP is a dynamic adaptor rather than an obligate complex subunit, and each partner-binding surface makes a distinct contribution to adhesion residence time.
Experiment: Map nuclear import determinants by CRISPR tiling mutagenesis of endogenous LPP, coupled to live-cell import/export measurements with and without CRM1 inhibition and mechanical stimulation.
Hypothesis: A regulated import determinant distinct from the known leucine-rich export signal controls stimulus-dependent nuclear accumulation.
Experiment: Compare chromatin occupancy, nascent transcription, and nuclear interactomes after acute endogenous LPP degradation and rescue with export-defective or adhesion-targeting-defective variants.
Hypothesis: If intact LPP has a physiological nuclear function, nuclear retention will produce reproducible endogenous transcriptional or chromatin-associated effects.
Experiment: Resolve transcripts initiated from the canonical and intronic promoters by long-read RNA sequencing and ribosome profiling in human smooth-muscle cells, followed by N-terminomics of endogenous LPP.
Hypothesis: The intronic promoter primarily changes tissue-specific LPP abundance unless it generates a translated protein species with a distinct N terminus.
What is not known β curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The endogenous composition, stoichiometry, and exchange kinetics of LPP- organized adhesion assemblies are unknown, including whether VASP, ACTN1, palladin, and SCRIB bind simultaneously or in mutually exclusive contexts.
Gap: The mechanism that imports intact LPP into the nucleus, the signals that regulate import versus CRM1-dependent export, and any endogenous nuclear binding partners or transcriptional targets remain unresolved.
Gap: It is unclear how force, matrix stiffness, phosphorylation, or other modifications change the accessibility and partner preferences of LPP's proline-rich region, LIM domains, and terminal PDZ-binding sequence.
Gap: Human physiological requirements for LPP in vascular smooth muscle and other normal tissues remain incompletely defined; pressure-dependent vascular phenotypes currently rely substantially on mouse knockout evidence.
Gap: An intronic promoter produces smooth-muscle-enriched LPP transcripts, but it is unknown whether these transcripts alter the protein product, translation, localization, or molecular function.
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