AFAP1L1 is an adaptor/scaffold protein of the AFAP family that links actin cytoskeleton structures to signaling pathways at invadosomes and podosomes. It contains two PH domains, a proline-rich SH3-binding motif, a leucine-zipper/coiled-coil region, and a C-terminal actin-binding region. AFAP1L1 binds cortactin (CTTN) via its proline-rich motif and localizes to invadosomes, podosomes, and stress fibers. It functions as an adaptor that promotes formation of actin-rich degradative structures supporting cell migration and invasion. Phosphorylation by Src family kinases creates docking sites for downstream effectors: pY136 binds Vav2 (a Rho GTPase GEF) and pY566 binds Nck2 (an actin-nucleating adaptor). In cancer, AFAP1L1 promotes EMT and metastasis via a VAV2-CDC42-ITGA5/integrin signaling axis. AFAP1L1 also regulates pathological angiogenesis through the YAP-DLL4-NOTCH signaling axis under hypoxic conditions, where HIF-1alpha directly activates AFAP1L1 transcription.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference supports cytosolic localization. The deep research and UniProt confirm cytoplasmic localization based on experimental evidence from PMID:21333378. Reason: IBA annotation is consistent with experimental evidence. PMID:21333378 describes AFAP1L1 as decorating actin filaments and moving to punctate actin structures in the cytoplasm. Supporting Evidence: PMID:21333378 AFAP1L1 was shown by fluorescence microscopy to decorate actin filaments and move to punctate actin structures file:human/AFAP1L1/AFAP1L1-deep-research-falcon.md AFAP1L1 contains two PH domains (PH1, PH2), a proline-rich SH3-binding motif |
| GO:0001725 stress fiber | IEA GO_REF:0000044 | ACCEPT | Summary: Stress fiber localization is supported by fluorescence microscopy evidence showing AFAP1L1 decorates actin filaments. Reason: PMID:21333378 states AFAP1L1 decorates actin filaments by fluorescence microscopy. The deep research confirms localization to actin stress fibers and cortical actin. Supporting Evidence: PMID:21333378 AFAP1L1 was shown by fluorescence microscopy to decorate actin filaments file:human/AFAP1L1/AFAP1L1-deep-research-falcon.md Subcellular localization: actin stress fibers and cortical actin |
| GO:0002102 podosome | IEA GO_REF:0000044 | ACCEPT | Summary: Podosome localization is a core functional aspect of AFAP1L1, directly supported by experimental evidence showing AFAP1L1 induces and localizes to podosomes. Reason: PMID:21333378 provides direct evidence that AFAP1L1 localizes to podosomes and can induce podosome formation upon overexpression in A7r5 cells. Supporting Evidence: PMID:21333378 Upon overexpression in A7r5 cells, AFAP1L1 had the ability to induce podosome formation and move to podosomes without stimulation |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Cytoplasm localization is experimentally validated. This is a broader term that encompasses the more specific localizations (stress fiber, podosome). Reason: PMID:21333378 demonstrates cytoplasmic localization through fluorescence microscopy showing AFAP1L1 decorates actin filaments and moves to punctate structures. Supporting Evidence: PMID:21333378 AFAP1L1 was shown by fluorescence microscopy to decorate actin filaments and move to punctate actin structures |
| GO:0042995 cell projection | IEA GO_REF:0000044 | ACCEPT | Summary: Cell projection localization is consistent with podosome and invadosome localization. Podosomes are actin-rich cell projections. Reason: PMID:21333378 shows AFAP1L1 localizes to invadosomes which are specialized cell projections involved in ECM degradation. Supporting Evidence: PMID:21333378 move to punctate actin structures and colocalize with cortactin, consistent with localization to invadosomes |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: This annotation is from a high-throughput interactome study. The term "protein binding" is uninformative and should be replaced with more specific molecular function terms. Reason: Per GO curation guidelines, "protein binding" (GO:0005515) is too vague and does not convey meaningful functional information. AFAP1L1's known binding partners include cortactin (via SH3 domain interaction) and VAV2. More informative annotations would be SH3 domain binding (GO:0017124) to capture its proline-rich motif-mediated interactions. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | REMOVE | Summary: This annotation is from a high-throughput study on genetic variants affecting protein interactions. The term "protein binding" is uninformative. Reason: Per GO curation guidelines, "protein binding" (GO:0005515) is too vague and does not convey meaningful functional information. The specific interactions (e.g., with cortactin via SH3 domain) should be annotated with more specific terms. Supporting Evidence: PMID:31515488 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: This annotation is from a high-throughput binary interactome study. The term "protein binding" is uninformative. Reason: Per GO curation guidelines, "protein binding" (GO:0005515) is too vague and does not convey meaningful functional information. AFAP1L1's characterized interactions are mediated by specific domains (SH3-binding motif, PH domains) and should be annotated with appropriate specific terms. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome. |
| GO:0017124 SH3 domain binding | IPI PMID:21333378 AFAP1L1 is a novel adaptor protein of the AFAP family that i... | NEW | Summary: AFAP1L1 contains a proline-rich SH3-binding motif (DLPPPLPNKP) that mediates its interaction with cortactin SH3 domain with approximately 9-fold higher affinity compared to cSrc. This is a core molecular function distinguishing AFAP1L1 from AFAP1. Reason: PMID:21333378 directly demonstrates that the SH3 binding motif of AFAP1L1 interacts with the SH3 domain of cortactin, and does so more efficiently than with cSrc. The cyberian deep research quantifies this as approximately 9-fold higher affinity for cortactin, which distinguishes AFAP1L1's function from AFAP1. Supporting Evidence: PMID:21333378 the SH3 binding motif of AFAP1L1 was more efficient at interacting with the SH3 domain of cortactin and not cSrc file:human/AFAP1L1/AFAP1L1-deep-research-cyberian.md the AFAP1L1 SH3 binding motif exhibits approximately 9-fold higher affinity for cortactin's SH3 domain compared to cSrc |
| GO:0071800 podosome assembly | IMP PMID:21333378 AFAP1L1 is a novel adaptor protein of the AFAP family that i... | NEW | Summary: AFAP1L1 induces podosome formation when overexpressed. This is a core biological process function. Reason: PMID:21333378 directly shows that AFAP1L1 overexpression induces podosome formation in A7r5 cells without stimulation. The authors hypothesize AFAP1L1 affects invadosome formation through unique protein interactions. Supporting Evidence: PMID:21333378 Upon overexpression in A7r5 cells, AFAP1L1 had the ability to induce podosome formation and move to podosomes without stimulation |
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Download this section (compressed HTML)Q: What is the precise mechanism by which AFAP1L1 promotes podosome/invadosome formation? Is it required for assembly or stabilization?
Q: Does AFAP1L1 have any role in normal physiological processes beyond cancer invasion, given its expression in microvasculature and muscle tissues?
Q: Are there other SH3 domain-containing proteins that AFAP1L1 interacts with besides cortactin?
Experiment: Knockout/knockdown studies in normal cell types to determine if AFAP1L1 is required for podosome formation or has redundant functions with AFAP1
Experiment: Detailed mapping of the AFAP1L1 interactome using proximity labeling approaches to identify additional binding partners at podosomes/invadopodia
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