| Functional aspect | Current understanding of FKBPL role | Key interaction partners / targets | Subcellular localization | Pathways / processes regulated | Evidence / notes | Citation |
|---|---|---|---|---|---|---|
| Molecular class / catalytic activity | FKBPL is a divergent FKBP-family immunophilin with a PPIase-like domain but is generally described as lacking significant peptidyl-prolyl cis-trans isomerase activity; current evidence supports a non-enzymatic co-chaperone/scaffold role rather than a classical catalytic isomerase role. | Hsp90-family machinery; client/regulatory proteins inferred through co-chaperone function | Primarily intracellular; also secreted/extracellular in some contexts | Proteostasis, signaling regulation, angiogenesis control | Reviews and experimental papers consistently describe FKBPL as a divergent immunophilin with little/no significant PPIase activity, aligning with its domain architecture and functional behavior. | (pqac-00000001, pqac-00000003, pqac-00000009) |
| Intracellular co-chaperone function | Intracellular FKBPL acts in complex with Hsp90 as a regulatory co-chaperone, contributing to protein stability/signaling rather than serving as an enzyme with defined small-molecule substrates. | Hsp90, p21; steroid receptors including ER, AR, and glucocorticoid receptor | Cytosol / intracellular chaperone complex | Cell-cycle regulation, steroid receptor signaling, cancer-related signaling | Multiple studies state that intracellular FKBPL stabilizes p21 and regulates ER/AR/GR signaling in an Hsp90-associated complex. | (pqac-00000001, pqac-00000003, pqac-00000004) |
| p21 stabilization / cell-cycle control | A key described intracellular function is stabilization of p21, consistent with a role in cell-cycle restraint and tumor-suppressive behavior. | p21, Hsp90 | Intracellular | Cell-cycle progression, response to stress, tumor suppression | FKBPL binding to p21 is reported to prevent proteasomal degradation; knockdown reduces p21 stability. | (pqac-00000001, pqac-00000004) |
| Secreted anti-angiogenic function | FKBPL also functions extracellularly as a secreted anti-angiogenic protein; peptide derivatives from its N-terminus recapitulate this activity. | CD44 is the main proposed cell-surface target/receptor; endothelial and tumor cells are responsive | Extracellular / secreted; acts at cell surface | Angiogenesis inhibition, endothelial migration inhibition, vascular homeostasis | FKBPL is described as secreted by fibroblasts/endothelial cells, and N-terminal peptides outside the Hsp90-binding region inhibit tumor and endothelial migration. | (pqac-00000000, pqac-00000001, pqac-00000012, pqac-00000014) |
| CD44-linked extracellular signaling | The anti-angiogenic and anti-cancer stem cell activities of FKBPL and derived peptides are linked to targeting CD44-dependent biology. | CD44 | Extracellular / cell-surface signaling interface | Angiogenesis, stemness, migration, metastasis | Several studies identify CD44 as a potential or functional target mediating extracellular FKBPL activity; some effects are CD44-dependent, though not all CSC effects appear fully dependent on CD44 alone. | (pqac-00000001, pqac-00000003, pqac-00000011, pqac-00000014) |
| CD44/STAT3 axis in ovarian cancer | FKBPL-derived peptide ALM201 suppresses ovarian cancer stem-cell features and angiogenesis in part through the CD44/STAT3 pathway. | CD44, STAT3 | Predominantly extracellular therapeutic mechanism with downstream intracellular signaling consequences | Cancer stemness, differentiation, angiogenesis | In HGSOC models, ALM201 reduced CSCs, induced differentiation, and targeted the CD44/STAT3 pathway, especially in vascularized tumors. | (pqac-00000001) |
| DLL4/Notch4 regulation in breast cancer stem cells | FKBPL overexpression or treatment with AD-01/ALM201 downregulates DLL4 and Notch4 signaling, suppressing cancer stem cell phenotypes and metastasis. | DLL4, Notch4, CD44 | Extracellular and intracellular effects both implicated | CSC maintenance, endocrine resistance, migration, invasion, metastasis | FKBPL overexpression reduced holoclone formation and DLL4; peptides lowered DLL4 and Notch4 ICD and inhibited metastasis-related behaviors. | (pqac-00000003, pqac-00000011) |
| NF-κB / vascular integrity / inflammation | FKBPL is a regulator of vascular integrity and inflammatory signaling; reduced FKBPL enhances endothelial permeability and NF-κB activation, while FKBPL-derived peptides suppress inflammatory outputs. | NF-κB pathway components including p65/RelA; VE-cadherin-associated junctional machinery | Intracellular and extracellular/therapeutic peptide effects | Endothelial barrier function, cytokine production, inflammation | FKBPL knockdown increased permeability, TNF expression, and p65 phosphorylation; AD-01/ALM201 reduced p65 activation and improved survival in LPS models. | (pqac-00000002, pqac-00000000) |
| Hypoxia / endothelial dysfunction | FKBPL restrains hypoxia-driven endothelial migration and dysfunction; peptide replacement restores vascular integrity-associated phenotypes under hypoxia. | HIF-1α, VE-cadherin, CD31; downstream tissue-remodeling proteins | Endothelial cell-associated; intracellular/extracellular peptide-responsive system | Hypoxia responses, angiogenesis, endothelial dysfunction | In ischemia/hypoxia models, FKBPL was downregulated; AD-01 restored VE-cadherin and normalized migration and endothelial markers. | (pqac-00000000) |
| ER-phagy scaffold function | Recent work identifies FKBPL as a cytosolic ER-phagy regulator that appears to act as a scaffold bridging ER-resident and autophagy machinery rather than as an enzyme. | CKAP4, LC3A/B/C, GABARAPL1; self-association/oligomerization | Cytosolic with ER-associated recruitment | ER fragmentation, ER-phagy, ER quality control, secretory regulation | 2024 data show FKBPL interacts with CKAP4 and LC3/GABARAP proteins, oligomerizes at the ER, and promotes ER fragmentation and ER-phagy. | (pqac-00000013) |
| Protein secretion / organelle homeostasis | Loss of the FKBPL-CKAP4 module impairs ER/Golgi/lysosome homeostasis and enhances secretion via ER-derived secretory vesicles and microvesicle shedding. | CKAP4; ER/Golgi/lysosome systems | Cytosol-ER interface | Protein secretion, secretory vesicle formation, organelle quality control | FKBPL-CKAP4 deficiency caused Golgi disassembly, lysosome impairment, and increased cytosolic protein secretion. | (pqac-00000013) |
| Developmental / vascular-essential role | FKBPL is required for normal embryonic and vascular development; complete loss is embryonic lethal and partial loss causes vascular dysfunction. | Vascular developmental machinery; exact direct partners incompletely defined | Organism-wide; especially vascular tissues | Developmental angiogenesis, vascular integrity | Homozygous knockout is embryonic lethal, and heterozygous deficiency produces early endothelial/vascular dysfunction phenotypes. | (pqac-00000000, pqac-00000001, pqac-00000007) |


*Table: This table summarizes the best-supported functions, partners, localization, and pathway roles of human FKBPL across intracellular, extracellular, and recent ER-phagy contexts. It is useful for distinguishing FKBPL's scaffold/co-chaperone roles from classical enzymatic FKBP activity.*