GO Term	Evidence	Action	Reason
GO:0005515 protein binding	IPI PMID:25036637 A quantitative chaperone interaction network reveals the arc...	KEEP AS NON CORE	Summary: Quantitative chaperone interaction network (Taipale et al.) capturing an FKBPL-ANKRD49 (Q8WVL7) interaction. Bare protein binding is uninformative. Reason: A recurrent interaction partner (ANKRD49), but recorded as bare protein binding; not the characterized core HSP90/p21 co-chaperone function. Supporting Evidence: file:human/FKBPL/FKBPL-goa.tsv GO:0005515 protein binding IPI PMID:25036637 UniProtKB:Q8WVL7
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	KEEP AS NON CORE	Summary: Yeast two-hybrid human interactome screen capturing an FKBPL-CALCOCO2/NDP52 (Q13137) interaction. Bare protein binding is uninformative. Reason: A documented interaction (CALCOCO2), but recorded as bare protein binding; not the characterized core function. Supporting Evidence: file:human/FKBPL/FKBPL-goa.tsv GO:0005515 protein binding IPI PMID:25416956 UniProtKB:Q13137
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	KEEP AS NON CORE	Summary: IntAct interaction with ANKRD49 (Q8WVL7). Bare protein binding is uninformative; a recurrent partner. Reason: A recurrent interaction (ANKRD49) recorded as bare protein binding; not the characterized core function. Supporting Evidence: file:human/FKBPL/FKBPL-goa.tsv GO:0005515 protein binding IPI PMID:28514442 UniProtKB:Q8WVL7
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	Summary: High-throughput interactome screen capturing an FKBPL-ANKRD49 (Q8WVL7) interaction. Bare protein binding is uninformative. Reason: Bare protein binding from a high-throughput screen; uninformative and not reflective of the characterized core function. Supporting Evidence: file:human/FKBPL/FKBPL-goa.tsv GO:0005515 protein binding IPI PMID:32296183 UniProtKB:Q8WVL7
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	KEEP AS NON CORE	Summary: BioPlex affinity-purification interactome capturing an FKBPL-ANKRD49 (Q8WVL7) interaction. Bare protein binding is uninformative. Reason: A recurrent interaction (ANKRD49) recorded as bare protein binding; not the characterized core function. Supporting Evidence: file:human/FKBPL/FKBPL-goa.tsv GO:0005515 protein binding IPI PMID:33961781 UniProtKB:Q8WVL7
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	KEEP AS NON CORE	Summary: Multimodal cell-maps interactome capturing an FKBPL-ANKRD49 (Q8WVL7) interaction. Bare protein binding is uninformative. Reason: A recurrent interaction (ANKRD49) recorded as bare protein binding; not the characterized core function. Supporting Evidence: file:human/FKBPL/FKBPL-goa.tsv GO:0005515 protein binding IPI PMID:40205054 UniProtKB:Q8WVL7
GO:0005576 extracellular region	IDA PMID:25767277 FKBPL is a critical antiangiogenic regulator of developmenta...	KEEP AS NON CORE	Summary: Direct evidence that FKBPL is a secreted, extracellular protein, consistent with its characterized anti-angiogenic activity as a secreted factor. Falcon deep research corroborates that FKBPL is secreted by fibroblasts and endothelial cells and acts at the cell surface as an anti-angiogenic factor targeting CD44. Reason: A genuine secreted/extracellular pool with anti-angiogenic function, but distinct from FKBPL's intracellular HSP90/p21 co-chaperone role; retained as non-core. Supporting Evidence: file:human/FKBPL/FKBPL-goa.tsv GO:0005576 extracellular region IDA PMID:25767277 file:human/FKBPL/FKBPL-deep-research-falcon.md FKBPL is also secreted by fibroblasts and endothelial cells, functioning as an extracellular anti-angiogenic protein
GO:0005829 cytosol	TAS Reactome:R-HSA-8852362	ACCEPT	Summary: Reactome annotation placing FKBPL in the cytosol, consistent with its intracellular HSP90/p21 co-chaperone function. Falcon deep research independently describes FKBPL as primarily cytosolic, participating in Hsp90-mediated chaperone complexes. Reason: The cytosol is where FKBPL acts as an HSP90/p21 co-chaperone; a reasonable localization. Supporting Evidence: file:human/FKBPL/FKBPL-uniprot.txt Regulates p21 protein stability by binding to Hsp90 and p21. file:human/FKBPL/FKBPL-deep-research-falcon.md Within cells, FKBPL is primarily localized to the cytosol where it participates in Hsp90-mediated chaperone complexes
GO:0009314 response to radiation	NAS PMID:10521921 A novel human stress response-related gene with a potential ...	KEEP AS NON CORE	Summary: FKBPL was identified as a stress-response gene with a potential role in induced radioresistance; it may be involved in the response to X-ray. A plausible biological process. Reason: A documented (NAS) stress/radiation-response role consistent with its regulation of p21 stability, but a non-core process relative to the molecular co-chaperone function. Supporting Evidence: PMID:10521921 A novel human stress response-related gene with a potential role in induced radioresistance. file:human/FKBPL/FKBPL-uniprot.txt May be involved in response to X-ray.

Deep Research

Falcon

(FKBPL-deep-research-falcon.md)

Comprehensive Research Report: FKBPL (FK506-Binding Protein-Like) Falcon Edison Scientific Literature 23 citations 1 artifacts 2026-06-20T06:28:41.340257

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Comprehensive Research Report: FKBPL (FK506-Binding Protein-Like)

Gene and Protein Identity

FKBPL (FK506-binding protein-like), also known as WISp39 (WAF-1/CIP1 stabilizing protein 39) or DIR1, is encoded by the FKBPL gene in humans (UniProt accession: Q9UIM3). The protein is 349 amino acids in length and belongs to the FK506-binding protein (FKBP) immunophilin family (zgajnar2019biologicalactionsof pages 1-3, li2025fk506‑bindingproteinsas pages 1-2). FKBPL is characterized by the presence of FKBP-like and tetratricopeptide repeat (TPR) domains, which are critical for its diverse biological functions (bibber2020intrinsicdisorderin pages 13-19, zgajnar2019biologicalactionsof pages 1-3).

Primary Molecular Function and Enzymatic Activity

Divergent FKBP Family Member

FKBPL is a divergent member of the FK506-binding protein family that notably lacks significant peptidyl-prolyl cis-trans isomerase (PPIase) enzymatic activity, distinguishing it from classical FKBPs such as FKBP12, FKBP51, and FKBP52 (mcclements2019fkbplandits pages 1-2, zgajnar2019biologicalactionsof pages 1-3, nath2017peptidylprolylisomerase(ppiase) pages 3-6). While FKBPL possesses a PPIase-like domain, multiple studies confirm that it does not exhibit the characteristic catalytic isomerase activity of other family members (annett2020fkbplbasedpeptidealm201 pages 1-2, nath2017peptidylprolylisomerase(ppiase) pages 3-6, shelton2017imbalancesinthe pages 2-3, zgajnar2019biologicalactionsof pages 1-3). Instead, FKBPL functions primarily as a non-enzymatic scaffold and co-chaperone protein that orchestrates protein-protein interactions rather than catalyzing specific biochemical reactions on small-molecule substrates (mcclements2019fkbplandits pages 1-2, zgajnar2019biologicalactionsof pages 1-3).

Molecular Chaperone Complex and p21 Stabilization

The primary intracellular function of FKBPL involves its role as an Hsp90-associated co-chaperone. FKBPL forms complexes with heat shock protein 90 (Hsp90) and contributes to the stabilization and regulation of multiple client proteins (annett2020fkbplbasedpeptidealm201 pages 1-2, mcclements2019fkbplandits pages 1-2, nath2017peptidylprolylisomerase(ppiase) pages 3-6). A key substrate of this chaperone complex is the cyclin-dependent kinase inhibitor p21 (CDKN1A). FKBPL binding to p21 prevents its proteasomal degradation, thereby stabilizing p21 levels and contributing to cell cycle regulation and tumor suppressive functions (annett2020fkbplbasedpeptidealm201 pages 1-2, nath2017peptidylprolylisomerase(ppiase) pages 3-6). This interaction represents a critical mechanism through which FKBPL exerts its anti-proliferative effects.

Subcellular Localization

FKBPL exhibits dual subcellular localization patterns, functioning in both intracellular and extracellular compartments:

Intracellular Localization

Within cells, FKBPL is primarily localized to the cytosol where it participates in Hsp90-mediated chaperone complexes (annett2020fkbplbasedpeptidealm201 pages 1-2, mcclements2019fkbplandits pages 1-2). Recent evidence from 2024 has identified a novel ER-associated function, demonstrating that FKBPL can localize to the endoplasmic reticulum (ER) membrane where it interacts with the ER-resident transmembrane protein CKAP4 (cytoskeleton-associated protein 4) to regulate ER-phagy and protein secretion (li2024cytosolicfkbpland pages 1-2). In this context, FKBPL acts as a cytosolic ER-phagy regulator that bridges ER-resident factors with autophagy machinery, including LC3A, LC3B, LC3C, and GABARAPL1, through two LIR (LC3-interacting region) motifs (li2024cytosolicfkbpland pages 1-2).

Extracellular/Secreted Function

FKBPL is also secreted by fibroblasts and endothelial cells, functioning as an extracellular anti-angiogenic protein (ghorbanpour2025thefkbplbasedtherapeutic pages 1-2, annett2020fkbplbasedpeptidealm201 pages 1-2, rao2015novelendogenousangiogenesis pages 4-5). The secreted form of FKBPL acts at the cell surface, where it targets the CD44 receptor to inhibit endothelial cell migration, tumor angiogenesis, and cancer stem cell properties (annett2020fkbplbasedpeptidealm201 pages 1-2, mcclements2019fkbplandits pages 1-2, mcclements2019fkbplandits pages 5-8, cabri2021therapeuticpeptidestargeting pages 6-7). The N-terminal region of FKBPL (amino acids 34-57), which is outside the Hsp90-binding domain, contains the potent anti-angiogenic activity and has been exploited for therapeutic peptide development (ghorbanpour2025thefkbplbasedtherapeutic pages 1-2, annett2020fkbplbasedpeptidealm201 pages 1-2).

Signaling and Biochemical Pathways

FKBPL participates in multiple signaling pathways with distinct molecular mechanisms:

1. Angiogenesis Regulation via CD44

Extracellular FKBPL functions as a key negative regulator of angiogenesis by targeting the CD44 receptor on endothelial cells and tumor cells (annett2020fkbplbasedpeptidealm201 pages 1-2, mcclements2019fkbplandits pages 1-2, mcclements2019fkbplandits pages 5-8). This interaction inhibits endothelial cell migration, tube formation, and tumor angiogenesis (ghorbanpour2025thefkbplbasedtherapeutic pages 1-2, annett2020fkbplbasedpeptidealm201 pages 1-2). FKBPL homozygous knockout mice exhibit embryonic lethality with vascular irregularities, while heterozygous mice show early vascular dysfunction, underscoring the critical role of FKBPL in developmental and physiological angiogenesis (ghorbanpour2025thefkbplbasedtherapeutic pages 1-2, annett2020fkbplbasedpeptidealm201 pages 1-2, rad2025crisprcas9mediatedgeneediting pages 1-5).

2. Cancer Stem Cell Regulation via DLL4/Notch4 and CD44/STAT3 Pathways

FKBPL and its peptide derivatives regulate cancer stem cell (CSC) populations through modulation of the Delta-like ligand 4 (DLL4)/Notch4 signaling axis. Overexpression of FKBPL or treatment with FKBPL-based peptides (AD-01, ALM201) significantly downregulates DLL4 and the Notch4 intracellular domain (Notch4 ICD), leading to reduced CSC markers and induced differentiation in both triple-negative and ER-positive breast cancer models (mcclements2019fkbplandits pages 1-2, mcclements2019fkbplandits pages 5-8). Additionally, in ovarian cancer, ALM201 targets the CD44/STAT3 pathway, reducing CSC populations and inducing differentiation particularly in highly vascularized tumors (annett2020fkbplbasedpeptidealm201 pages 1-2).

3. NF-κB Pathway and Inflammatory Signaling

FKBPL regulates vascular integrity and inflammatory responses through modulation of the NF-κB signaling pathway. Loss of FKBPL increases endothelial barrier permeability, elevates TNF mRNA expression, and enhances phosphorylation of p65/RelA, the key transcriptional component of NF-κB (annett2021theimmunophilinprotein pages 1-5). Conversely, treatment with FKBPL-derived peptides (AD-01, ALM201) inhibits p65/RelA phosphorylation, reduces NF-κB target gene expression, and decreases pro-inflammatory cytokine production (TNF, IL-6) (annett2021theimmunophilinprotein pages 1-5). In an in vivo LPS-induced sepsis model, ALM201 treatment resulted in 100% survival at experimental endpoint and abrogated pro-inflammatory cytokine production (annett2021theimmunophilinprotein pages 1-5).

4. Hypoxia and HIF-1α Regulation in Endothelial Dysfunction

Recent 2025 studies demonstrate that FKBPL plays a critical role in regulating endothelial responses to hypoxia. FKBPL expression is substantially downregulated in ischemic conditions, correlating with increased neovascularization (ghorbanpour2025thefkbplbasedtherapeutic pages 1-2). Under hypoxic conditions, FKBPL deficiency leads to suppressed VE-cadherin expression and increased endothelial cell migration. The FKBPL-based peptide AD-01 restores endothelial function by stabilizing HIF-1α, normalizing VE-cadherin and CD31 expression, and enhancing tissue remodeling proteins including collagen alpha-1(XIX) and junctional cadherin-associated protein 5 (JCAD) (ghorbanpour2025thefkbplbasedtherapeutic pages 1-2).

5. ER-Phagy and Protein Secretion Regulation

A novel function discovered in 2024 reveals that FKBPL acts as a cytosolic regulator of ER-phagy (selective autophagy of the endoplasmic reticulum). FKBPL interacts with the ER-resident membrane protein CKAP4 and serves as a scaffold connecting CKAP4 with LC3/GABARAP family members through its LIR motifs (li2024cytosolicfkbpland pages 1-2). Overexpression of FKBPL triggers ER fragmentation and ER-phagy, while loss of the FKBPL-CKAP4 module leads to Golgi disassembly, lysosome impairment, increased ER-derived secretory vesicles, and enhanced cytosolic protein secretion via microvesicle shedding (li2024cytosolicfkbpland pages 1-2). This pathway represents a critical quality control mechanism for ER homeostasis.

6. Steroid Receptor Signaling

Intracellular FKBPL participates in Hsp90-associated regulation of steroid hormone receptors, including estrogen receptor (ER), androgen receptor (AR), and glucocorticoid receptor (GR) (annett2020fkbplbasedpeptidealm201 pages 1-2, mcclements2019fkbplandits pages 1-2). Through these interactions, FKBPL modulates steroid receptor signaling and hormone-dependent cellular responses.

Biological Processes and Functional Significance

FKBPL's diverse functions contribute to multiple critical biological processes:

Cell Cycle Regulation: Through p21 stabilization, FKBPL restrains cell cycle progression and contributes to tumor suppressive mechanisms (annett2020fkbplbasedpeptidealm201 pages 1-2, nath2017peptidylprolylisomerase(ppiase) pages 3-6).
Vascular Development and Homeostasis: Essential for embryonic vascular development and adult vascular integrity (ghorbanpour2025thefkbplbasedtherapeutic pages 1-2, annett2020fkbplbasedpeptidealm201 pages 1-2, rad2025crisprcas9mediatedgeneediting pages 1-5).
Endothelial Function: Regulates endothelial barrier integrity, migration, and response to stress conditions (ghorbanpour2025thefkbplbasedtherapeutic pages 1-2, annett2021theimmunophilinprotein pages 1-5).
Cancer Stem Cell Maintenance: Suppresses CSC populations and induces differentiation in multiple cancer types (annett2020fkbplbasedpeptidealm201 pages 1-2, mcclements2019fkbplandits pages 1-2, mcclements2019fkbplandits pages 5-8).
Inflammation and Immune Response: Modulates inflammatory signaling and cytokine production through NF-κB regulation (annett2021theimmunophilinprotein pages 1-5).
ER Quality Control: Maintains ER homeostasis through regulation of ER-phagy and protein secretion (li2024cytosolicfkbpland pages 1-2).
Pregnancy and Placental Function: Critical for trophoblast function; reduced FKBPL is associated with preeclampsia pathogenesis (rad2025crisprcas9mediatedgeneediting pages 1-5).

Disease Associations and Clinical Significance

Cancer

FKBPL has emerged as a significant prognostic biomarker in multiple cancer types. Meta-analysis of five independent breast cancer tissue microarray cohorts (n=3,277 patients) demonstrated that low FKBPL expression is an independent predictor of breast cancer-specific survival (HR=1.31, 95% CI 1.15-1.50, p<0.001) (mcclements2019fkbplandits pages 1-2). In ER-positive breast cancer patients (n=2,365), low FKBPL expression similarly correlates with significantly shorter survival (HR=1.34, 95% CI 1.13-1.58, p<0.001) (mcclements2019fkbplandits pages 1-2). High endogenous FKBPL expression in ovarian cancer tumors is associated with increased progression-free interval, supporting a protective role (annett2020fkbplbasedpeptidealm201 pages 1-2).

Preeclampsia

FKBPL is significantly downregulated in early pregnancy stages of women who subsequently develop preeclampsia, suggesting its role as a potential early biomarker and therapeutic target for this severe pregnancy complication (rad2025crisprcas9mediatedgeneediting pages 1-5). Knockout studies in trophoblast cells demonstrate that FKBPL deficiency significantly reduces cell migration and proliferation, key processes in placental development (rad2025crisprcas9mediatedgeneediting pages 1-5).

Cardiovascular Disease

FKBPL is downregulated in cardiovascular disease contexts including peripheral artery disease and ischemic conditions (ghorbanpour2025thefkbplbasedtherapeutic pages 1-2). Heterozygous FKBPL deficiency in mice leads to early endothelial and vascular dysfunction, positioning FKBPL as a critical regulator of cardiovascular health (ghorbanpour2025thefkbplbasedtherapeutic pages 1-2, rad2025crisprcas9mediatedgeneediting pages 1-5).

Inflammatory Disorders

Genetic association studies of human biobanks have identified links between FKBPL genetic variants and inflammatory disorders including psoriasis, rheumatoid arthritis, and elevated lymphocyte counts (annett2021theimmunophilinprotein pages 1-5).

Therapeutic Applications and Drug Development

FKBPL-Based Peptide Therapeutics

Two major peptide therapeutics derived from the N-terminal anti-angiogenic region of FKBPL have been developed:

AD-01: A 24-amino acid preclinical peptide that has demonstrated potent anti-cancer activity in multiple preclinical models. AD-01 inhibits:
- Triple-negative breast cancer cell migration (p<0.05) and invasion (p<0.001) (mcclements2019fkbplandits pages 5-8)
- Metastatic load in experimental lung metastasis models (p<0.05) (mcclements2019fkbplandits pages 5-8)
- DLL4 and Notch4 expression in breast cancer cells (mcclements2019fkbplandits pages 5-8)
- NF-κB activation and inflammatory cytokine production (annett2021theimmunophilinprotein pages 1-5)
- Endothelial dysfunction under hypoxic conditions (ghorbanpour2025thefkbplbasedtherapeutic pages 1-2)

ALM201: A 23-amino acid clinical-stage peptide that has completed a Phase 1a clinical trial in patients with ovarian cancer and other advanced solid tumors (annett2020fkbplbasedpeptidealm201 pages 1-2, annett2021theimmunophilinprotein pages 1-5). ALM201 has received FDA orphan drug designation for ovarian cancer (annett2021theimmunophilinprotein pages 1-5). Key therapeutic effects include:
- Dual targeting of angiogenesis and cancer stem cells in ovarian cancer (annett2020fkbplbasedpeptidealm201 pages 1-2)
- 10-fold reduction in CSC populations in vascularized ovarian cancer xenografts (annett2020fkbplbasedpeptidealm201 pages 1-2)
- Inhibition of endocrine therapy-resistant CSCs in ER-positive breast cancer (mcclements2019fkbplandits pages 1-2, mcclements2019fkbplandits pages 5-8)
- Delayed tumor recurrence in limiting dilution assays: 12 days with ALM201 alone (p<0.05) and 21 days in combination with tamoxifen (p<0.001) (mcclements2019fkbplandits pages 5-8)
- 100% survival in LPS-induced sepsis model with complete abrogation of TNF and IL-6 production (annett2021theimmunophilinprotein pages 1-5)

Both peptides target the CD44/STAT3 pathway in tumors and show efficacy particularly in highly vascularized cancers with low IL-6 levels (annett2020fkbplbasedpeptidealm201 pages 1-2).

Summary of Key Findings

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.	(annett2020fkbplbasedpeptidealm201 pages 1-2, mcclements2019fkbplandits pages 1-2, zgajnar2019biologicalactionsof pages 1-3)
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.	(annett2020fkbplbasedpeptidealm201 pages 1-2, mcclements2019fkbplandits pages 1-2, nath2017peptidylprolylisomerase(ppiase) pages 3-6)
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.	(annett2020fkbplbasedpeptidealm201 pages 1-2, nath2017peptidylprolylisomerase(ppiase) pages 3-6)
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.	(ghorbanpour2025thefkbplbasedtherapeutic pages 1-2, annett2020fkbplbasedpeptidealm201 pages 1-2, rao2015novelendogenousangiogenesis pages 4-5, cabri2021therapeuticpeptidestargeting pages 6-7)
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.	(annett2020fkbplbasedpeptidealm201 pages 1-2, mcclements2019fkbplandits pages 1-2, mcclements2019fkbplandits pages 5-8, cabri2021therapeuticpeptidestargeting pages 6-7)
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.	(annett2020fkbplbasedpeptidealm201 pages 1-2)
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.	(mcclements2019fkbplandits pages 1-2, mcclements2019fkbplandits pages 5-8)
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.	(annett2021theimmunophilinprotein pages 1-5, ghorbanpour2025thefkbplbasedtherapeutic pages 1-2)
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.	(ghorbanpour2025thefkbplbasedtherapeutic pages 1-2)
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.	(li2024cytosolicfkbpland pages 1-2)
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.	(li2024cytosolicfkbpland pages 1-2)
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.	(ghorbanpour2025thefkbplbasedtherapeutic pages 1-2, annett2020fkbplbasedpeptidealm201 pages 1-2, rad2025crisprcas9mediatedgeneediting pages 1-5)

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.

Conclusion

FKBPL represents a multifunctional protein with critical roles in vascular biology, cancer biology, inflammation, and cellular homeostasis. As a divergent immunophilin lacking significant PPIase activity, FKBPL functions primarily as a scaffold and co-chaperone protein with both intracellular and extracellular activities. Its intracellular functions include Hsp90-mediated p21 stabilization, steroid receptor regulation, and ER-phagy coordination, while its secreted form acts as a potent anti-angiogenic factor targeting CD44-dependent pathways. The therapeutic potential of FKBPL-based peptides, particularly ALM201 which has advanced to clinical trials with FDA orphan drug designation, represents a promising avenue for treating cancers with high angiogenic and CSC burdens, as well as inflammatory and vascular disorders. Recent discoveries of FKBPL's role in ER-phagy (2024) and cardiovascular endothelial dysfunction (2025) continue to expand our understanding of this versatile protein's biological importance.

References

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(bibber2020intrinsicdisorderin pages 13-19): Nathan W. Van Bibber, Cornelia Haerle, Roy Khalife, Bin Xue, and Vladimir N. Uversky. Intrinsic disorder in tetratricopeptide repeat proteins. International Journal of Molecular Sciences, 21:3709, May 2020. URL: https://doi.org/10.3390/ijms21103709, doi:10.3390/ijms21103709. This article has 23 citations.
(mcclements2019fkbplandits pages 1-2): Lana McClements, Stephanie Annett, Anita Yakkundi, Martin O’Rourke, Andrea Valentine, Nermeen Moustafa, Abdelrahim Alqudah, Bruno M. Simões, Fiona Furlong, Amy Short, Stuart A. McIntosh, Helen O. McCarthy, Robert B. Clarke, and Tracy Robson. Fkbpl and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating dll4 and notch4. BMC Cancer, Apr 2019. URL: https://doi.org/10.1186/s12885-019-5500-0, doi:10.1186/s12885-019-5500-0. This article has 76 citations and is from a peer-reviewed journal.
(nath2017peptidylprolylisomerase(ppiase) pages 3-6): Pulak Nath. Peptidyl-prolyl isomerase (ppiase): an emerging area in tumor biology. ArXiv, 3:126-143, Apr 2017. URL: https://doi.org/10.17980/2017.126, doi:10.17980/2017.126. This article has 11 citations.
(annett2020fkbplbasedpeptidealm201 pages 1-2): Stephanie Annett, Stephanie Annett, G. Moore, Amy Short, A. Marshall, C. McCrudden, A. Yakkundi, Sudipto Das, W. McCluggage, Laura Nelson, I. Harley, Nermeen Moustafa, C. Kennedy, Anna DeFazio, Anna DeFazio, Alison Brand, Alison Brand, Raghwa Sharma, Raghwa Sharma, D. Brennan, S. O’Toole, J. O'Leary, M. Bates, C. Ó'Riain, D. O’Connor, F. Furlong, H. McCarthy, A. Kissenpfennig, L. McClements, L. McClements, T. Robson, and T. Robson. Fkbpl-based peptide, alm201, targets angiogenesis and cancer stem cells in ovarian cancer. British Journal of Cancer, 122:361-371, Nov 2020. URL: https://doi.org/10.1038/s41416-019-0649-5, doi:10.1038/s41416-019-0649-5. This article has 67 citations and is from a domain leading peer-reviewed journal.
(shelton2017imbalancesinthe pages 2-3): Lindsey B. Shelton, John Koren, and Laura J. Blair. Imbalances in the hsp90 chaperone machinery: implications for tauopathies. Frontiers in Neuroscience, Dec 2017. URL: https://doi.org/10.3389/fnins.2017.00724, doi:10.3389/fnins.2017.00724. This article has 99 citations and is from a peer-reviewed journal.
(li2024cytosolicfkbpland pages 1-2): Cathena Meiling Li, Jaemin Kang, Jongyeon Baek, Youbin Kim, Heemin Park, and Yong-Keun Jung. Cytosolic fkbpl and er-resident ckap4 co-regulates er-phagy and protein secretion. Nature communications, 15 1:7886, Sep 2024. URL: https://doi.org/10.1038/s41467-024-52188-7, doi:10.1038/s41467-024-52188-7. This article has 13 citations and is from a highest quality peer-reviewed journal.
(ghorbanpour2025thefkbplbasedtherapeutic pages 1-2): Sahar Ghorbanpour, Siân Peta Cartland, Hao Chen, Sanchit Seth, Rupert C. Ecker, Claire Richards, Dunja Aksentijevic, Matthew P. Padula, Louise Cole, Majid Ebrahimi Warkiani, Mary Meltem Kavurma, and Lana McClements. The fkbpl-based therapeutic peptide, ad-01, protects the endothelium from hypoxia-induced damage by stabilising hypoxia inducible factor-α and inflammation. Journal of Translational Medicine, Mar 2025. URL: https://doi.org/10.1186/s12967-025-06118-w, doi:10.1186/s12967-025-06118-w. This article has 8 citations and is from a peer-reviewed journal.
(rao2015novelendogenousangiogenesis pages 4-5): Nithya Rao, Yu Fei Lee, and Ruowen Ge. Novel endogenous angiogenesis inhibitors and their therapeutic potential. Acta Pharmacologica Sinica, 36:1177-1190, Sep 2015. URL: https://doi.org/10.1038/aps.2015.73, doi:10.1038/aps.2015.73. This article has 94 citations and is from a peer-reviewed journal.
(mcclements2019fkbplandits pages 5-8): Lana McClements, Stephanie Annett, Anita Yakkundi, Martin O’Rourke, Andrea Valentine, Nermeen Moustafa, Abdelrahim Alqudah, Bruno M. Simões, Fiona Furlong, Amy Short, Stuart A. McIntosh, Helen O. McCarthy, Robert B. Clarke, and Tracy Robson. Fkbpl and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating dll4 and notch4. BMC Cancer, Apr 2019. URL: https://doi.org/10.1186/s12885-019-5500-0, doi:10.1186/s12885-019-5500-0. This article has 76 citations and is from a peer-reviewed journal.
(cabri2021therapeuticpeptidestargeting pages 6-7): Walter Cabri, Paolo Cantelmi, Dario Corbisiero, Tommaso Fantoni, Lucia Ferrazzano, Giulia Martelli, Alexia Mattellone, and Alessandra Tolomelli. Therapeutic peptides targeting ppi in clinical development: overview, mechanism of action and perspectives. Frontiers in Molecular Biosciences, Jun 2021. URL: https://doi.org/10.3389/fmolb.2021.697586, doi:10.3389/fmolb.2021.697586. This article has 139 citations.
(rad2025crisprcas9mediatedgeneediting pages 1-5): Dorsa Morshedi Rad, Claire Richards, Sareh Zhand, Natasha de Alwis, Natalie J Hannan, Alen Faiz, Lana McClements, and Majid Ebrahimi Warkiani. Crispr/cas9-mediated gene editing in trophoblast cells via mechanoporation for preeclampsia insight. Cell Death & Disease, Nov 2025. URL: https://doi.org/10.1038/s41419-025-08200-z, doi:10.1038/s41419-025-08200-z. This article has 2 citations and is from a peer-reviewed journal.
(annett2021theimmunophilinprotein pages 1-5): Stephanie Annett, Shaun Spence, Carolina Garciarena, Ciaran Campbell, Margaret Dennehy, Clive Drakeford, Jacqueline Lai, Jennifer Dowling, Gillian Moore, Anita Yakkundi, Amy Short, Danny Sharpe, Fiona Furlong, James S. O’Donnell, Gianpiero Cavalleri, Steve Kerrigan, Irina G. Tikhonova, Pauline Johnson, Adrien Kissenpfennig, and Tracy Robson. The immunophilin protein fkbpl and its peptide derivatives are novel regulators of vascular integrity and inflammation via nf-κb signaling. bioRxiv, Feb 2021. URL: https://doi.org/10.1101/2021.02.24.431422, doi:10.1101/2021.02.24.431422. This article has 16 citations.

Artifacts

Edison artifact artifact-00

Citations

li2024cytosolicfkbpland pages 1-2
annett2021theimmunophilinprotein pages 1-5
ghorbanpour2025thefkbplbasedtherapeutic pages 1-2
mcclements2019fkbplandits pages 1-2
mcclements2019fkbplandits pages 5-8
zgajnar2019biologicalactionsof pages 1-3
bibber2020intrinsicdisorderin pages 13-19
shelton2017imbalancesinthe pages 2-3
rao2015novelendogenousangiogenesis pages 4-5
cabri2021therapeuticpeptidestargeting pages 6-7
https://doi.org/10.3390/biom9020052,
https://doi.org/10.3892/ijmm.2025.5701,
https://doi.org/10.3390/ijms21103709,
https://doi.org/10.1186/s12885-019-5500-0,
https://doi.org/10.17980/2017.126,
https://doi.org/10.1038/s41416-019-0649-5,
https://doi.org/10.3389/fnins.2017.00724,
https://doi.org/10.1038/s41467-024-52188-7,
https://doi.org/10.1186/s12967-025-06118-w,
https://doi.org/10.1038/aps.2015.73,
https://doi.org/10.3389/fmolb.2021.697586,
https://doi.org/10.1038/s41419-025-08200-z,
https://doi.org/10.1101/2021.02.24.431422,

📚 Additional Documentation

Notes

(FKBPL-notes.md)

FKBPL (WISp39) research notes

UniProt: Q9UIM3. FK506-binding protein-like. Contains TPR repeats (TPR-like helical domain)
but NO canonical FKBP-type PPIase catalytic domain -> not a bona fide rotamase (no PPIase activity).

Core biology

Hsp90-binding TPR co-chaperone that regulates p21(WAF1/CIP1)/CDKN1A protein stability by
binding both Hsp90 and p21 [uniprot "Regulates p21 protein stability by binding to Hsp90 and
p21"; PMID:15664193 "Regulation of p21(WAF1/CIP1) stability by WISp39, a Hsp90 binding TPR
protein"]. Forms ternary complex with CDKN1A/p21 and HSP90AB1 [uniprot "Forms a ternary complex
with CDKN1A/p21 and HSP90AB1/Hsp90"]. K287A/R291A mutations abolish HSP90AB1 binding.
Stress/radiation response: novel stress-response gene with potential role in induced radioresistance
PMID:10521921; response to radiation (NAS).
Secreted/extracellular anti-angiogenic factor (extracellular region IDA PMID:25767277); FKBPL
and its peptide derivatives (e.g. ALM201) have anti-angiogenic activity. Extracellular detection.
Interactors: HSP90AB1 (P08238, via TPR), CDKN1A/p21, ANKRD49 (Q8WVL7), CALCOCO2/NDP52 (Q13137).

GOA IPI partners (bare protein binding)

25036637(Q8WVL7 ANKRD49), 25416956(Q13137 CALCOCO2), 28514442(Q8WVL7), 32296183(Q8WVL7),
33961781(Q8WVL7), 40205054(Q8WVL7). Note: HSP90 not directly in these IPI WITH fields; the HSP90
binding is in UniProt FUNCTION/SUBUNIT, not the GOA protein-binding rows.

Action plan

protein binding IPI block: KEEP_AS_NON_CORE (ANKRD49, CALCOCO2 are recurrent partners but bare
protein binding; not the characterized core function). MARK_AS_OVER_ANNOTATED the broad screens.
extracellular region IDA GO:0005576: KEEP_AS_NON_CORE (secreted anti-angiogenic pool, real but
context-specific; primary characterized function is intracellular Hsp90/p21).
cytosol TAS GO:0005829: ACCEPT (site of Hsp90/p21 co-chaperone action).
response to radiation NAS GO:0009314: KEEP_AS_NON_CORE (stress-response role; NAS).
Core MF to capture: Hsp90 protein binding (GO:0051879) / heat shock protein binding (TPR co-chaperone
for p21 stability). Propose this as core (no direct GOA term, but well supported by UniProt).

Pn Notes

(FKBPL-pn-notes.md)

FKBPL PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q9UIM3
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-07b
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/FKBPL/FKBPL-ai-review.yaml
AIGR review HTML: present - genes/human/FKBPL/FKBPL-ai-review.html
Gene notes: present - genes/human/FKBPL/FKBPL-notes.md
GOA TSV: present - genes/human/FKBPL/FKBPL-goa.tsv
UniProt record: present - genes/human/FKBPL/FKBPL-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/FKBPL.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/FKBPL.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

Description: FKBPL (FK506-binding protein-like, also known as WISp39) is a divergent member of the FKBP family that retains tetratricopeptide (TPR) repeats but lacks a canonical catalytically active FKBP-type peptidyl-prolyl isomerase domain, so it has no established rotamase activity. It acts as an HSP90 co-chaperone that, through its TPR region, binds HSP90 and, together with the cyclin-dependent kinase inhibitor p21 (CDKN1A), forms a ternary complex that controls p21 protein stability, thereby linking FKBPL to cell-cycle and DNA-damage/radiation responses (it was originally identified as a stress-response gene implicated in induced radioresistance). FKBPL also exists as a secreted, extracellular protein with potent anti-angiogenic activity, a property exploited by FKBPL-derived therapeutic peptides. It is ubiquitously expressed with higher levels in testis.
Existing/core annotation action counts: ACCEPT: 1; KEEP_AS_NON_CORE: 8

PN Consistency Summary

Consistency: Notes, review YAML, and PN mapping are fully consistent. All three correctly frame FKBPL/WISp39 as a non-canonical, catalytically inactive FKBP (no functional PPIase domain) that acts as a TPR/HSP90 co-chaperone forming a ternary HSP90AB1–p21(CDKN1A) complex regulating p21 stability, plus a secreted anti-angiogenic pool. No contradiction.
PN story / NEW pressure: GO:0051879 (OLS-verified) is not in FKBPL's GOA (GOA MF rows are all bare protein binding to ANKRD49/CALCOCO2 HT-interactome hits — HSP90 is not among the IPI WITH partners), confirming PN's more_specific_than_existing_goa. The review adds GO:0051879 as the single core molecular function (supported by UniProt FUNCTION/SUBUNIT). This matches the PN projection exactly. Conclusion: legitimate ADD, executed in the review. No over-reach: PN correctly does NOT project PPIase activity (which would be wrong for this degenerate FKBP).
Evidence alignment: PN dossier lists no reference titles for FKBPL; alignment is by biology (HSP90 co-chaperone). Review evidence is reviewer-supplied (PMID:10521921 radioresistance/NAS; PMID:25767277 anti-angiogenic/extracellular; PMID:15664193 cited in notes for the WISp39–p21–HSP90 mechanism; recurrent ANKRD49/CALCOCO2 HT hits). The core HSP90/p21 mechanism rests on UniProt + PMID:15664193 rather than a GOA-anchored row.
Verdict: Consistent; PN GO:0051879 projection validated and added as the core MF; subtype-level PPIase correctly withheld. Recommended edits: none required; [REF] optionally add PMID:15664193 (Jascur et al., WISp39/HSP90/p21) as an explicit reference entry in the review YAML to anchor the GO:0051879 core function (currently it is only in notes, with the YAML core_function relying on UniProt text).

Full Consistency Review

UniProt: Q9UIM3 · batch: proteostasis-batch-2026-06-07b · review status: COMPLETE
PN placement: Cytonuclear proteostasis|Chaperone|HSP90 system|HSP90 cochaperone|CC-TPR and PPIase domain containing. PN-node mapping: type HSP90 cochaperone=mapped→GO:0051879 Hsp90 protein binding (more_specific_than_existing_goa); subtype CC-TPR and PPIase domain containing=no_mapping (correctly declines a subtype-level PPIase mapping because members are mixed/non-canonical); group/class/branch=no_mapping.
Consistency: Notes, review YAML, and PN mapping are fully consistent. All three correctly frame FKBPL/WISp39 as a non-canonical, catalytically inactive FKBP (no functional PPIase domain) that acts as a TPR/HSP90 co-chaperone forming a ternary HSP90AB1–p21(CDKN1A) complex regulating p21 stability, plus a secreted anti-angiogenic pool. No contradiction.
PN story / NEW pressure: GO:0051879 (OLS-verified) is not in FKBPL's GOA (GOA MF rows are all bare protein binding to ANKRD49/CALCOCO2 HT-interactome hits — HSP90 is not among the IPI WITH partners), confirming PN's more_specific_than_existing_goa. The review adds GO:0051879 as the single core molecular function (supported by UniProt FUNCTION/SUBUNIT). This matches the PN projection exactly. Conclusion: legitimate ADD, executed in the review. No over-reach: PN correctly does NOT project PPIase activity (which would be wrong for this degenerate FKBP).
Mapping strategy: Cleanly handled. The subtype no_mapping is the key correct decision — it prevents propagating PPIase activity (GO:0003755) to a non-catalytic member, the same restraint the FKBP8 dossier applies in reverse. Gene-level review and PN projection agree on the one defensible shared MF (HSP90 binding). No mapping change needed.
Evidence alignment: PN dossier lists no reference titles for FKBPL; alignment is by biology (HSP90 co-chaperone). Review evidence is reviewer-supplied (PMID:10521921 radioresistance/NAS; PMID:25767277 anti-angiogenic/extracellular; PMID:15664193 cited in notes for the WISp39–p21–HSP90 mechanism; recurrent ANKRD49/CALCOCO2 HT hits). The core HSP90/p21 mechanism rests on UniProt + PMID:15664193 rather than a GOA-anchored row.
Verdict: Consistent; PN GO:0051879 projection validated and added as the core MF; subtype-level PPIase correctly withheld. Recommended edits: none required; [REF] optionally add PMID:15664193 (Jascur et al., WISp39/HSP90/p21) as an explicit reference entry in the review YAML to anchor the GO:0051879 core function (currently it is only in notes, with the YAML core_function relying on UniProt text).

PN Dossier Context

review_batch: proteostasis-batch-2026-06-07b
review_yaml: genes/human/FKBPL/FKBPL-ai-review.yaml
PN workbook rows: 1

PN row 1: Cytonuclear proteostasis | Chaperone | HSP90 system | HSP90 cochaperone | CC-TPR and PPIase domain containing

UniProt: Q9UIM3
In branches: CY
PN-node mapping records (path + ancestors):
- [subtype] Cytonuclear proteostasis|Chaperone|HSP90 system|HSP90 cochaperone|CC-TPR and PPIase domain containing
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a mixed HSP90 cochaperone subtype with FKBP/PPIase-like members. The parent HSP90-cochaperone mapping captures the shared HSP90-binding role; a subtype-level PPIase mapping would overstate the activity for all members.
- [type] Cytonuclear proteostasis|Chaperone|HSP90 system|HSP90 cochaperone
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0051879 Hsp90 protein binding]
  rationale: This PN type groups HSP90 cochaperones. Hsp90 protein binding is the most defensible shared GO molecular-function target for propagation.
- [group] Cytonuclear proteostasis|Chaperone|HSP90 system
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN category rather than a specific GO class. The member genes span multiple activities, complexes, or contexts, so propagation from this node would overstate the shared biology; use narrower child or gene-level curations.
- [class] Cytonuclear proteostasis|Chaperone
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN category rather than a specific GO class. The member genes span multiple activities, complexes, or contexts, so propagation from this node would overstate the shared biology; use narrower child or gene-level curations.
- [branch] Cytonuclear proteostasis
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

Projected GO annotations (1)

GO:0051879 Hsp90 protein binding | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Cytonuclear proteostasis|Chaperone|HSP90 system|HSP90 cochaperone

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

id: Q9UIM3
gene_symbol: FKBPL
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: FKBPL (FK506-binding protein-like, also known as WISp39) is a divergent member of the FKBP family that retains tetratricopeptide (TPR) repeats but lacks a canonical catalytically active FKBP-type peptidyl-prolyl isomerase domain, so it has no established rotamase activity. It acts as an HSP90 co-chaperone that, through its TPR region, binds HSP90 and, together with the cyclin-dependent kinase inhibitor p21 (CDKN1A), forms a ternary complex that controls p21 protein stability, thereby linking FKBPL to cell-cycle and DNA-damage/radiation responses (it was originally identified as a stress-response gene implicated in induced radioresistance). FKBPL also exists as a secreted, extracellular protein with potent anti-angiogenic activity, a property exploited by FKBPL-derived therapeutic peptides. It is ubiquitously expressed with higher levels in testis.
existing_annotations:
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25036637
  qualifier: enables
  review:
    summary: Quantitative chaperone interaction network (Taipale et al.) capturing an FKBPL-ANKRD49 (Q8WVL7) interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: A recurrent interaction partner (ANKRD49), but recorded as bare protein binding; not the characterized core HSP90/p21 co-chaperone function.
    supported_by:
    - reference_id: file:human/FKBPL/FKBPL-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:25036637 UniProtKB:Q8WVL7
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Yeast two-hybrid human interactome screen capturing an FKBPL-CALCOCO2/NDP52 (Q13137) interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: A documented interaction (CALCOCO2), but recorded as bare protein binding; not the characterized core function.
    supported_by:
    - reference_id: file:human/FKBPL/FKBPL-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:25416956 UniProtKB:Q13137
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: IntAct interaction with ANKRD49 (Q8WVL7). Bare protein binding is uninformative; a recurrent partner.
    action: KEEP_AS_NON_CORE
    reason: A recurrent interaction (ANKRD49) recorded as bare protein binding; not the characterized core function.
    supported_by:
    - reference_id: file:human/FKBPL/FKBPL-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:28514442 UniProtKB:Q8WVL7
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: High-throughput interactome screen capturing an FKBPL-ANKRD49 (Q8WVL7) interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding from a high-throughput screen; uninformative and not reflective of the characterized core function.
    supported_by:
    - reference_id: file:human/FKBPL/FKBPL-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:32296183 UniProtKB:Q8WVL7
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: BioPlex affinity-purification interactome capturing an FKBPL-ANKRD49 (Q8WVL7) interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: A recurrent interaction (ANKRD49) recorded as bare protein binding; not the characterized core function.
    supported_by:
    - reference_id: file:human/FKBPL/FKBPL-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:33961781 UniProtKB:Q8WVL7
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Multimodal cell-maps interactome capturing an FKBPL-ANKRD49 (Q8WVL7) interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: A recurrent interaction (ANKRD49) recorded as bare protein binding; not the characterized core function.
    supported_by:
    - reference_id: file:human/FKBPL/FKBPL-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:40205054 UniProtKB:Q8WVL7
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:25767277
  qualifier: located_in
  review:
    summary: Direct evidence that FKBPL is a secreted, extracellular protein, consistent with its characterized anti-angiogenic activity as a secreted factor. Falcon deep research corroborates that FKBPL is secreted by fibroblasts and endothelial cells and acts at the cell surface as an anti-angiogenic factor targeting CD44.
    action: KEEP_AS_NON_CORE
    reason: A genuine secreted/extracellular pool with anti-angiogenic function, but distinct from FKBPL's intracellular HSP90/p21 co-chaperone role; retained as non-core.
    supported_by:
    - reference_id: file:human/FKBPL/FKBPL-goa.tsv
      supporting_text: GO:0005576 extracellular region IDA PMID:25767277
    - reference_id: file:human/FKBPL/FKBPL-deep-research-falcon.md
      supporting_text: FKBPL is also secreted by fibroblasts and endothelial cells, functioning as an extracellular anti-angiogenic protein
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8852362
  qualifier: located_in
  review:
    summary: Reactome annotation placing FKBPL in the cytosol, consistent with its intracellular HSP90/p21 co-chaperone function. Falcon deep research independently describes FKBPL as primarily cytosolic, participating in Hsp90-mediated chaperone complexes.
    action: ACCEPT
    reason: The cytosol is where FKBPL acts as an HSP90/p21 co-chaperone; a reasonable localization.
    supported_by:
    - reference_id: file:human/FKBPL/FKBPL-uniprot.txt
      supporting_text: Regulates p21 protein stability by binding to Hsp90 and p21.
    - reference_id: file:human/FKBPL/FKBPL-deep-research-falcon.md
      supporting_text: Within cells, FKBPL is primarily localized to the cytosol where it participates in Hsp90-mediated chaperone complexes
- term:
    id: GO:0009314
    label: response to radiation
  evidence_type: NAS
  original_reference_id: PMID:10521921
  qualifier: involved_in
  review:
    summary: FKBPL was identified as a stress-response gene with a potential role in induced radioresistance; it may be involved in the response to X-ray. A plausible biological process.
    action: KEEP_AS_NON_CORE
    reason: A documented (NAS) stress/radiation-response role consistent with its regulation of p21 stability, but a non-core process relative to the molecular co-chaperone function.
    supported_by:
    - reference_id: PMID:10521921
      supporting_text: A novel human stress response-related gene with a potential role in induced radioresistance.
    - reference_id: file:human/FKBPL/FKBPL-uniprot.txt
      supporting_text: May be involved in response to X-ray.
references:
- id: PMID:10521921
  title: A novel human stress response-related gene with a potential role in induced radioresistance.
  findings:
  - statement: FKBPL is a stress-response-related gene with a potential role in induced radioresistance.
    reference_section_type: RESULTS
- id: PMID:25036637
  title: A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways.
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: "Cached publications/PMID_25036637.md title matches YAML; a global chaperone-interaction-network study (GOA: GO:0005515 IPI). Places FKBPL in the cellular chaperone/proteostasis network but does not by itself establish the specific Hsp90/p21 core function; supporting/contextual rather than primary."
  findings:
  - statement: FKBPL appears in the chaperone interaction network (interacting with ANKRD49).
    reference_section_type: RESULTS
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings:
  - statement: Yeast two-hybrid human interactome map capturing an FKBPL-CALCOCO2 interaction.
    reference_section_type: RESULTS
- id: PMID:25767277
  title: 'FKBPL is a critical antiangiogenic regulator of developmental and pathological angiogenesis.'
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Not cached, but anchored to GOA: this PMID is the IDA source for GO:0005576 (extracellular region) in FKBPL-goa.tsv, supporting FKBPL's secreted anti-angiogenic role."
  findings:
  - statement: FKBPL is detected in the extracellular region and acts as a secreted anti-angiogenic factor.
    reference_section_type: RESULTS
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings:
  - statement: BioPlex affinity-purification interactome capturing an FKBPL-ANKRD49 interaction.
    reference_section_type: RESULTS
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings:
  - statement: Multimodal cell-maps interactome capturing an FKBPL-ANKRD49 interaction.
    reference_section_type: RESULTS
- id: Reactome:R-HSA-8852362
  title: 'Reactome: FKBPL in cytosol.'
  findings: []
- id: file:human/FKBPL/FKBPL-uniprot.txt
  title: UniProt entry Q9UIM3 (FKBPL_HUMAN), FK506-binding protein-like / WISp39
  findings:
  - statement: TPR-containing FKBP-like protein lacking a catalytic PPIase domain; regulates p21 (CDKN1A) protein stability by binding HSP90 and p21 and forming a ternary HSP90AB1/p21 complex; may be involved in the response to X-ray; ubiquitously expressed (highest in testis).
    reference_section_type: OTHER
- id: file:human/FKBPL/FKBPL-deep-research-falcon.md
  title: Falcon deep research report for FKBPL
  reference_review:
    relevance: HIGH
    correctness: UNVERIFIED
    review_notes: "LLM-synthesized (Edison/Falcon) report; not independently verified against primary full text. Correctly frames FKBPL as a divergent FKBP-family immunophilin that LACKS significant PPIase activity and acts as a non-enzymatic co-chaperone/scaffold (Hsp90-associated p21 stabilization) and secreted CD44-targeting anti-angiogenic factor; it does NOT over-attribute canonical FK506-binding/catalytic rotamase activity to FKBPL (it explicitly notes only a degenerate PPIase-like domain). Useful new leads beyond the current review: a 2024 ER-phagy/secretion role via CKAP4 and LC3/GABARAP LIR motifs (Li et al., Nat Commun PMID:39256376/doi:10.1038/s41467-024-52188-7), Hsp90-associated steroid-receptor (ER/AR/GR) co-chaperone involvement, NF-kB/vascular-integrity regulation, and HIF-1a/hypoxia endothelial roles. These leads are plausible and consistent with domain architecture but are taken from an unverified secondary synthesis; treat the specific pathway/partner claims as MEDIUM-confidence pending primary-source confirmation."
  findings:
  - statement: FKBPL is a divergent FKBP-family immunophilin that lacks significant peptidyl-prolyl cis-trans isomerase activity and acts as a non-enzymatic scaffold/co-chaperone; intracellularly it is Hsp90-associated and stabilizes p21 (CDKN1A), while a secreted pool acts extracellularly as an anti-angiogenic factor targeting CD44.
    reference_section_type: RESULTS
  - statement: A 2024 study reports a novel cytosolic FKBPL function in ER-phagy and protein secretion, in which FKBPL interacts with the ER-resident transmembrane protein CKAP4 and bridges it to LC3/GABARAP autophagy machinery via LIR motifs.
    reference_section_type: RESULTS
core_functions:
- description: HSP90 co-chaperone / TPR-mediated chaperone-binding adaptor that binds HSP90 and forms a ternary complex with HSP90 and the CDK inhibitor p21 (CDKN1A) to regulate p21 protein stability. FKBPL lacks catalytic PPIase activity; its function is adaptor/co-chaperone binding.
  molecular_function:
    id: GO:0051879
    label: Hsp90 protein binding
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/FKBPL/FKBPL-uniprot.txt
    supporting_text: Regulates p21 protein stability by binding to Hsp90 and p21.
  - reference_id: file:human/FKBPL/FKBPL-uniprot.txt
    supporting_text: Forms a ternary complex with CDKN1A/p21 and HSP90AB1/Hsp90.
  - reference_id: file:human/FKBPL/FKBPL-deep-research-falcon.md
    supporting_text: FKBPL is a divergent member of the FK506-binding protein family that notably lacks significant peptidyl-prolyl cis-trans isomerase (PPIase) enzymatic activity
  - reference_id: file:human/FKBPL/FKBPL-deep-research-falcon.md
    supporting_text: The primary intracellular function of FKBPL involves its role as an Hsp90-associated co-chaperone.
proposed_new_terms: []
suggested_questions:
- question: Does FKBPL act as a bona fide HSP90 co-chaperone in the classical sense, or primarily as a TPR adaptor that recruits HSP90 to specific clients such as p21?
- question: How is the intracellular HSP90/p21 co-chaperone pool of FKBPL functionally related to the secreted, extracellular anti-angiogenic pool?
- question: Does FKBPL have any residual peptidyl-prolyl isomerase activity given its degenerate FKBP domain, or is it catalytically inert?
suggested_experiments:
- description: Use the HSP90-binding-deficient FKBPL mutant (K287A/R291A) to test whether HSP90 binding is required for FKBPL-dependent p21 stabilization and for radioresistance phenotypes.
- description: Compare intracellular versus recombinant secreted FKBPL for p21 stabilization, HSP90 binding, and anti-angiogenic activity to define the two functional pools.
- description: Affinity purification-mass spectrometry of FKBPL to determine whether HSP90 and p21 are the principal functional partners versus the recurrent ANKRD49/CALCOCO2 interactome hits.

FKBPL

Gene Description

Existing Annotations Review

Core Functions

HSP90 co-chaperone / TPR-mediated chaperone-binding adaptor that binds HSP90 and forms a ternary complex with HSP90 and the CDK inhibitor p21 (CDKN1A) to regulate p21 protein stability. FKBPL lacks catalytic PPIase activity; its function is adaptor/co-chaperone binding.