FIP1L1

Summary

FIP1L1 (factor interacting with PAPOLA and CPSF1, HGNC:19124) is a protein-coding gene on chromosome 4q12, encoding Pre-mRNA 3’-end-processing factor FIP1 (Q6UN15). Component of the cleavage and polyadenylation specificity factor (CPSF) complex that plays a key role in pre-mRNA 3’-end formation, recognizing the AAUAAA signal sequence and interacting with poly(A) polymerase and other factors to bring about cleavage and poly(A) addition. It is a common-essential gene (DepMap: required in 94.0% of cancer cell lines).

This gene encodes a subunit of the CPSF (cleavage and polyadenylation specificity factor) complex that polyadenylates the 3’ end of mRNA precursors. This gene, the homolog of yeast Fip1 (factor interacting with PAP), binds to U-rich sequences of pre-mRNA and stimulates poly(A) polymerase activity. Its N-terminus contains a PAP-binding site and its C-terminus an RNA-binding domain. An interstitial chromosomal deletion on 4q12 creates an in-frame fusion of human genes FIP1L1 and PDGFRA (platelet-derived growth factor receptor, alpha). The FIP1L1-PDGFRA fusion gene encodes a constitutively activated tyrosine kinase that joins the first 233 amino acids of FIP1L1 to the last 523 amino acids of PDGFRA. This gene fusion and chromosomal deletion is the cause of some forms of idiopathic hypereosinophilic syndrome (HES). This syndrome, recently reclassified as chronic eosinophilic leukemia (CEL), is responsive to treatment with tyrosine kinase inhibitors. Alternative splicing results in multiple transcript variants encoding distinct isoforms.

Source: NCBI Gene 81608 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 99 total
• Phenotypes (HPO): 36
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 94.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_030917

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19124
Approved symbol	FIP1L1
Name	factor interacting with PAPOLA and CPSF1
Location	4q12
Locus type	gene with protein product
Status	Approved
Aliases	DKFZp586K0717, FIP1, hFip1
Ensembl gene	ENSG00000145216
Ensembl biotype	protein_coding
OMIM	607686
Entrez	81608

Gene structure

Transcript identifiers

Ensembl transcripts: 106 — 82 protein_coding, 12 retained_intron, 9 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000306932, ENST00000337488, ENST00000358575, ENST00000504094, ENST00000505125, ENST00000507206, ENST00000507922, ENST00000510668, ENST00000511055, ENST00000511376, ENST00000513008, ENST00000513975, ENST00000514543, ENST00000703451, ENST00000703452, ENST00000703453, ENST00000703454, ENST00000703455, ENST00000703456, ENST00000703457, ENST00000703458, ENST00000703459, ENST00000703460, ENST00000703461, ENST00000703462, ENST00000703463, ENST00000703464, ENST00000703465, ENST00000703466, ENST00000703467, ENST00000703468, ENST00000703469, ENST00000703470, ENST00000703471, ENST00000703472, ENST00000703473, ENST00000703474, ENST00000703475, ENST00000703476, ENST00000703477, ENST00000703478, ENST00000703479, ENST00000703480, ENST00000703481, ENST00000703482, ENST00000703483, ENST00000703484, ENST00000703485, ENST00000703486, ENST00000703487, ENST00000703488, ENST00000703489, ENST00000703490, ENST00000703491, ENST00000703492, ENST00000703493, ENST00000703494, ENST00000703495, ENST00000703496, ENST00000703497, ENST00000703498, ENST00000703499, ENST00000703500, ENST00000703501, ENST00000703502, ENST00000703503, ENST00000871718, ENST00000871719, ENST00000871720, ENST00000871721, ENST00000871722, ENST00000871723, ENST00000871724, ENST00000871725, ENST00000871726, ENST00000871727, ENST00000871728, ENST00000871729, ENST00000871730, ENST00000871731, ENST00000871732, ENST00000871733, ENST00000928370, ENST00000928371, ENST00000928372, ENST00000928373, ENST00000928374, ENST00000928375, ENST00000928376, ENST00000928377, ENST00000928378, ENST00000942743, ENST00000942744, ENST00000942745, ENST00000942746, ENST00000942747, ENST00000942748, ENST00000942749, ENST00000942750, ENST00000942751, ENST00000942752, ENST00000942753, ENST00000942754, ENST00000942755, ENST00000942756, ENST00000942757

RefSeq mRNA: 47 — MANE Select: NM_030917 NM_001134937, NM_001134938, NM_001376744, NM_001376745, NM_001376746, NM_001376747, NM_001376748, NM_001376749, NM_001376750, NM_001376751, NM_001376752, NM_001376753, NM_001376754, NM_001376755, NM_001376756, NM_001376757, NM_001376758, NM_001376759, NM_001376760, NM_001376761, NM_001376762, NM_001376764, NM_001376765, NM_001376766, NM_001376767, NM_001376768, NM_001376769, NM_001376770, NM_001376771, NM_001376772, NM_001376773, NM_001376774, NM_001376775, NM_001376776, NM_001376777, NM_001376778, NM_001376779, NM_001376780, NM_001376781, NM_001376782, NM_001376783, NM_001376784, NM_001376785, NM_001376786, NM_001410723, NM_001410724, NM_030917

CCDS: CCDS3491, CCDS47055, CCDS47056, CCDS93495, CCDS93496, CCDS93497, CCDS93498, CCDS93499, CCDS93500, CCDS93501, CCDS93502, CCDS93503, CCDS93504, CCDS93506, CCDS93507, CCDS93508, CCDS93509, CCDS93510, CCDS93511, CCDS93512, CCDS93513, CCDS93514, CCDS93515, CCDS93516, CCDS93517, CCDS93518, CCDS93519, CCDS93520, CCDS93521, CCDS93522, CCDS93523, CCDS93524, CCDS93525, CCDS93526

Canonical transcript exons

ENST00000337488 — 18 exons

Exon	Start	End
ENSE00003562497	53458653	53458790
ENSE00003577822	53442653	53442707
ENSE00003593809	53452920	53453133
ENSE00003599744	53444048	53444103
ENSE00003669922	53428027	53428183
ENSE00003775751	53390521	53390628
ENSE00003776550	53389809	53389873
ENSE00003776785	53414615	53414722
ENSE00003778889	53382278	53382335
ENSE00003779186	53391009	53391139
ENSE00003780665	53425872	53425965
ENSE00003780982	53379225	53379264
ENSE00003781663	53379073	53379117
ENSE00003782436	53383773	53383876
ENSE00003783380	53399730	53399839
ENSE00003989015	53377641	53377923
ENSE00003989018	53391430	53391498
ENSE00003989035	53459302	53460862

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 99.36.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 55.0636 / max 664.7939, expressed in 1826 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
47620	53.3386	1826
47621	1.6498	1045
47622	0.0752	13

Top tissues by expression

292 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	99.36	gold quality
calcaneal tendon	UBERON:0003701	98.21	gold quality
tendon	UBERON:0000043	98.11	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	97.70	gold quality
left testis	UBERON:0004533	96.36	gold quality
sural nerve	UBERON:0015488	96.36	gold quality
right testis	UBERON:0004534	96.09	gold quality
ventricular zone	UBERON:0003053	95.81	gold quality
left ovary	UBERON:0002119	95.40	gold quality
testis	UBERON:0000473	95.35	gold quality
ganglionic eminence	UBERON:0004023	95.27	gold quality
medial globus pallidus	UBERON:0002477	95.07	gold quality
right ovary	UBERON:0002118	94.69	gold quality
stromal cell of endometrium	CL:0002255	94.51	gold quality
cortical plate	UBERON:0005343	94.26	gold quality
anterior cingulate cortex	UBERON:0009835	94.10	gold quality
endocervix	UBERON:0000458	94.02	gold quality
ovary	UBERON:0000992	93.96	gold quality
cingulate cortex	UBERON:0003027	93.93	gold quality
mucosa of transverse colon	UBERON:0004991	93.93	gold quality
metanephros cortex	UBERON:0010533	93.92	gold quality
right lung	UBERON:0002167	93.88	gold quality
ectocervix	UBERON:0012249	93.81	gold quality
adrenal tissue	UBERON:0018303	93.80	gold quality
right frontal lobe	UBERON:0002810	93.75	gold quality
left lobe of thyroid gland	UBERON:0001120	93.68	gold quality
body of uterus	UBERON:0009853	93.65	gold quality
minor salivary gland	UBERON:0001830	93.60	gold quality
left adrenal gland	UBERON:0001234	93.59	gold quality
skin of abdomen	UBERON:0001416	93.59	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.49
E-GEOD-93593	yes	4.38
E-CURD-10	no	538.32

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

42 targeting FIP1L1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-548AG	99.77	69.25	1492
HSA-MIR-548AI	99.69	69.24	1494
HSA-MIR-548BA	99.69	69.14	1514
HSA-MIR-570-5P	99.69	69.24	1494
HSA-MIR-7161-5P	99.68	68.92	1592
HSA-MIR-548U	99.65	67.78	1463
HSA-MIR-3136-3P	99.57	66.59	781
HSA-MIR-7155-3P	99.57	66.48	794
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-142-5P	99.48	70.92	2416
HSA-MIR-5590-3P	99.48	70.91	2429
HSA-MIR-578	99.46	68.36	1787
HSA-MIR-302A-5P	99.39	68.21	1913
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-130A-5P	99.33	70.26	2623
HSA-MIR-3978	99.24	68.39	2201
HSA-MIR-6768-3P	99.14	67.38	1319
HSA-MIR-3606-3P	99.11	69.84	3254
HSA-MIR-6876-3P	98.97	65.69	765
HSA-MIR-626	98.89	66.21	762
HSA-MIR-6794-3P	98.76	66.99	894

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 94.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 32)

• Describes the fusion gene Fip1-like-1-PDGFRalpha in patients with idiopathic hypereosinophilic syndrome, mostly responsive to imatinib therapy. (PMID:12660384)
• The hypereosinophilic syndrome may result from a novel fusion tyrosine kinase - FIP1L1-PDGFRalpha - that is a consequence of an interstitial chromosomal deletion. (PMID:12660384)
• observations suggest that the FIP1L1-PDGFRA rearrangement occurs in an early hematopoietic progenitor and suggests that the molecular pathogenesis for a subset of SMCD patients is similar to that of HES (PMID:12842979)
• results indicate that the fusion of FIP1L1 to PDGFRA occurs rarely in leukemia cell lines (PMID:14630792)
• FIP1L1-PDGFRA is a relatively infrequent but treatment-relevant mutation in primary eosinophilia that is indicative of an underlying systemic mastocytosis. (PMID:15284118)
• the newly identified hFip1 protein, which has been shown to enhance polyadenylation through U-rich upstream elements, interacted specifically with the HPV-16 upstream element. (PMID:15767428)
• Fusion protein is detected in hypereosinophilic syndrome and chronic eosinophilic leukemia. (PMID:16502585)
• FIP1L1-PDGFRalpha activation requires disruption of the juxtamembrane domain of PDGFRalpha and is FIP1L1-independent (PMID:16690743)
• data and previous reports suggest that FIP1L1-PDGFRA - positive HES is a distinct clinical entity with myeloproliferative features and showing a poor response to corticosteroid treatment (PMID:17261495)
• FIP1L1 and PDGFRalpha have roles in response to imatinib mesylate in chronic eosinophilic leukemia (PMID:17299092)
• FIP1L1-PDGFRA-positive patients who presented with acute myeloid leukemia (AML, n=5) or lymphoblastic T-cell non-Hodgkin-lymphoma (n=2) in conjunction with AML or Eos-MPD. (PMID:17377585)
• Fluorescence in situ hybridization and reverse transcriptase-polymerase chain reaction protocols were developed for an accurate del(4)(q12q12) and FIP1L1-PDGFRA fusion gene detection. (PMID:17591942)
• FIP1L1-PDGFRalpha emerges as a relatively homogeneous clinicobiological entity that co-exists with other abnormalities of tyrosine kinase family genes. It reflects the disease progression and there is a good response to imatinib. (PMID:18706197)
• characterized FIP1L1-PDGFRA junction sequences from 113 patients at the mRNA (n=113) and genomic DNA (n=85) levels (PMID:18987651)
• studied a new FISH method to detect CHIC2 deletion, FIP1L1/PDGFRA fusion and PDGFRA translocation in patients with myeloid neoplasms associated with eosinophilia (PMID:19118897)
• FIP1L1/PDGFRA fusion gene-positive myeloproliferative disorders with eosinophilia are discussed. (PMID:21399396)
• Treatment with imatinib is associated with an excellent prognosis in FIP1L1-PDGFRA-positive chronic eosinophilic leukemia in first chronic phase (PMID:21818111)
• Data show that the cyclin-dependent kinase 7/9 inhibitor (CDK7/9 inhibitor) potently inhibits FIP1L1-PDGFRalpha-positive Bcr-Abl-positive chronic myeloid leukemia (CML) cells. (PMID:22447844)
• results strongly suggest that JAK2 is activated by Fip1-like1 (FIP1L1)-platelet-derived growth factor receptor alpha (F/P) and is required for F/P stimulation of cellular proliferation and infiltration in chronic eosinophilic leukemia (PMID:22523564)
• description of polycythemia vera concurrent with FIP1L1-PDGFRA-positive myeloproliferative neoplasm with eosinophilia [case report] (PMID:22944561)
• Oncostatin M is a FIP1L1/PDGFRA-dependent mediator of cytokine production in chronic eosinophilic leukemia. (PMID:23621172)
• FP fusion gene favors secondary KIT mutations in MCs via growth and proliferation signals or that a yet unknown mechanism causes genomic instability with independent evolution of FP and KIT D816V (PMID:24458279)
• FIP1L1 differentially contributes to the pathogenesis of distinct types of leukemia. (PMID:24763514)
• F604S exchange in FIP1L1-PDGFRA enhances FIP1L1-PDGFRA protein stability via SHP-2 and SRC and is associated with kinase inhibitor resistance in hypereosinophilic syndrome and chronic eosinophilic leukemia. (PMID:25761934)
• FIP1L1/ PDGFRA associated chronic eosinophilic leukemia has an excellent long-term prognosis following imatinib therapy. (PMID:27120808)
• Case Report: concurrent development of myeloproliferative hypereosinophilic syndrome and lymphomatoid papulosis associated with FIP1L1-PDGFRA gene fusion. (PMID:28374041)
• The authors define the molecular architecture of the core human CPSF complex comprising CPSF160, WDR33, CPSF30 and Fip1 and identify specific domains involved in inter-subunit interactions. Together, these results shed light on the function of CPSF in mediating polyA signal-dependent RNA cleavage and polyadenylation. (PMID:29274231)
• Herein, we report a case of a 53-year-old man with eosinophilia and a well-differentiated extramedullary myeloid tumor with evidence of FIP1L1/PDGFRA rearrangement by fluorescent in situ hybridization in the extramedullary tissue. (PMID:29310833)
• Two identified variants revealed novel candidate genes for hip and knee osteoarthritis. OLIG3 and FIP1L1 have specific roles in transcription and may effect expression of other genes. Identified variants in these genes may thus have a role in the regulatory events leading to osteoarthritis. (PMID:30157244)
• Exquisite response to imatinib mesylate in FIP1L1-PDGFRA-mutated hypereosinophilic syndrome: a 12-year experience of the Polish Hypereosinophilic Syndrome Study Group. (PMID:32125294)
• FIP1L1-PDGFRA-Associated Hypereosinophilic Syndrome as a Treatable Cause of Watershed Infarction. (PMID:34304603)
• Fip1 is a multivalent interaction scaffold for processing factors in human mRNA 3’ end biogenesis. (PMID:36073787)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

Pre-mRNA 3’-end-processing factor FIP1 — Q6UN15 (reviewed: Q6UN15)

Alternative names: FIP1-like 1 protein, Factor interacting with PAP, Rearranged in hypereosinophilia

All UniProt accessions (47): A0A994J3I9, A0A994J3J1, A0A994J3J6, A0A994J3K1, A0A994J3K5, A0A994J3L0, Q6UN15, A0A994J3L5, A0A994J3M0, A0A994J3M5, A0A994J3P6, A0A994J3Q0, A0A994J3Q5, A0A994J3R0, A0A994J3R5, A0A994J3S0, A0A994J3S6, A0A994J3T0, A0A994J3T5, A0A994J438, A0A994J442, A0A994J448, A0A994J453, A0A994J458, A0A994J464, A0A994J469, A0A994J474, A0A994J6B4, A0A994J6B8, A0A994J6C2, A0A994J6C6, A0A994J6C9, A0A994J6D3, A0A994J6D6, A0A994J6E0, A0A994J6E2, A0A994J6N5, A0A994J6P0, A0A994J6P3, A0A994J6P8, A0A994J6Q2, A0A994J6Q5, A0A994J6R0, A0A994J6R4, A0A994J6R9, H0Y8J4, H0Y8P7

UniProt curated annotations — full annotation on UniProt →

Function. Component of the cleavage and polyadenylation specificity factor (CPSF) complex that plays a key role in pre-mRNA 3’-end formation, recognizing the AAUAAA signal sequence and interacting with poly(A) polymerase and other factors to bring about cleavage and poly(A) addition. FIP1L1 contributes to poly(A) site recognition and stimulates poly(A) addition. Binds to U-rich RNA sequence elements surrounding the poly(A) site. May act to tether poly(A) polymerase to the CPSF complex.

Subunit / interactions. Component of the cleavage and polyadenylation specificity factor (CPSF) complex, composed of CPSF1, CPSF2, CPSF3, CPSF4 and FIP1L1. Found in a complex with CPSF1, FIP1L1 and PAPOLA. Interacts with CPSF1, CPSF4, CSTF2 and CSTF3. Interacts with AHCYL1 (when phosphorylated); the interaction is direct and associates AHCYL1 with the CPSF complex and RNA. Interacts with NUDT21/CPSF5; this interaction occurs in a RNA sequence-specific manner. Interacts (preferentially via unphosphorylated form and Arg/Glu/Asp-rich domain) with CPSF6 (via Arg/Ser-rich domain); this interaction mediates, at least in part, the interaction between the CFIm and CPSF complexes and may be inhibited by CPSF6 hyper-phosphorylation. Interacts (preferentially via unphosphorylated form and Arg/Asp/Glu-rich domain) with CPSF7 (via Arg/Ser-rich domain); this interaction mediates, at least in part, the interaction between the CFIm and CPSF complexes and may be inhibited by CPSF7 hyper-phosphorylation. Interacts with PAPOLA; the interaction seems to be increased by the interaction with AHCYL1.

Subcellular location. Nucleus.

Disease relevance. A chromosomal aberration involving FIP1L1 is found in some cases of hypereosinophilic syndrome. Interstitial chromosomal deletion del(4)(q12q12) causes the fusion of FIP1L1 and PDGFRA (FIP1L1-PDGFRA).

Similarity. Belongs to the FIP1 family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q6UN15-1	1	yes
Q6UN15-3	3
Q6UN15-4	4
Q6UN15-5	5

RefSeq proteins (47): NP_001128409, NP_001128410, NP_001363673, NP_001363674, NP_001363675, NP_001363676, NP_001363677, NP_001363678, NP_001363679, NP_001363680, NP_001363681, NP_001363682, NP_001363683, NP_001363684, NP_001363685, NP_001363686, NP_001363687, NP_001363688, NP_001363689, NP_001363690, NP_001363691, NP_001363693, NP_001363694, NP_001363695, NP_001363696, NP_001363697, NP_001363698, NP_001363699, NP_001363700, NP_001363701, NP_001363702, NP_001363703, NP_001363704, NP_001363705, NP_001363706, NP_001363707, NP_001363708, NP_001363709, NP_001363710, NP_001363711, NP_001363712, NP_001363713, NP_001363714, NP_001363715, NP_001397652, NP_001397653, NP_112179* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007854	Fip1_dom	Domain
IPR051187	Pre-mRNA_3’-end_processing_reg	Family

Pfam: PF05182

UniProt features (47 total): compositionally biased region 11, modified residue 10, region of interest 8, splice variant 6, helix 5, sequence conflict 3, chain 1, site 1, strand 1, turn 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
7K95	X-RAY DIFFRACTION	1.9
7ZYH	X-RAY DIFFRACTION	2.2
7ZY4	X-RAY DIFFRACTION	2.55

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UN15-F1	56.38	0.03

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 339–340 (breakpoint for interstitial deletion to form the fip1l1-pdgfra fusion protein)

Post-translational modifications (10): 85, 87, 89, 304, 426, 492, 494, 496, 500, 554

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-159231	Transport of Mature mRNA Derived from an Intronless Transcript
R-HSA-72187	mRNA 3’-end processing
R-HSA-73856	RNA Polymerase II Transcription Termination
R-HSA-77595	Processing of Intronless Pre-mRNAs
R-HSA-9673766	Signaling by cytosolic PDGFRA and PDGFRB fusion proteins
R-HSA-9770562	mRNA Polyadenylation
R-HSA-9918481	Dengue Virus-Host Interactions
R-HSA-72203	Processing of Capped Intron-Containing Pre-mRNA

MSigDB gene sets: 181 (showing top): CCAWYNNGAAR_UNKNOWN, LHX3_01, REACTOME_MRNA_3_END_PROCESSING, REACTOME_PROCESSING_OF_CAPPED_INTRON_CONTAINING_PRE_MRNA, GOBP_MRNA_3_END_PROCESSING, AAAGACA_MIR511, TATA_C, AACTTT_UNKNOWN, GOBP_HISTONE_MRNA_METABOLIC_PROCESS, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS, ACEVEDO_LIVER_CANCER_UP, AR_Q2, REACTOME_METABOLISM_OF_RNA, GOCC_MRNA_CLEAVAGE_FACTOR_COMPLEX, GRYDER_PAX3FOXO1_TOP_ENHANCERS

GO Biological Process (1): mRNA processing (GO:0006397)

GO Molecular Function (2): RNA binding (GO:0003723), protein binding (GO:0005515)

GO Cellular Component (4): nucleoplasm (GO:0005654), cytosol (GO:0005829), mRNA cleavage and polyadenylation specificity factor complex (GO:0005847), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Transport of Mature mRNAs Derived from Intronless Transcripts	1
Processing of Capped Intron-Containing Pre-mRNA	1
RNA Polymerase II Transcription	1
Processing of Capped Intronless Pre-mRNA	1
Signaling by PDGFR in disease	1
mRNA 3’-end processing	1
Dengue Virus Infection	1
Metabolism of RNA	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
RNA processing	1
mRNA metabolic process	1
nucleic acid binding	1
binding	1
nuclear lumen	1
cytoplasm	1
mRNA cleavage factor complex	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1788 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FIP1L1	CPSF1	Q10570	993
FIP1L1	CPSF2	Q9P2I0	992
FIP1L1	WDR33	Q9C0J8	982
FIP1L1	PDGFRA	P16234	981
FIP1L1	CPSF3	Q9UKF6	979
FIP1L1	CPSF4	O95639	971
FIP1L1	PAPOLA	P51003	827
FIP1L1	PCF11	O94913	821
FIP1L1	PAPOLG	Q9BWT3	798
FIP1L1	PDGFRB	P09619	797
FIP1L1	PAPOLB	Q9NRJ5	794
FIP1L1	CSTF2	P33240	783
FIP1L1	SYMPK	Q92797	774
FIP1L1	CHIC2	Q9UKJ5	766
FIP1L1	CSTF3	Q12996	748

IntAct

153 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
CPSF4	FIP1L1	psi-mi:“MI:0914”(association)	0.660
CPSF4	FIP1L1	psi-mi:“MI:0915”(physical association)	0.660
CPSF3	CPSF4	psi-mi:“MI:0914”(association)	0.640
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
CDC73	CSTF2	psi-mi:“MI:0914”(association)	0.580
FIP1L1	NAA10	psi-mi:“MI:0915”(physical association)	0.560
FIP1L1	GOLGA2	psi-mi:“MI:0915”(physical association)	0.560
ZMYND19	FIP1L1	psi-mi:“MI:0915”(physical association)	0.560
GOLGA2	FIP1L1	psi-mi:“MI:0915”(physical association)	0.560
YTH1	FIP1L1	psi-mi:“MI:0915”(physical association)	0.560
NS1	PIK3R2	psi-mi:“MI:0914”(association)	0.560
CPSF1	CPSF4	psi-mi:“MI:0915”(physical association)	0.560
SYMPK	CPSF4	psi-mi:“MI:0914”(association)	0.530
WDR33	CPSF4	psi-mi:“MI:0914”(association)	0.530
ZC3H18	AQR	psi-mi:“MI:0914”(association)	0.530
CPSF4L	CCNH	psi-mi:“MI:0914”(association)	0.530
SRSF3	CASC3	psi-mi:“MI:0914”(association)	0.530
rep	FIP1L1	psi-mi:“MI:0915”(physical association)	0.480
CPSF6	DDX39A	psi-mi:“MI:0914”(association)	0.480
FIP1L1	WWOX	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (318): FIP1L1 (Two-hybrid), FIP1L1 (Two-hybrid), FIP1L1 (Two-hybrid), FIP1L1 (Two-hybrid), ZMYND19 (Two-hybrid), FIP1L1 (Affinity Capture-MS), FIP1L1 (Affinity Capture-MS), FIP1L1 (Affinity Capture-MS), FIP1L1 (Affinity Capture-MS), FIP1L1 (Affinity Capture-MS), FIP1L1 (Affinity Capture-MS), FIP1L1 (Affinity Capture-MS), FIP1L1 (Two-hybrid), FIP1L1 (Affinity Capture-MS), CPSF1 (Co-fractionation)

ESM2 similar proteins: A0A1I8MUL8, A2AG58, A2AJT9, A6ZWC8, B3LKV0, B5VT41, B9UYK6, C1IWT1, C5IY45, C7GJ78, C8ZIQ5, E7KIY3, E7KVI3, E7M1C7, E7QAA9, E7QLB7, O14269, O23372, O94687, P0CO26, P0CO27, P11596, P30414, P30415, P33419, P97868, Q03063, Q08D57, Q18221, Q1LY77, Q23935, Q24669, Q3UC65, Q3YPH5, Q4R626, Q5LJZ2, Q5R840, Q5RAA7, Q5U2S0, Q66J90

Diamond homologs: F4JC20, F4KDH9, P45976, Q09801, Q5AGC1, Q5RAA7, Q5U317, Q5XJD3, Q6BGR9, Q6C784, Q6CPC3, Q6FJ55, Q6UN15, Q751K8, Q9D824, Q4WM95, Q5BAJ7, Q4IF44, Q7SAX8

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
FIP1L1	“form complex”	“CPSF complex”	binding
FIP1L1	up-regulates	PAPOLA	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 165 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Processing of Intronless Pre-mRNAs	12	61.7×	5e-18
mRNA 3’-end processing	19	33.7×	4e-22
RNA Polymerase II Transcription Termination	16	31.7×	2e-18
Transport of Mature Transcript to Cytoplasm	7	24.0×	6e-07
Transport of Mature mRNA Derived from an Intronless Transcript	8	19.6×	3e-07
mRNA Polyadenylation	24	19.0×	4e-22
HIV Transcription Elongation	5	15.1×	6e-04
mRNA Splicing	14	13.8×	8e-11

GO biological processes:

GO term	Partners	Fold	FDR
mRNA 3’-end processing	9	35.9×	8e-10
negative regulation of mRNA splicing, via spliceosome	5	27.2×	1e-04
positive regulation of transcription elongation by RNA polymerase II	7	14.9×	7e-05
mRNA splicing, via spliceosome	20	13.0×	6e-14
mRNA export from nucleus	5	10.5×	9e-03
regulation of alternative mRNA splicing, via spliceosome	6	10.4×	2e-03
mRNA processing	17	9.5×	8e-10
RNA splicing	14	8.8×	2e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

99 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	44
Likely benign	7
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

3208 predictions. Top by Δscore:

Variant	Effect	Δscore
4:53377905:G:GT	donor_gain	1.0000
4:53377924:G:GG	donor_gain	1.0000
4:53379216:A:AG	acceptor_gain	1.0000
4:53379216:ACTT:A	acceptor_gain	1.0000
4:53379219:T:A	acceptor_gain	1.0000
4:53379219:T:TA	acceptor_gain	1.0000
4:53379223:A:AG	acceptor_gain	1.0000
4:53379224:G:GG	acceptor_gain	1.0000
4:53379224:GAT:G	acceptor_gain	1.0000
4:53379263:AGG:A	donor_loss	1.0000
4:53379265:GTTA:G	donor_loss	1.0000
4:53382276:A:AG	acceptor_gain	1.0000
4:53382277:G:GG	acceptor_gain	1.0000
4:53383761:A:AG	acceptor_gain	1.0000
4:53383761:AT:A	acceptor_gain	1.0000
4:53383762:T:G	acceptor_gain	1.0000
4:53383762:T:TA	acceptor_gain	1.0000
4:53383767:A:AG	acceptor_gain	1.0000
4:53383767:AT:A	acceptor_gain	1.0000
4:53383768:T:G	acceptor_gain	1.0000
4:53383768:T:TA	acceptor_gain	1.0000
4:53383769:GTAG:G	acceptor_loss	1.0000
4:53383771:A:AG	acceptor_gain	1.0000
4:53383771:A:C	acceptor_loss	1.0000
4:53383772:G:GC	acceptor_gain	1.0000
4:53383772:G:GT	acceptor_gain	1.0000
4:53383772:GA:G	acceptor_gain	1.0000
4:53383772:GAA:G	acceptor_gain	1.0000
4:53383772:GAAA:G	acceptor_gain	1.0000
4:53383872:TATGG:T	donor_gain	1.0000

AlphaMissense

3904 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:53383837:T:A	V98D	1.000
4:53383843:T:A	I100K	1.000
4:53383843:T:G	I100R	1.000
4:53390616:T:A	W165R	1.000
4:53390616:T:C	W165R	1.000
4:53390617:G:C	W165S	1.000
4:53390618:G:C	W165C	1.000
4:53390618:G:T	W165C	1.000
4:53390619:C:A	R166S	1.000
4:53390620:G:C	R166P	1.000
4:53390628:G:C	G169R	1.000
4:53391009:G:A	G169D	1.000
4:53391011:G:C	A170P	1.000
4:53391012:C:A	A170D	1.000
4:53391021:C:T	S173F	1.000
4:53391023:G:C	D174H	1.000
4:53391024:A:C	D174A	1.000
4:53391024:A:G	D174G	1.000
4:53391024:A:T	D174V	1.000
4:53391026:T:C	Y175H	1.000
4:53391026:T:G	Y175D	1.000
4:53391029:T:A	F176I	1.000
4:53391029:T:C	F176L	1.000
4:53391029:T:G	F176V	1.000
4:53391030:T:C	F176S	1.000
4:53391030:T:G	F176C	1.000
4:53391031:T:A	F176L	1.000
4:53391031:T:G	F176L	1.000
4:53391034:T:A	N177K	1.000
4:53391034:T:G	N177K	1.000

dbSNP variants (sampled 300 via entrez): RS1000005829 (4:53421503 T>A), RS1000011605 (4:53385847 A>C,G), RS1000038480 (4:53421837 G>A), RS1000047125 (4:53385592 A>G), RS10000723 (4:53432494 G>A,T), RS10000746 (4:53415564 T>A,C,G), RS10001201 (4:53402929 G>A), RS1000140231 (4:53397778 A>G), RS1000185031 (4:53446517 G>C,T), RS1000232419 (4:53402145 G>A,C), RS1000253056 (4:53439414 CTT>C,CTTT), RS1000263663 (4:53402384 A>C), RS1000315801 (4:53410317 C>T), RS1000427475 (4:53446179 A>G), RS1000457953 (4:53390454 G>T)

Disease associations

OMIM: gene MIM:607686 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

36 total (30 of 36 shown, HPO-id order):

HPO	Term
HP:0000212	Gingival overgrowth
HP:0000225	Gingival bleeding
HP:0000421	Epistaxis
HP:0000790	Hematuria
HP:0000967	Petechiae
HP:0000978	Bruising susceptibility
HP:0000979	Purpura
HP:0001324	Muscle weakness
HP:0001824	Weight loss
HP:0001873	Thrombocytopenia
HP:0001875	Decreased total neutrophil count
HP:0001876	Pancytopenia
HP:0001882	Decreased total leukocyte count
HP:0001892	Abnormal bleeding
HP:0001903	Anemia
HP:0001945	Fever
HP:0001974	Increased total leukocyte count
HP:0002027	Abdominal pain
HP:0002039	Anorexia
HP:0002321	Vertigo
HP:0002653	Bone pain
HP:0002716	Lymphadenopathy
HP:0002875	Exertional dyspnea
HP:0005521	Disseminated intravascular coagulation
HP:0010280	Stomatitis
HP:0011900	Hypofibrinogenemia
HP:0012378	Fatigue
HP:0025420	Diffuse alveolar hemorrhage
HP:0030140	Oral cavity bleeding
HP:0030955	Addictive alcohol use

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST002058_19	DNA methylation (variation)	9.000000e-07
GCST002698_1	Serum VEGFR2 concentration	5.000000e-25
GCST004332_3	Red blood cell count	4.000000e-10
GCST010699_1	Brain morphology (min-P)	3.000000e-11
GCST010701_128	Cortical surface area (MOSTest)	2.000000e-10
GCST010702_22	Subcortical volume (MOSTest)	5.000000e-50
GCST010703_288	Brain morphology (MOSTest)	5.000000e-15
GCST90002388_341	Lymphocyte count	8.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0022599	DNA methylation
EFO:0004305	erythrocyte count
EFO:0004346	neuroimaging measurement
EFO:0004587	lymphocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724686 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs113100019	Toxicity	3	meperidine	adverse events

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs113100019	FIP1L1	3	0.00	1	meperidine

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.72	IC50	190	nM	MOLIBRESIB

PubChem BioAssay actives

1 with measured affinity, of 6 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178740: Inhibition of FIP1L1 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	0.1900	uM

CTD chemical–gene interactions

37 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, decreases methylation, decreases expression, increases expression	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, decreases expression, affects cotreatment	2
Hydrogen Peroxide	affects expression, affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Valproic Acid	affects expression, decreases expression	2
FR900359	affects phosphorylation	1
TAK-243	decreases sumoylation	1
sodium arsenate	decreases expression	1
2-bromopalmitate	increases abundance, increases palmitoylation, decreases reaction	1
coumarin	affects phosphorylation	1
CGP 52608	affects binding, increases reaction	1
nutlin 3	affects cotreatment, increases secretion	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	affects expression	1
jinfukang	affects cotreatment, decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
Imatinib Mesylate	affects binding, increases response to substance	1
Dasatinib	decreases phosphorylation	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Arsenic	affects methylation	1
Atrazine	increases expression	1
Cadmium	decreases reaction, increases abundance, increases palmitoylation	1
Caffeine	affects phosphorylation	1
Cisplatin	decreases expression, affects cotreatment	1
Dactinomycin	affects cotreatment, increases secretion	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ivermectin	decreases expression	1
Phenobarbital	affects expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697470	Binding	Inhibition of FIP1L1 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 factor-dependent cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0258	EoL-1	Cancer cell line	Male
CVCL_9973	SUP-T13	Cancer cell line	Female
CVCL_E8UB	ICLU-E	Cancer cell line	Male
CVCL_XZ11	Ba/F3 FIP1L1-PDGFRA-D842V	Factor-dependent cell line

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.