FGFR4 - fibroblast growth factor receptor 4 Gene

Also Known as TKF; JTK2; CD334

Species: Homo sapiens

Gene Type: protein coding

Gene ID: 2264

About FGFR4

Cytogenetic location: 5q35.2 Genomic coordinates (GRCh38): 5:177,086,915-177,098,144 (from NCBI)

This gene has 16 transcripts (splice variants), 120 orthologues, 53 paralogues and is associated with 104 phenotypes. Broad expression in lung (RPKM 16.7), kidney (RPKM 12.5) and 15 other tissues.

Summary

The protein encoded by this gene is a tyrosine kinase and cell surface receptor for fibroblast growth factors. The encoded protein is involved in the regulation of several pathways, including cell proliferation, cell differentiation, cell migration, lipid metabolism, bile acid biosynthesis, vitamin D metabolism, glucose uptake, and phosphate homeostasis. This protein consists of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment, and a cytoplasmic tyrosine kinase domain. The extracellular portion interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. [provided by RefSeq, Aug 2017]

FGFR4 Products (5)

mRNA	Protein	Name
NM_001354984.2	NP_001341913.1	fibroblast growth factor receptor 4 isoform 1 precursor
NM_213647.3	NP_998812.1	fibroblast growth factor receptor 4 isoform 1 precursor
NM_022963.3	NP_075252.2	fibroblast growth factor receptor 4 isoform 2 precursor
NM_001291980.2	NP_001278909.1	fibroblast growth factor receptor 4 isoform 3 precursor
NM_002011.5	NP_002002.3	fibroblast growth factor receptor 4 isoform 1 precursor

Gene Ontology

Molecular Function
Biological Process
Cellular Component

Molecular Function GO Annotation	Evidence	References	Source
enables fibroblast growth factor binding	IDA IDA: Inferred from direct assay	8663044	GOA
enables fibroblast growth factor binding	IPI IPI: Inferred from physical interaction	10525310	GOA
enables fibroblast growth factor receptor activity	IDA IDA: Inferred from direct assay	8663044	GOA
enables fibroblast growth factor receptor activity	IGI IGI: Inferred from genetic interaction	10525310	GOA
enables heparin binding	IDA IDA: Inferred from direct assay	18480409	GOA
enables protein binding	IPI IPI: Inferred from physical interaction	17627937	GOA

Biological Process GO Annotation	Evidence	References	Source
involved in cell migration	IMP IMP: Inferred from mutant phenotype	20876804	GOA
involved in fibroblast growth factor receptor signaling pathway	IDA IDA: Inferred from direct assay	18480409	GOA
acts upstream of or within fibroblast growth factor receptor signaling pathway	IGI IGI: Inferred from genetic interaction	8663044	GOA
acts upstream of or within fibroblast growth factor receptor signaling pathway	IPI IPI: Inferred from physical interaction	10525310	GOA
involved in peptidyl-tyrosine phosphorylation	IDA IDA: Inferred from direct assay	20683963	GOA
involved in positive regulation of DNA biosynthetic process	IMP IMP: Inferred from mutant phenotype	21653700	GOA
involved in positive regulation of ERK1 and ERK2 cascade	IMP IMP: Inferred from mutant phenotype	21653700	GOA
involved in positive regulation of catalytic activity	IMP IMP: Inferred from mutant phenotype	20798051	GOA
involved in positive regulation of cell population proliferation	IDA IDA: Inferred from direct assay	8663044	GOA
acts upstream of or within positive regulation of cell population proliferation	IGI IGI: Inferred from genetic interaction	8663044	GOA
involved in positive regulation of gene expression	IMP IMP: Inferred from mutant phenotype	19085950	GOA
involved in positive regulation of proteolysis	IMP IMP: Inferred from mutant phenotype	20798051	GOA
involved in protein autophosphorylation	IDA IDA: Inferred from direct assay	20798051	GOA
involved in regulation of bile acid biosynthetic process	IMP IMP: Inferred from mutant phenotype	17623664	GOA
involved in regulation of extracellular matrix disassembly	IMP IMP: Inferred from mutant phenotype	20876804	GOA
NOT involved in response to bile acid	IMP IMP: Inferred from mutant phenotype	19085950	GOA

Cellular Component GO Annotation	Evidence	References	Source
located in Golgi apparatus	IDA IDA: Inferred from direct assay	18061161	GOA
colocalizes with cell-cell junction	IDA IDA: Inferred from direct assay	20798051	GOA
located in endoplasmic reticulum	IDA IDA: Inferred from direct assay	20683963	GOA
located in plasma membrane	IDA IDA: Inferred from direct assay	18061161	GOA
located in transport vesicle	IDA IDA: Inferred from direct assay	18061161	GOA

EXP: Inferred from Experiment IDA: Inferred from direct assay IPI: Inferred from physical interaction IMP: Inferred from mutant phenotype IGI: Inferred from genetic interaction IEP: Inferred from expression pattern

FGFR4 Protein Structure

I-set

Pkinase_Tyr

0
200
400
600
802 a.a.

Protein Preferred Names	Protein Names
fibroblast growth factor receptor 4	hydroxyaryl-protein kinase protein-tyrosine kinase tyrosine kinase related to fibroblast growth factor receptor tyrosylprotein kinase

FGFR4 Protein-protein interaction Information

Type	Protein Name	Protein ID	Interactor	Interactor Species	Interactor ID	Detection Method	References
Intra	FGFR4	P22455	FGFR1	Homo sapiens	P11362	BioID	35384245
Intra	FGFR4	P22455	FGFR1	Homo sapiens	P11362	Anti Tag CoIP	35384245
Intra	FGFR4	P22455	FGFR1	Homo sapiens	P11362	Affinity Chrom	35384245
Intra	FGFR4	P22455	MMP14	Homo sapiens	P50281	Anti Bait CoIP	20798051

Cross: Cross-species interaction Intra: Intraspecies interaction

Recombinant FGFR4 Proteins

Cat. No.	Product Name	Accession	Purity
HY-P73057	FGFR-4 Protein, Human (HEK293, Fc)	NP_002002.3 (L22-D369)	≥ 95%, as determined by reducing SDS-PAGE.
HY-P73059	FGFR-4 Protein, Human (HEK293, His)	P22455-1 (L22-D369)	≥ 90%, as determined by reducing SDS-PAGE.
HY-P77549	FGFR-4 Protein, Human (Biotinylated, HEK293, His)	P22455-1 (L22-D369)	≥ 90%, as determined by reducing SDS-PAGE.
HY-P78127	FGFR-4 Protein, Human (Biotinylated, HEK293, His-Avi)	P22455-1 (L22-D369)	≥ 95%, as determined by Bis-Tris PAGE.
HY-P78441	FGFR-4 Protein, Human (HEK293, His-Avi)	P22455-1 (L22-D369)	≥ 95%, as determined by Bis-Tris PAGE.

FGFR4 Antibodies

Cat. No.	Product Name	Application	Reactivity
HY-P81843	FGFR4 Antibody (YA1588)	WB	Human, Mouse, Rat
HY-P84188	FGFR4 Antibody (YA3885)	IHC-P, ELISA	Human
HY-P84188A	FGFR4 Antibody (YA3885)(PBS only)	IHC-P, ELISA	Human
HY-P84189	FGFR4 Antibody (YA3886)	WB, FC, ELISA	Human
HY-P84189A	FGFR4 Antibody (YA3886)(PBS only)	WB, FC, ELISA	Human
HY-P85161	FGFR4 Antibody (YA4853)	WB, ICC/IF, ELISA	Human

Related Diseases

Diseases	Alias
Primary Biliary Cholangitis	Primary Biliary Cirrhosis Biliary Liver Cirrhosis Chronic Nonsuppurative Destructive Cholangitis Familial Primary Biliary Cirrhosis Pbc Hanot Syndrome Cholestatic Cirrhosis Biliary Cirrhosis Primary Liver Cirrhosis, Biliary Hanot'S Cirrhosis Biliary Cirrhosis Pericholangiolic Biliary Cirrhosis Tannhauser-Magendantz Syndrome Hanot-Rossle Syndrome Hypertrophic Cirrhosis Todd Cirrhosis Hanot Cirrhosis Charcot Cirrhosis Mahon-Tannhauser Syndrome Toxic Cirrhosis Hypertrophic Biliary Cirrhosis Monolobular Cirrhosis Unilobar Cirrhosis Xanthomatous Biliary Cirrhosis
Rhabdomyosarcoma 2	Alveolar Rhabdomyosarcoma Rhabdomyosarcoma, Alveolar Rhabdomyosarcoma Alveolar RMS2 Rmsa Rhabdomyosarcoma 2, Alveolar Alveolar Childhood Rhabdomyosarcoma Arms Rhabdomyosarcoma, Type 2
Hypochondroplasia	HCH Hypochondrodysplasia Chondrogenesis Imperfecta Hypochondroplastic Dwarfism Hypochondroplastic Short Stature
Orbit Embryonal Rhabdomyosarcoma	Embryonal Rhabdomyosarcoma Of The Orbit
Pleomorphic Rhabdomyosarcoma	Adult Pleomorphic Rhabdomyosarcoma Anaplastic Rhabdomyosarcoma Pleomorphic Rhabdomyosarcoma, Adult Type
Rhabdomyosarcoma
Lacrimoauriculodentodigital Syndrome	Ladd Syndrome Levy-Hollister Syndrome Lacrimo-Auriculo-Dento-Digital Syndrome LADD Lacrimoauriculodento-Digital Syndrome Levy Hollister Syndrome Lard Syndrome Lacrimoauriculoradiodental Syndrome LADDS Congenital Duodenal Obstruction Due To Malrotation Of Intestine
Hepatocellular Clear Cell Carcinoma	Clear Cell Carcinoma Of The Liver Cells Hepatocellular Carcinoma, Clear Cell Type Clear Cell Hepatocellular Carcinoma
Hypophosphatemic Rickets, X-Linked Dominant	Xlh Vitamin D-Resistant Rickets, X-Linked X-Linked Hypophosphatemia XLHR Hyp Hypophosphatemic Vitamin D-Resistant Rickets Hpdr X-Linked Hypophosphatemic Rickets X-Linked Dominant Hypophosphatemic Rickets Familial Hypophosphatemic Rickets Hypophosphatemia, X-Linked Hypophosphatemia, Vitamin D-Resistant Rickets Hypophosphatemic Rickets X-Linked Dominant X-Linked Vitamin D-Resistant Rickets Hypophophatemia, X-Linked Hypophophatemic Vitamin D-Resistant Rickets Hypophosphatemia X-Linked Vitamin D-Resistant Rickets X-Linked Vitamin D-Resistant Rickets Rickets, X-Linked Hypophosphatemic
Squamous Cell Carcinoma, Head And Neck	Squamous Cell Carcinoma Of The Head And Neck HNSCC Head And Neck Squamous Cell Carcinoma Head And Neck Cancer Squamous Cell Carcinoma Of Lip Squamous Cell Carcinoma, Head And Neck, Somatic Carcinoma Of The Head And Neck Squamous Cell Carcinomas Of Head And Neck Scchn Squamous Cell Carcinoma Of The Hypopharynx Squamous Cell Carcinoma Of The Oropharynx Squamous Cell Carcinoma Of Salivary Glands Squamous Cell Carcinoma Of The Nasal Cavity And Paranasal Sinuses Squamous Cell Carcinoma Of The Nasal Cavity And Sinuses Squamous Cell Carcinoma Of The Oral Cavity Squamous Cell Carcinoma Of The Lip Carcinoma, Squamous Cell Of Head And Neck Lip Squamous Cell Carcinoma Cancer, Head/Neck Carcinoma, Squamous Cell, Head And Neck Salivary Gland Squamous Cell Carcinoma Cancer Of Head And Neck Squamous Cell Carcinoma Of Oropharynx Nos
Prostate Cancer	Prostate Carcinoma Prostate Cancer, Familial Prostate Neoplasm Prostate Cancer, Somatic Prostate Cancer, Susceptibility To Prostatic Cancer Prostatic Neoplasms Hereditary Prostate Cancer Prostatic Neoplasm Cancer Of Prostate Carcinoma Of Prostate Familial Prostate Cancer Familial Prostate Carcinoma Malignant Tumor Of Prostate Malignant Neoplasm Of Prostate Prostate Cancer, Familial, Susceptibility To Malignant Tumor Of The Prostate Ngp - New Growth Of Prostate Tumor Of The Prostate Prostate Cancer, Hereditary Cancer Of The Prostate Malignant Neoplasm Of The Prostate Prostatic Carcinoma PC Prca Cancer, Prostate Malignant Prostatic Tumour Malignant Tumour Of Prostate Primary Prostate Cancer Primary Malignant Neoplasm Of Prostate Prostate Gland Cancer
Apert Syndrome	Acrocephalosyndactyly Type I Acs1 Acrocephalosyndactylia Acs I Apert-Crouzon Disease Acrocephalosyndactyly Acrocephalosyndactyly Type 1 Acrocephalosyndactyly, Type I Acs 1 Acrocephalo-Syndactyly Type 1 Syndactylic Oxycephaly Apert'S Syndrome Type I Acrocephalosyndactyly APRS
Embryonal Rhabdomyosarcoma	Rhabdomyosarcoma, Embryonal Rhabdomyosarcoma Embryonal Botryoid Rhabdomyosarcoma Erms Spindle Cell Rhabdomyosarcomas
Craniosynostosis	Premature Closure Of Cranial Sutures Craniostenosis Craniosynostosis Syndrome Cso Craniosynostoses Congenital Ossification Of Cranial Sutures Congenital Ossification Of Sutures Of Skull Craniostosis Imperfect Fusion Of Skull Congenital Imperfect Closure Skull Imperfect Closure Skull Premature Closure Cranium Sutures Deficiency Of Craniofacial Axis
Crouzon Syndrome	Crouzon Craniofacial Dysostosis Craniofacial Dysostosis Cfd1 Craniofacial Dysostosis Type 1 Crouzon Disease Crouzon'S Disease Craniofacial Dysostosis, Type I Craniofacial Dysarthrosis Craniofacial Dysostosis Syndrome CS Craniofacial Dysostosis Type I Vogt Cephalosyndactyly
Extrahepatic Cholestasis	Cholestasis, Extrahepatic Extrahepatic Biliary Stasis Extrahepatic Obstructive Biliary Disease Cholestasis Extrahepatic
Pancreatic Cancer	Pancreatic Carcinoma Familial Pancreatic Carcinoma Pancreatic Neoplasm Carcinoma Of Pancreas Pancreatic Carcinoma, Familial Malignant Neoplasm Of Pancreas Pancreatic Acinar Carcinoma Pancreatic Tumor Familial Pancreatic Cancer Neoplasm Of The Pancreas Pancreatic Carcinoma, Somatic Pancreatic Cancer, Somatic Ca Body Of Pancreas Ca Head Of Pancreas Ca Tail Of Pancreas Malignant Neoplasm Of Body Of Pancreas Malignant Neoplasm Of Head Of Pancreas Malignant Neoplasm Of Tail Of Pancreas Pancreas Neoplasm Exocrine Cancer Exocrine Pancreas Carcinoma Hereditary Pancreatic Cancer Hereditary Pancreatic Carcinoma PNCA Cancer Of The Pancreas Pancreatic Cancer, Susceptibility To Carcinoma Of Head Of Pancreas Pancreatic Neoplasms Pancreatic Tumors Cancer, Pancreatic Cancer Of Pancreas Mixed Islet Cell With Exocrine Carcinoma Of Unspecified Site
Lung Cancer Susceptibility 3	Lung Adenocarcinoma Adenocarcinoma Of Lung LNCR3 Adenocarcinoma Of Lung, Susceptibility To Bronchogenic Lung Adenocarcinoma Nonsmall Cell Adenocarcinoma Adenocarcinoma Lung Lung Adenocarcinomas Non-Small Cell Adenocarcinoma
Tumoral Calcinosis, Hyperphosphatemic, Familial, 1	Hyperphosphatemic Familial Tumoral Calcinosis Hftc Hyperostosis-Hyperphosphatemia Syndrome Familial Hyperphosphatemic Tumoral Calcinosis/Hyperphosphatemic Hyperostosis Syndrome Tumoral Calcinosis, Hyperphosphatemic, Familial Phptc Lipocalcinogranulomatosis Morbus Teutschlaender Hhs Hyperostosis With Hyperphosphatemia Cortical Hyperostosis With Hyperphosphatemia Primary Hyperphosphatemic Tumoral Calcinosis Familial Tumoral Calcinosis HFTC1 Hypercalcemic Tumoral Calcinosis Hyperphosphatemia Hyperostosis Hyperphosphatemia Hyperostosis Syndrome Hyperphosphatemia Tumoral Calcinosis Calcinosis, Tumoral, With Hyperphosphatemia Tumoral Calcinosis, Primary Hyperphosphatemic Teutschlaender Disease, Familial Familial Teutschlaender Disease Tumoral Calcinosis With Hyperphosphatemia Familial Tumoral Calcinosis/Hyperostosis-Hyperphosphatemia Syndrome Ftc/Hhs Familial Tumoral Calcinosis With Hyperphosphatemia Teutschlaender Disease Tumoral Calcinosis Primary Hyperphosphatemic Calcinosis, Tumoral, Hyperphosphatemic, Familial Tumoral Calcinosis
Outlet Dysfunction Constipation
Diarrhea	Diarrhoea Diarrhea Of Presumed Infectious Origin
Breast Cancer	Breast Carcinoma Breast Cancer, Familial Malignant Neoplasm Of Breast Male Breast Cancer Breast Cancer, Susceptibility To Breast Cancer, Early-Onset Malignant Tumor Of Breast Carcinoma Of Male Breast Breast Cancer, Invasive Ductal Breast Cancer, Protection Against Breast Cancer, Somatic Breast Cancer, Male Breast Cancer, Lobular, Somatic Breast Tumor Mammary Cancer Mammary Tumor Malignant Neoplasm Of Male Breast Mammary Carcinoma Male Breast Carcinoma Familial Cancer Of Breast Invasive Ductal Breast Carcinoma Breast Cancer Susceptibility Breast Cancer, Male, Susceptibility To Breast Cancer, Early-Onset, Susceptibility To Malignant Tumor Of The Breast Mammary Neoplasm Primary Breast Cancer Neoplasm Of Male Breast Carcinoma Of Breast Breast Cancer In Men Familial Breast Cancer Cancer Of Breast BC Breast Cancer Familial Breast Cancer Familial Male Breast Cancer, Familial Male Breast Male Carcinoma Breast Neoplasms Breast Neoplasms, Male Mammary Tumors Mammary Carcinomas Cancer, Breast Cancer, Breast, Susceptibility Invasive Breast Ductal Carcinoma Breast Neoplasm Susceptibility To Breast Cancer Mammary Neoplasms Animal Mammary Neoplasms Primary Malignant Neoplasm Of Breast Infiltrating Ductal Carcinoma Of Breast Infiltrating Duct Carcinoma Of Unspecified Site Infiltrating Ductular Carcinoma Of Unspecified Site Invasive Breast Carcinoma Of No Special Type Microinvasive Carcinoma Of Breast Carcinoma With Apocrine Differentiation
Muscle Cancer	Myosarcoma Malignant Neoplasm Of Muscle Malignant Tumor Of Muscle Malignant Tumor Of The Muscle Muscle Neoplasms Myomatous Neoplasm
Parameningeal Embryonal Rhabdomyosarcoma
Functional Diarrhea	Functional Diarrhoea
Neuroma
Adenoid Cystic Carcinoma	Adenocystic Carcinoma Cribriform Carcinoma Cylindroma Carcinoma Adenoid Cystic Carcinoma, Adenoid Cystic Adenoid Cystic Carcinoma Of Salivary Gland Eccrine Dermal Cylindroma Carcinoma, Cribriform
Phosphorus Metabolism Disease	Phosphorus Metabolism Disorders Disorder Of Phosphorus Metabolism Phosphorus Disorder Phosphorus Metabolism Disorder
Achondroplasia, Severe, With Developmental Delay And Acanthosis Nigricans	SADDAN Saddan Dysplasia Severe Achondroplasia-Developmental Delay-Acanthosis Nigricans Syndrome Severe Achondroplasia With Developmental Delay And Acanthosis Nigricans Ssb Syndrome Skeleton Skin Brain Syndrome Skeleton-Skin-Brain Syndrome Achondroplasia
Thanatophoric Dysplasia, Type I	Thanatophoric Dysplasia Thanatophoric Dwarfism Thanatophoric Dysplasia Type 1 TD1 Td Thanatophoric Short Stature Thanatophoric Dwarfism Type 1 Thanatophoric Dysplasia Type I Platyspondylic Lethal Skeletal Dysplasia, San Diego Type Lethal Short-Limbed Platyspondylic Dwarfism, San Diego Type Skeletal Dysplasia, San Diego Type Plsd San Diego Type Thanatophoric Dwarfism 1 Dwarfism Thanatophoric Dwarf, Thanatophoric Thanatophoric Dysplasia 1 Lethal Short-Limbed Platyspondylic Dwarfism San Diego Type Platyspondylic Lethal Skeletal Dysplasia San Diego Type Thanatophoric Dwarf Thanatophoric Dwarfism Or Short Stature Thanatophoric Dwarfism Syndrome Td - [Thanatophoric Dwarfism]
Skeletal Muscle Cancer	Malignant Tumor Of Skeletal Muscle Skeletal Muscle Neoplasm
Muenke Syndrome	Muenke Nonsyndromic Coronal Craniosynostosis Fgfr3-Related Craniosynostosis Fgfr3-Associated Coronal Synostosis Coronal Craniosynostosis MNKES Syndrome Of Coronal Craniosynostosis MNKS Fgfr3-Related Isolated Coronal Synostosis Muenke Non-Syndromic Coronal Craniosynostosis
Anaplastic Astrocytoma	Grade Iii Astrocytoma Grade Iii Astrocytic Tumor Astrocytoma, Anaplastic
Intrahepatic Cholestasis Of Pregnancy	Recurrent Intrahepatic Cholestasis Of Pregnancy Gravidic Intrahepatic Cholestasis Pregnancy-Related Cholestasis Icp Pregnancy Related Cholestasis Cholestasis, Intrahepatic Of Pregnancy Familial Intrahepatic Cholestasis Of Pregnancy Familial Recurrent Intrahepatic Cholestasis Of Pregnancy Ricp Obstetric Cholestasis
Orbit Rhabdomyosarcoma	Rhabdomyosarcoma Of The Orbit Rhabdomyosarcoma Of Orbit
Colorectal Cancer	Colon Cancer Colorectal Carcinoma Colon Carcinoma Colorectal Cancer, Susceptibility To Carcinoma Of Colon CRC Colorectal Cancer With Chromosomal Instability, Somatic Colon Cancer, Somatic Colon Cancer, Susceptibility To Colonic Neoplasms Colorectal Neoplasms Colorectal Cancer, Somatic Colon Cancer, Advanced, Somatic Colonic Carcinoma Colorectal Carcinomas Colon Cancers Colorectal Cancers Cancer, Colorectal, Somatic Cancer, Colon Cancer, Colorectal, Susceptibility To Colorectal Neoplasm Colonic Neoplasm Malignant Tumor Of Colon

Diseases	Alias
Waldenstroem'S Macroglobulinemia	Waldenstroem'S Macroglobulinemia Waldenstroem'S Macroglobulinemia Macroglobulinemia Of Waldenstrom Lymphoplasmacytic Lymphoma With Igm Gammopathy Lymphoplasmacytic Lymphoma Waldenstroem'S Macroglobulinemia Waldenstroem'S Macroglobulinemia Macroglobulinemia Of Waldenstrom Lymphoplasmacytic Lymphoma With Igm Gammopathy Lymphoplasmacytic Lymphoma

Related Agents

Pre-clinical Phase

Pre-clinical Phase

Bioactive Molecules (5)

Cat. No.	Product Name	Effect	Purity	Rare Diseases
HY-184598	CYB-5067	Degrader	/	Unkown
HY-184250	FGFR-IN-28	Inhibitor	/	Unkown
HY-181752	FGFR3-IN-12	Inhibitor	/	Unkown
HY-183780	FGFR-IN-27	Inhibitor	/	Unkown
HY-183909	EphB1-IN-2	Inhibitor	/	Unkown

Orthologs Information

Species	Symbol	Source	ID
Felis catus	FGFR4	VGNC	VGNC:62260
Rattus norvegicus	FGFR4	RGD	RGD:2612
Macaca mulatta	FGFR4	VGNC	VGNC:72654
Canis familiaris	FGFR4	VGNC	VGNC:40861
Mus musculus	FGFR4	MGD	MGI:95525
Bos taurus	FGFR4	VGNC	VGNC:28988
Others	FGFR4	NCBI