AiPD: Autoinhibited Protein Database

P18461

Gene name	FGFR2 (CEK3)
Protein name	Fibroblast growth factor receptor 2
Names	FGFR-2 , EC 2.7.10.1 , Tyrosine kinase receptor CEK3
Species	Gallus gallus (Chicken)
KEGG Pathway	gga:396259
EC number	2.7.10.1: Protein-tyrosine kinases
Protein Class

Descriptions

Fibroblast growth factor receptor 1 (FGFR1) is one of the members of FGFR family belonging to the receptor tyrosine kinases (RTK) in cell proliferation, differentiation, migration, and maintenance of cellular homeostasis. FGFR1 consists of the ligand-binding region (immunoglobulin (Ig) domain 1-like domains) designated D1, D2, and D3, and a kinase domain. The D1 domain and the acid box (AB)-containing linker between D1 and D2 are involved in autoinhibition. Loss of D1 or the linker enhances the affinity of FGFR for FGF and HS and increases the signaling capacity of FGFR. Specifically, the AB region blocks the heparan sulfate (HS)-binding site on the D2 domain in cis to suppress HS-binding affinity of EGFR. D1 is dispensable for autoinhibition but plays a minor role in autoinhibition.

Autoinhibitory domains (AIDs)

130-154 (AB/linker region) SS

Target domain	25-129 (D2 domain)
Relief mechanism	Others
Assay

AID

130-154 (AB/linker region)

Target domain

25-129 (D2 domain)

Relief mechanism

Others (Substitution of the acidic residues in AB subregion with alanines without changing the length of AB/linker)

Assay

471-473 (Helix αN) SS

Target domain	483-770 (Protein kinase domain)
Relief mechanism	Ligand binding, PTM
Assay

AID

471-473 (Helix αN)

Target domain

483-770 (Protein kinase domain)

Relief mechanism

Ligand binding (Binding of the glial cell line-derived neurotrophic factor (GDNF) family ligand), PTM (Phosphorylation at Tyr-905)

Assay

524-528 (Autoinhibitory segment) SS

Target domain	483-770 (Protein kinase domain)
Relief mechanism	Ligand binding, PTM
Assay

AID

524-528 (Autoinhibitory segment)

Target domain

483-770 (Protein kinase domain)

Relief mechanism

Ligand binding (Binding of the glial cell line-derived neurotrophic factor (GDNF) family ligand), PTM (Phosphorylation at Tyr-905)

Assay

Accessory elements

645-670 (Activation loop from InterPro)

Target domain	483-772 (Protein kinase domain)
Relief mechanism
Assay

645-670 (Activation loop from InterPro)

Target domain	483-772 (Protein kinase domain)
Relief mechanism
Assay

References

Yeon JH et al. (2016) "Systems-wide Identification of cis-Regulatory Elements in Proteins", Cell systems, 2, 89-100

Lew ED et al. (2007) "Structural basis for reduced FGFR2 activity in LADD syndrome: Implications for FGFR autoinhibition and activation", Proceedings of the National Academy of Sciences of the United States of America, 104, 19802-7

Kalinina J et al. (2012) "The alternatively spliced acid box region plays a key role in FGF receptor autoinhibition", Structure (London, England : 1993), 20, 77-88

Uchikawa E et al. (2019) "Activation mechanism of the insulin receptor revealed by cryo-EM structure of the fully liganded receptor-ligand complex", eLife, 8,

Nielsen J et al. (2022) "Structural Investigations of Full-Length Insulin Receptor Dynamics and Signalling", Journal of molecular biology, 434, 167458

Chen YS et al. (2021) "Insertion of a synthetic switch into insulin provides metabolite-dependent regulation of hormone-receptor activation", Proceedings of the National Academy of Sciences of the United States of America, 118,

Craddock BP et al. (2007) "Autoinhibition of the insulin-like growth factor I receptor by the juxtamembrane region", FEBS letters, 581, 3235-40

Klein T et al. (2015) "Structural and dynamic insights into the energetics of activation loop rearrangement in FGFR1 kinase", Nature communications, 6, 7877

Huang X et al. (2009) "Structural insights into the inhibited states of the Mer receptor tyrosine kinase", Journal of structural biology, 165, 88-96

Olsen SK et al. (2004) "Insights into the molecular basis for fibroblast growth factor receptor autoinhibition and ligand-binding promiscuity", Proceedings of the National Academy of Sciences of the United States of America, 101, 935-40

Knowles PP et al. (2006) "Structure and chemical inhibition of the RET tyrosine kinase domain", The Journal of biological chemistry, 281, 33577-87

Autoinhibited structure

Activated structure

1 structures for P18461

Entry ID	Method	Resolution	Chain	Position	Source
AF-P18461-F1	Predicted				AlphaFoldDB

No variants for P18461

Variant ID(s)	Position	Change	Description	Diseaes Association	Provenance
No variants for P18461

No associated diseases with P18461

15 regional properties for P18461

Type	Name	Position	InterPro Accession
domain	Protein kinase domain	483 - 772	IPR000719
domain	Serine-threonine/tyrosine-protein kinase, catalytic domain	483 - 759	IPR001245
domain	Immunoglobulin subtype 2	56 - 117	IPR003598-1
domain	Immunoglobulin subtype 2	172 - 240	IPR003598-2
domain	Immunoglobulin subtype 2	271 - 351	IPR003598-3
domain	Immunoglobulin subtype	50 - 128	IPR003599-1
domain	Immunoglobulin subtype	166 - 251	IPR003599-2
domain	Immunoglobulin subtype	265 - 362	IPR003599-3
domain	Immunoglobulin-like domain	42 - 128	IPR007110-1
domain	Immunoglobulin-like domain	156 - 249	IPR007110-2
domain	Immunoglobulin-like domain	258 - 360	IPR007110-3
active_site	Tyrosine-protein kinase, active site	624 - 636	IPR008266
domain	Immunoglobulin I-set	173 - 250	IPR013098
binding_site	Protein kinase, ATP binding site	489 - 519	IPR017441
domain	Tyrosine-protein kinase, catalytic domain	483 - 759	IPR020635

Functions

		Description
EC Number	2.7.10.1	Protein-tyrosine kinases
Subcellular Localization	Cell membrane; Single-pass type I membrane protein Golgi apparatus Cytoplasmic vesicle	Detected on osteoblast plasma membrane lipid rafts After ligand binding, the activated receptor is rapidly internalized and degraded (By similarity)
PANTHER Family
PANTHER Subfamily
PANTHER Protein Class
PANTHER Pathway Category	No pathway information available

4 GO annotations of cellular component

Name	Definition
cytoplasmic vesicle	A vesicle found in the cytoplasm of a cell.
Golgi apparatus	A membrane-bound cytoplasmic organelle of the endomembrane system that further processes the core oligosaccharides (e.g. N-glycans) added to proteins in the endoplasmic reticulum and packages them into membrane-bound vesicles. The Golgi apparatus operates at the intersection of the secretory, lysosomal, and endocytic pathways.
plasma membrane	The membrane surrounding a cell that separates the cell from its external environment. It consists of a phospholipid bilayer and associated proteins.
receptor complex	Any protein complex that undergoes combination with a hormone, neurotransmitter, drug or intracellular messenger to initiate a change in cell function.

3 GO annotations of molecular function

Name	Definition
ATP binding	Binding to ATP, adenosine 5'-triphosphate, a universally important coenzyme and enzyme regulator.
fibroblast growth factor binding	Binding to a fibroblast growth factor.
fibroblast growth factor receptor activity	Combining with a fibroblast growth factor receptor ligand and transmitting the signal across the plasma membrane to initiate a change in cell activity.

3 GO annotations of biological process

Name	Definition
apoptotic process	A programmed cell death process which begins when a cell receives an internal (e.g. DNA damage) or external signal (e.g. an extracellular death ligand), and proceeds through a series of biochemical events (signaling pathway phase) which trigger an execution phase. The execution phase is the last step of an apoptotic process, and is typically characterized by rounding-up of the cell, retraction of pseudopodes, reduction of cellular volume (pyknosis), chromatin condensation, nuclear fragmentation (karyorrhexis), plasma membrane blebbing and fragmentation of the cell into apoptotic bodies. When the execution phase is completed, the cell has died.
phosphorylation	The process of introducing a phosphate group into a molecule, usually with the formation of a phosphoric ester, a phosphoric anhydride or a phosphoric amide.
positive regulation of cell population proliferation	Any process that activates or increases the rate or extent of cell proliferation.

76 homologous proteins in AiPD

UniProt AC	Gene Name	Protein Name	Species	Evidence Code
P43481	KIT	Mast/stem cell growth factor receptor Kit	Bos taurus (Bovine)	SS
Q06805	TIE1	Tyrosine-protein kinase receptor Tie-1	Bos taurus (Bovine)	PR
Q06807	TEK	Angiopoietin-1 receptor	Bos taurus (Bovine)	SS
Q28889	KIT	Mast/stem cell growth factor receptor Kit	Felis catus (Cat) (Felis silvestris catus)	SS
P13369	CSF1R	Macrophage colony-stimulating factor 1 receptor	Felis catus (Cat) (Felis silvestris catus)	SS
P18460	FGFR3	Fibroblast growth factor receptor 3	Gallus gallus (Chicken)	SS
P21804	FGFR1	Fibroblast growth factor receptor 1	Gallus gallus (Chicken)	SS
Q08156	KIT	Mast/stem cell growth factor receptor Kit	Gallus gallus (Chicken)	SS
Q8AXY6	MUSK	Muscle, skeletal receptor tyrosine protein kinase	Gallus gallus (Chicken)	SS
Q5F3X2	DDR1	receptor protein-tyrosine kinase	Gallus gallus (Chicken)	SS
Q91987	NTRK2	BDNF/NT-3 growth factors receptor	Gallus gallus (Chicken)	SS
Q91044	NTRK3	NT-3 growth factor receptor	Gallus gallus (Chicken)	SS
Q8QHL3	FLT1	Vascular endothelial growth factor receptor 1	Gallus gallus (Chicken)	SS
Q98949	TYRO3	Tyrosine-protein kinase receptor TYRO3	Gallus gallus (Chicken)	PR
Q9PUF6	PDGFRA	Platelet-derived growth factor receptor alpha	Gallus gallus (Chicken)	SS
Q91009	NTRK1	High affinity nerve growth factor receptor	Gallus gallus (Chicken)	SS
Q07494	EPHB1	Ephrin type-B receptor 1	Gallus gallus (Chicken)	SS
Q07407	htl	Fibroblast growth factor receptor homolog 1	Drosophila melanogaster (Fruit fly)	PR
Q6J9G0	STYK1	Tyrosine-protein kinase STYK1	Homo sapiens (Human)	PR
P36888	FLT3	Receptor-type tyrosine-protein kinase FLT3	Homo sapiens (Human)	EV
P16234	PDGFRA	Platelet-derived growth factor receptor alpha	Homo sapiens (Human)	EV
P09619	PDGFRB	Platelet-derived growth factor receptor beta	Homo sapiens (Human)	EV
P35916	FLT4	Vascular endothelial growth factor receptor 3	Homo sapiens (Human)	SS
P35968	KDR	Vascular endothelial growth factor receptor 2	Homo sapiens (Human)	EV
P17948	FLT1	Vascular endothelial growth factor receptor 1	Homo sapiens (Human)	SS
P07333	CSF1R	Macrophage colony-stimulating factor 1 receptor	Homo sapiens (Human)	SS
P10721	KIT	Mast/stem cell growth factor receptor Kit	Homo sapiens (Human)	EV
P07949	RET	Proto-oncogene tyrosine-protein kinase receptor Ret	Homo sapiens (Human)	EV
P35590	TIE1	Tyrosine-protein kinase receptor Tie-1	Homo sapiens (Human)	PR
Q02763	TEK	Angiopoietin-1 receptor	Homo sapiens (Human)	SS
P11362	FGFR1	Fibroblast growth factor receptor 1	Homo sapiens (Human)	EV
P22455	FGFR4	Fibroblast growth factor receptor 4	Homo sapiens (Human)	SS
P22607	FGFR3	Fibroblast growth factor receptor 3	Homo sapiens (Human)	EV
P21802	FGFR2	Fibroblast growth factor receptor 2	Homo sapiens (Human)	EV
Q03142	Fgfr4	Fibroblast growth factor receptor 4	Mus musculus (Mouse)	PR
P05532	Kit	Mast/stem cell growth factor receptor Kit	Mus musculus (Mouse)	PR
Q91V87	Fgfrl1	Fibroblast growth factor receptor-like 1	Mus musculus (Mouse)	PR
P35917	Flt4	Vascular endothelial growth factor receptor 3	Mus musculus (Mouse)	SS
P05622	Pdgfrb	Platelet-derived growth factor receptor beta	Mus musculus (Mouse)	SS
P09581	Csf1r	Macrophage colony-stimulating factor 1 receptor	Mus musculus (Mouse)	SS
P35969	Flt1	Vascular endothelial growth factor receptor 1	Mus musculus (Mouse)	SS
P35546	Ret	Proto-oncogene tyrosine-protein kinase receptor Ret	Mus musculus (Mouse)	SS
Q06806	Tie1	Tyrosine-protein kinase receptor Tie-1	Mus musculus (Mouse)	SS
Q00342	Flt3	Receptor-type tyrosine-protein kinase FLT3	Mus musculus (Mouse)	SS
Q6J9G1	Styk1	Tyrosine-protein kinase STYK1	Mus musculus (Mouse)	PR
Q61851	Fgfr3	Fibroblast growth factor receptor 3	Mus musculus (Mouse)	PR
Q02858	Tek	Angiopoietin-1 receptor	Mus musculus (Mouse)	SS
P35918	Kdr	Vascular endothelial growth factor receptor 2	Mus musculus (Mouse)	PR
P26618	Pdgfra	Platelet-derived growth factor receptor alpha	Mus musculus (Mouse)	SS
P16092	Fgfr1	Fibroblast growth factor receptor 1	Mus musculus (Mouse)	SS
P21803	Fgfr2	Fibroblast growth factor receptor 2	Mus musculus (Mouse)	SS
Q2HWD6	KIT	Mast/stem cell growth factor receptor Kit	Sus scrofa (Pig)	SS
Q7TQM3	Fgfrl1	Fibroblast growth factor receptor-like 1	Rattus norvegicus (Rat)	PR
P53767	Flt1	Vascular endothelial growth factor receptor 1	Rattus norvegicus (Rat)	PR
P20786	Pdgfra	Platelet-derived growth factor receptor alpha	Rattus norvegicus (Rat)	SS
Q91ZT1	Flt4	Vascular endothelial growth factor receptor 3	Rattus norvegicus (Rat)	SS
Q04589	Fgfr1	Fibroblast growth factor receptor 1	Rattus norvegicus (Rat)	SS
G3V9H8	Ret	Proto-oncogene tyrosine-protein kinase receptor Ret	Rattus norvegicus (Rat)	SS
Q05030	Pdgfrb	Platelet-derived growth factor receptor beta	Rattus norvegicus (Rat)	SS
O08775	Kdr	Vascular endothelial growth factor receptor 2	Rattus norvegicus (Rat)	SS
Q498D6	Fgfr4	Fibroblast growth factor receptor 4	Rattus norvegicus (Rat)	PR
Q17833	old-1	Tyrosine-protein kinase receptor old-1	Caenorhabditis elegans	PR
Q19238	F09A5.2	Putative tyrosine-protein kinase F09A5.2	Caenorhabditis elegans	SS
P34892	kin-16	Receptor-like tyrosine-protein kinase kin-16	Caenorhabditis elegans	PR
G5ED65	ver-1	Protein ver-1	Caenorhabditis elegans	PR
Q10656	egl-15	Myoblast growth factor receptor egl-15	Caenorhabditis elegans	PR
Q8AXB3	kdrl	Vascular endothelial growth factor receptor kdr-like	Danio rerio (Zebrafish) (Brachydanio rerio)	SS
Q5GIT4	kdr	Vascular endothelial growth factor receptor 2	Danio rerio (Zebrafish) (Brachydanio rerio)	SS
O73791	tek	Angiopoietin-1 receptor	Danio rerio (Zebrafish) (Brachydanio rerio)	SS
Q9I8N6	csf1r	Macrophage colony-stimulating factor 1 receptor	Danio rerio (Zebrafish) (Brachydanio rerio)	SS
Q90413	fgfr4	Fibroblast growth factor receptor 4	Danio rerio (Zebrafish) (Brachydanio rerio)	SS
Q9DE49	pdgfra	Platelet-derived growth factor receptor alpha	Danio rerio (Zebrafish) (Brachydanio rerio)	SS
Q8JFR5	kita	Mast/stem cell growth factor receptor kita	Danio rerio (Zebrafish) (Brachydanio rerio)	SS
Q5MD89	flt4	Vascular endothelial growth factor receptor 3	Danio rerio (Zebrafish) (Brachydanio rerio)	SS
Q90Z00	fgfr1a	Fibroblast growth factor receptor 1-A	Danio rerio (Zebrafish) (Brachydanio rerio)	SS
Q8JG38	fgfr2	Fibroblast growth factor receptor 2	Danio rerio (Zebrafish) (Brachydanio rerio)	SS

10	20	30	40	50	60
MVSWDSGCLI	CLVVVTMAGL	SLARPSFNLV	VEDATLEPEE	PPTKYQISQP	DVHSALPGEP
70	80	90	100	110	120
LELRCQLKDA	VMISWTKDGV	PLGPDNRTVI	IGEYLQIKDA	SPRDSGLYAC	TAIRTLDSDT
130	140	150	160	170	180
LYFIVNVTDA	LSSGDDEDDN	DGSEDFVNDS	NQMRAPYWTH	TDKMEKRLHA	VPAANTVKFR
190	200	210	220	230	240
CPAMGNPTPT	MRWLKNGKEF	KQEHRIGGYK	VRNQHWSLIM	ESVVPSDKGN	YTCIVENQYG
250	260	270	280	290	300
SINHTYHLDV	VERSPHRPIL	QAGLPANASA	VVGGDVEFVC	KVYSDAQPHI	QWIKHVERNG
310	320	330	340	350	360
SKYGPDGLPY	LQVLKAAGVN	TTDKEIEVLY	IRNVTFEDAG	EYTCLAGNSI	GISFHTAWLT
370	380	390	400	410	420
VLPAPEKEKE	FPTSPDYLEI	AIYCIGVFLI	ACMVLTVILC	RMKNTTKKPD	FSSQPAVHKL
430	440	450	460	470	480
TKRIPLRRQV	TVSADSSSSM	NSNTPLVRIT	TRLSSTADAP	MLAGVSEYEL	PEDPKWEFPR
490	500	510	520	530	540
DKLTLGKPLG	EGCFGQVVMA	EAVGIDKDRP	KEAVTVAVKM	LKDDATEKDL	SDLVSEMEMM
550	560	570	580	590	600
KMIGKHKNII	NLLGACTQDG	PLYVIVEYAS	KGNLREYLRA	RRPPGMEYSF	DINRVPEEQM
610	620	630	640	650	660
TFKDLVSCTY	QLARGMEYLA	SQKCIHRDLA	ARNVLVTENN	VMKIADFGLA	RDINNIDYYK
670	680	690	700	710	720
KTTNGRLPVK	WMAPEALFDR	VYTHQSDVWS	FGVLMWEIFT	LGGSPYPGIP	VEELFKLLKE
730	740	750	760	770	780
GHRMDKPANC	TNELYMMMRD	CWQAVPSQRP	TFKQLVEDLD	RILTLTTNEE	YLDLSGPLEQ
790	800	810	820
YSPSYPDTRS	SCSSGDDSVF	SPDPMPYEPC	LPKYQHMNGS	VKT

Descriptions

Annotation based on sequence homology with P11362

Autoinhibitory domains (AIDs)

Accessory elements

645-670 (Activation loop from InterPro)

645-670 (Activation loop from InterPro)

References

Autoinhibited structure

Activated structure

1 structures for P18461

No variants for P18461

No associated diseases with P18461

15 regional properties for P18461

Functions

4 GO annotations of cellular component

3 GO annotations of molecular function

3 GO annotations of biological process

76 homologous proteins in AiPD