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Protein

Protein-tyrosine kinase 2-beta

Gene

PTK2B

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Non-receptor protein-tyrosine kinase that regulates reorganization of the actin cytoskeleton, cell polarization, cell migration, adhesion, spreading and bone remodeling. Plays a role in the regulation of the humoral immune response, and is required for normal levels of marginal B-cells in the spleen and normal migration of splenic B-cells. Required for normal macrophage polarization and migration towards sites of inflammation. Regulates cytoskeleton rearrangement and cell spreading in T-cells, and contributes to the regulation of T-cell responses. Promotes osteoclastic bone resorption; this requires both PTK2B/PYK2 and SRC. May inhibit differentiation and activity of osteoprogenitor cells. Functions in signaling downstream of integrin and collagen receptors, immune receptors, G-protein coupled receptors (GPCR), cytokine, chemokine and growth factor receptors, and mediates responses to cellular stress. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and of the AKT1 signaling cascade. Promotes activation of NOS3. Regulates production of the cellular messenger cGMP. Promotes activation of the MAP kinase signaling cascade, including activation of MAPK1/ERK2, MAPK3/ERK1 and MAPK8/JNK1. Promotes activation of Rho family GTPases, such as RHOA and RAC1. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Acts as a scaffold, binding to both PDPK1 and SRC, thereby allowing SRC to phosphorylate PDPK1 at 'Tyr-9, 'Tyr-373', and 'Tyr-376'. Promotes phosphorylation of NMDA receptors by SRC family members, and thereby contributes to the regulation of NMDA receptor ion channel activity and intracellular Ca2+ levels. May also regulate potassium ion transport by phosphorylation of potassium channel subunits. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ASAP1, NPHP1, KCNA2 and SHC1. Promotes phosphorylation of ASAP2, RHOU and PXN; this requires both SRC and PTK2/PYK2.25 Publications

Miscellaneous

Promotes bone resorption, and thus PTK2B/PYK2 inhibitors might be used to treat osteoporosis.

Catalytic activityi

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.PROSITE-ProRule annotation6 Publications

Activity regulationi

Activated in response to stimuli that lead to increased intracellular Ca2+ levels; this activation is indirect and may be mediated by calcium-mediated production of reactive oxygen species (ROS). Activated by autophosphorylation at Tyr-402; this creates a binding site for SRC family kinases and leads to phosphorylation at additional tyrosine residues. Phosphorylation at Tyr-402, Tyr-579 and Tyr-580 is required for optimal kinase activity. Inhibited by PF-562,271, BIRB796, PF-4618433 and by PF-431396, PF-2318841 and their derivatives. Inhibited by sulfoximine-substituted trifluoromethylpyrimidines. Inhibited by 4-amino and 5-aryl substituted pyridinone compounds.4 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei457ATPCombined sources1 Publication1
Active sitei549Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi431 – 439ATPCombined sources1 Publication9
Nucleotide bindingi503 – 509ATPCombined sources1 Publication7

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionKinase, Transferase, Tyrosine-protein kinase
Biological processAdaptive immunity, Angiogenesis, Immunity
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.10.2 2681
ReactomeiR-HSA-391160 Signal regulatory protein family interactions
R-HSA-4420097 VEGFA-VEGFR2 Pathway
R-HSA-9020558 Interleukin-2 signaling
SignaLinkiQ14289
SIGNORiQ14289

Names & Taxonomyi

Protein namesi
Recommended name:
Protein-tyrosine kinase 2-beta (EC:2.7.10.2)
Alternative name(s):
Calcium-dependent tyrosine kinase
Short name:
CADTK
Calcium-regulated non-receptor proline-rich tyrosine kinase
Cell adhesion kinase beta
Short name:
CAK-beta
Short name:
CAKB
Focal adhesion kinase 2
Short name:
FADK 2
Proline-rich tyrosine kinase 2
Related adhesion focal tyrosine kinase
Short name:
RAFTK
Gene namesi
Name:PTK2B
Synonyms:FAK2, PYK2, RAFTK
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 8

Organism-specific databases

EuPathDBiHostDB:ENSG00000120899.17
HGNCiHGNC:9612 PTK2B
MIMi601212 gene
neXtProtiNX_Q14289

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell junction, Cell membrane, Cell projection, Cytoplasm, Membrane, Nucleus

Pathology & Biotechi

Involvement in diseasei

Aberrant PTK2B/PYK2 expression may play a role in cancer cell proliferation, migration and invasion, in tumor formation and metastasis. Elevated PTK2B/PYK2 expression is seen in gliomas, hepatocellular carcinoma, lung cancer and breast cancer.

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi402Y → F: Abolishes autophosphorylation. Abolishes interaction with SRC. 1 Publication1
Mutagenesisi457K → A: Abolishes kinase activity. 1 Publication1
Mutagenesisi859P → A: Loss of interaction with NPHP1. 1 Publication1
Mutagenesisi881Y → F: Loss of phosphorylation site. Strongly reduced interaction with GRB2. 1 Publication1

Organism-specific databases

DisGeNETi2185
OpenTargetsiENSG00000120899
PharmGKBiPA33956

Chemistry databases

ChEMBLiCHEMBL5469
DrugBankiDB01645 Genistein
DB01097 Leflunomide
GuidetoPHARMACOLOGYi2181

Polymorphism and mutation databases

BioMutaiPTK2B
DMDMi3183003

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000880811 – 1009Protein-tyrosine kinase 2-betaAdd BLAST1009

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei361PhosphoserineCombined sources1
Modified residuei375PhosphoserineCombined sources1
Modified residuei399PhosphoserineCombined sources1
Modified residuei402Phosphotyrosine; by autocatalysis7 Publications1
Modified residuei579PhosphotyrosineBy similarity1
Modified residuei580Phosphotyrosine; by SRC, FYN and LCK2 Publications1
Modified residuei722PhosphotyrosineCombined sources1
Modified residuei762PhosphoserineCombined sources1
Modified residuei765PhosphothreonineCombined sources1
Modified residuei819PhosphotyrosineCombined sources1
Modified residuei834PhosphotyrosineCombined sources1
Modified residuei839PhosphoserineCombined sources1
Modified residuei842PhosphothreonineCombined sources1
Modified residuei849PhosphotyrosineCombined sources1
Modified residuei866PhosphoserineCombined sources1
Modified residuei881Phosphotyrosine; by SRC1 Publication1

Post-translational modificationi

Phosphorylated on tyrosine residues in response to various stimuli that elevate the intracellular calcium concentration; this activation is indirect and may be mediated by production of reactive oxygen species (ROS). Tyr-402 is the major autophosphorylation site, but other kinases can also phosphorylate Tyr-402. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Phosphorylation at Tyr-402 promotes interaction with SRC and SRC family members, leading to phosphorylation at Tyr-579; Tyr-580 and Tyr-881. Phosphorylation at Tyr-881 is important for interaction with GRB2. Phosphorylated on tyrosine residues upon activation of FGR and PKC. Recruitment by NPHP1 to cell matrix adhesions initiates Tyr-402 phosphorylation. In monocytes, adherence to substrata is required for tyrosine phosphorylation and kinase activation. Angiotensin II, thapsigargin and L-alpha-lysophosphatidic acid (LPA) also induce autophosphorylation and increase kinase activity. Phosphorylation by MYLK promotes ITGB2 activation and is thus essential to trigger neutrophil transmigration during lung injury. Dephosphorylated by PTPN12.9 Publications

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiQ14289
MaxQBiQ14289
PaxDbiQ14289
PeptideAtlasiQ14289
PRIDEiQ14289
ProteomicsDBi59955
59956 [Q14289-2]
TopDownProteomicsiQ14289-2 [Q14289-2]

PTM databases

iPTMnetiQ14289
PhosphoSitePlusiQ14289

Expressioni

Tissue specificityi

Most abundant in the brain, with highest levels in amygdala and hippocampus. Low levels in kidney (at protein level). Also expressed in spleen and lymphocytes.2 Publications

Gene expression databases

BgeeiENSG00000120899 Expressed in 195 organ(s), highest expression level in right hemisphere of cerebellum
CleanExiHS_PTK2B
ExpressionAtlasiQ14289 baseline and differential
GenevisibleiQ14289 HS

Organism-specific databases

HPAiCAB003850
HPA026091
HPA026276

Interactioni

Subunit structurei

Homodimer, or homooligomer. Interacts with SIRPA and SH2D3C. Interacts with ARHGAP10. Interacts with DLG4 (By similarity). Interacts with KCNA2 (By similarity). Interacts with NPHP1, ASAP1, ASAP2, ARHGAP26, SKAP2 and TGFB1I1. The Tyr-402 phosphorylated form interacts with SRC (via SH2 domain) and SRC family members. Forms a signaling complex with EPHA1, LCK and phosphatidylinositol 3-kinase; upon activation by EFNA1. Interacts with GRB2 (via SH2 domain). Interacts with P53/TP53 and MDM2. Interacts with MYLK. Interacts with BCAR1. Interacts with PDPK1. Interacts (hypophosphorylated) with PXN. Interacts with RB1CC1. Interacts with RHOU. Interacts with VAV1. Interacts with LPXN and PTPN12.By similarity21 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi108480, 63 interactors
CORUMiQ14289
ELMiQ14289
IntActiQ14289, 23 interactors
MINTiQ14289
STRINGi9606.ENSP00000332816

Chemistry databases

BindingDBiQ14289

Structurei

Secondary structure

11009
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliQ14289
SMRiQ14289
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ14289

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini39 – 359FERMPROSITE-ProRule annotationAdd BLAST321
Domaini425 – 683Protein kinasePROSITE-ProRule annotationAdd BLAST259

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni801 – 1009Interaction with TGFB1I1By similarityAdd BLAST209
Regioni868 – 1009Focal adhesion targeting (FAT)Add BLAST142

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi702 – 767Pro-richAdd BLAST66
Compositional biasi831 – 869Pro-richAdd BLAST39

Sequence similaritiesi

Belongs to the protein kinase superfamily. Tyr protein kinase family. FAK subfamily.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG4257 Eukaryota
ENOG410ZH9Y LUCA
GeneTreeiENSGT00760000118799
HOGENOMiHOG000069938
HOVERGENiHBG004018
InParanoidiQ14289
KOiK05871
OMAiQMLTASH
OrthoDBiEOG091G03BN
PhylomeDBiQ14289
TreeFamiTF316643

Family and domain databases

CDDicd14473 FERM_B-lobe, 1 hit
Gene3Di1.20.80.10, 1 hit
2.30.29.30, 1 hit
InterProiView protein in InterPro
IPR019749 Band_41_domain
IPR014352 FERM/acyl-CoA-bd_prot_sf
IPR035963 FERM_2
IPR019748 FERM_central
IPR000299 FERM_domain
IPR036137 Focal_adhe_kin_target_dom_sf
IPR005189 Focal_adhesion_kin_target_dom
IPR011009 Kinase-like_dom_sf
IPR011993 PH-like_dom_sf
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR030610 PTK2B
IPR001245 Ser-Thr/Tyr_kinase_cat_dom
IPR008266 Tyr_kinase_AS
IPR020635 Tyr_kinase_cat_dom
IPR029071 Ubiquitin-like_domsf
PANTHERiPTHR24418:SF94 PTHR24418:SF94, 1 hit
PfamiView protein in Pfam
PF00373 FERM_M, 1 hit
PF03623 Focal_AT, 1 hit
PF07714 Pkinase_Tyr, 1 hit
PRINTSiPR00109 TYRKINASE
ProDomiView protein in ProDom or Entries sharing at least one domain
PD006413 Focal_adhesion_target_reg, 1 hit
SMARTiView protein in SMART
SM00295 B41, 1 hit
SM00219 TyrKc, 1 hit
SUPFAMiSSF47031 SSF47031, 1 hit
SSF54236 SSF54236, 1 hit
SSF56112 SSF56112, 1 hit
SSF68993 SSF68993, 1 hit
PROSITEiView protein in PROSITE
PS50057 FERM_3, 1 hit
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00109 PROTEIN_KINASE_TYR, 1 hit

Sequences (2+)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

This entry has 2 described isoforms and 5 potential isoforms that are computationally mapped.iShow all

Isoform 1 (identifier: Q14289-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide
        10         20         30         40         50
MSGVSEPLSR VKLGTLRRPE GPAEPMVVVP VDVEKEDVRI LKVCFYSNSF
60 70 80 90 100
NPGKNFKLVK CTVQTEIREI ITSILLSGRI GPNIRLAECY GLRLKHMKSD
110 120 130 140 150
EIHWLHPQMT VGEVQDKYEC LHVEAEWRYD LQIRYLPEDF MESLKEDRTT
160 170 180 190 200
LLYFYQQLRN DYMQRYASKV SEGMALQLGC LELRRFFKDM PHNALDKKSN
210 220 230 240 250
FELLEKEVGL DLFFPKQMQE NLKPKQFRKM IQQTFQQYAS LREEECVMKF
260 270 280 290 300
FNTLAGFANI DQETYRCELI QGWNITVDLV IGPKGIRQLT SQDAKPTCLA
310 320 330 340 350
EFKQIRSIRC LPLEEGQAVL QLGIEGAPQA LSIKTSSLAE AENMADLIDG
360 370 380 390 400
YCRLQGEHQG SLIIHPRKDG EKRNSLPQIP MLNLEARRSH LSESCSIESD
410 420 430 440 450
IYAEIPDETL RRPGGPQYGI AREDVVLNRI LGEGFFGEVY EGVYTNHKGE
460 470 480 490 500
KINVAVKTCK KDCTLDNKEK FMSEAVIMKN LDHPHIVKLI GIIEEEPTWI
510 520 530 540 550
IMELYPYGEL GHYLERNKNS LKVLTLVLYS LQICKAMAYL ESINCVHRDI
560 570 580 590 600
AVRNILVASP ECVKLGDFGL SRYIEDEDYY KASVTRLPIK WMSPESINFR
610 620 630 640 650
RFTTASDVWM FAVCMWEILS FGKQPFFWLE NKDVIGVLEK GDRLPKPDLC
660 670 680 690 700
PPVLYTLMTR CWDYDPSDRP RFTELVCSLS DVYQMEKDIA MEQERNARYR
710 720 730 740 750
TPKILEPTAF QEPPPKPSRP KYRPPPQTNL LAPKLQFQVP EGLCASSPTL
760 770 780 790 800
TSPMEYPSPV NSLHTPPLHR HNVFKRHSMR EEDFIQPSSR EEAQQLWEAE
810 820 830 840 850
KVKMRQILDK QQKQMVEDYQ WLRQEEKSLD PMVYMNDKSP LTPEKEVGYL
860 870 880 890 900
EFTGPPQKPP RLGAQSIQPT ANLDRTDDLV YLNVMELVRA VLELKNELCQ
910 920 930 940 950
LPPEGYVVVV KNVGLTLRKL IGSVDDLLPS LPSSSRTEIE GTQKLLNKDL
960 970 980 990 1000
AELINKMRLA QQNAVTSLSE ECKRQMLTAS HTLAVDAKNL LDAVDQAKVL

ANLAHPPAE
Length:1,009
Mass (Da):115,875
Last modified:July 15, 1998 - v2
Checksum:i420B21046274E7C2
GO
Isoform 2 (identifier: Q14289-2) [UniParc]FASTAAdd to basket
Also known as: PYK2H

The sequence of this isoform differs from the canonical sequence as follows:
     739-780: Missing.

Show »
Length:967
Mass (Da):111,183
Checksum:i4AFDAA83908F2902
GO

Computationally mapped potential isoform sequencesi

There are 5 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
C9JHV9C9JHV9_HUMAN
Protein-tyrosine kinase 2-beta
PTK2B
213Annotation score:
E5RJ77E5RJ77_HUMAN
Protein-tyrosine kinase 2-beta
PTK2B
184Annotation score:
H0YB74H0YB74_HUMAN
Protein-tyrosine kinase 2-beta
PTK2B
194Annotation score:
E5RK84E5RK84_HUMAN
Protein-tyrosine kinase 2-beta
PTK2B
103Annotation score:
E5RHL2E5RHL2_HUMAN
Protein-tyrosine kinase 2-beta
PTK2B
68Annotation score:

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti23A → G in BAA08289 (PubMed:7673154).Curated1
Sequence conflicti23A → G in AAC05330 (PubMed:7673154).Curated1
Sequence conflicti256G → P in AAB47217 (PubMed:8838818).Curated1
Sequence conflicti435F → L in AAC05330 (PubMed:7673154).Curated1
Sequence conflicti780R → G in AAB47217 (PubMed:8838818).Curated1
Sequence conflicti985V → M in AAH36651 (PubMed:15489334).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_041687359Q → E1 PublicationCorresponds to variant dbSNP:rs56175011Ensembl.1
Natural variantiVAR_041688698R → H1 PublicationCorresponds to variant dbSNP:rs35174236Ensembl.1
Natural variantiVAR_041689808L → P1 PublicationCorresponds to variant dbSNP:rs55747955Ensembl.1
Natural variantiVAR_020284838K → TCombined sources1 PublicationCorresponds to variant dbSNP:rs751019Ensembl.1
Natural variantiVAR_041690970E → K1 PublicationCorresponds to variant dbSNP:rs56263944Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_004981739 – 780Missing in isoform 2. 1 PublicationAdd BLAST42

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U33284 mRNA Translation: AAC50203.1
L49207 mRNA Translation: AAB47217.1
D45853 mRNA Translation: BAA08289.1
U43522 mRNA Translation: AAC05330.1
S80542 mRNA Translation: AAB35701.1
AF311103 Genomic DNA No translation available.
CH471080 Genomic DNA Translation: EAW63553.1
CH471080 Genomic DNA Translation: EAW63555.1
CH471080 Genomic DNA Translation: EAW63556.1
BC036651 mRNA Translation: AAH36651.1
BC042599 mRNA Translation: AAH42599.1
CCDSiCCDS6057.1 [Q14289-1]
CCDS6058.1 [Q14289-2]
PIRiS60248
RefSeqiNP_004094.3, NM_004103.4 [Q14289-1]
NP_775266.1, NM_173174.2 [Q14289-1]
NP_775267.1, NM_173175.2 [Q14289-2]
NP_775268.1, NM_173176.2 [Q14289-1]
XP_005273504.1, XM_005273447.4 [Q14289-1]
XP_011542743.1, XM_011544441.2 [Q14289-1]
XP_016868703.1, XM_017013214.1 [Q14289-1]
UniGeneiHs.491322
Hs.735450

Genome annotation databases

EnsembliENST00000346049; ENSP00000332816; ENSG00000120899 [Q14289-1]
ENST00000397501; ENSP00000380638; ENSG00000120899 [Q14289-1]
ENST00000420218; ENSP00000391995; ENSG00000120899 [Q14289-2]
ENST00000517339; ENSP00000427931; ENSG00000120899 [Q14289-2]
GeneIDi2185
KEGGihsa:2185
UCSCiuc003xfn.3 human [Q14289-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiFAK2_HUMAN
AccessioniPrimary (citable) accession number: Q14289
Secondary accession number(s): D3DST0
, Q13475, Q14290, Q16709, Q6PID4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 15, 1998
Last sequence update: July 15, 1998
Last modified: September 12, 2018
This is version 212 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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