P70600 (FAK2_RAT) Reviewed, UniProtKB/Swiss-Prot
Last modified November 13, 2013. Version 135. History...
Names and origin
|Protein names||Recommended name:|
Protein-tyrosine kinase 2-beta
Calcium-dependent tyrosine kinase
Calcium-regulated non-receptor proline-rich tyrosine kinase
Cell adhesion kinase beta
Focal adhesion kinase 2
Short name=FADK 2
Proline-rich tyrosine kinase 2
|Organism||Rattus norvegicus (Rat) [Reference proteome]|
|Taxonomic identifier||10116 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus|
|Sequence length||1009 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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' By similarity. 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 By similarity. Ref.5 Ref.6 Ref.8 Ref.9 Ref.10 Ref.12
ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. Ref.10
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 By similarity.
Homodimer, or homooligomer. 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 RB1CC1. Interacts with RHOU. Interacts with VAV1. Interacts with PDPK1. Interacts with LPXN and PTPN12 By similarity. Interacts with SIRPA and SH2D3C. Interacts (hypophosphorylated) with PXN. Interacts with ARHGAP10. Ref.6 Ref.7 Ref.11 Ref.13
Cytoplasm. Cytoplasm › perinuclear region By similarity. Cell membrane; Peripheral membrane protein; Cytoplasmic side. Cell projection › lamellipodium By similarity. Cytoplasm › cell cortex By similarity. Nucleus By similarity. Note: Colocalizes with integrins at the cell periphery. Interaction with NPHP1 induces the membrane-association of the kinase. Colocalizes with PXN at the microtubule-organizing center. The tyrosine phosphorylated form is detected at cell-cell contacts By similarity. Ref.3
Highly expressed in pulmonary vein endothelial cells, lung and brain (at protein level). Isoform 1 is expressed at high levels in the brain (hippocampus, cerebral cortex and olfactory bulb) and poorly in the spleen and other tissues, whereas isoforms 2 and 3 are expressed in the spleen and brain (highest in cerebellum). Ref.8
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 By similarity. Ref.5 Ref.6 Ref.10 Ref.11 Ref.13
Contains 1 FERM domain.
Contains 1 protein kinase domain.
|This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]|
|Isoform 1 (identifier: P70600-1) |
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.
|Isoform 2 (identifier: P70600-2) |
Also known as: PRNK;
The sequence of this isoform differs from the canonical sequence as follows:
772-780: NVFKRHSMR → MGLIVLSSQ
|Isoform 3 (identifier: P70600-3) |
Also known as: PYK2s;
The sequence of this isoform differs from the canonical sequence as follows:
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 1009||1009||Protein-tyrosine kinase 2-beta||PRO_0000088083|
|Domain||39 – 359||321||FERM|
|Domain||425 – 683||259||Protein kinase|
|Nucleotide binding||431 – 439||9||ATP By similarity|
|Nucleotide binding||503 – 509||7||ATP By similarity|
|Region||801 – 1009||209||Interaction with TGFB1I1|
|Region||868 – 1009||142||Focal adhesion targeting (FAT)|
|Compositional bias||701 – 767||67||Pro-rich|
|Compositional bias||831 – 869||39||Pro-rich|
|Active site||549||1||Proton acceptor By similarity|
|Binding site||457||1||ATP By similarity|
Amino acid modifications
|Modified residue||361||1||Phosphoserine By similarity|
|Modified residue||375||1||Phosphoserine By similarity|
|Modified residue||399||1||Phosphoserine By similarity|
|Modified residue||402||1||Phosphotyrosine; by autocatalysis Ref.10 Ref.13|
|Modified residue||440||1||Phosphotyrosine By similarity|
|Modified residue||579||1||Phosphotyrosine; by SRC, LYN and LCK Ref.13|
|Modified residue||580||1||Phosphotyrosine; by SRC, LYN and LCK Ref.10 Ref.13|
|Modified residue||722||1||Phosphotyrosine By similarity|
|Modified residue||762||1||Phosphoserine By similarity|
|Modified residue||765||1||Phosphothreonine By similarity|
|Modified residue||834||1||Phosphotyrosine By similarity|
|Modified residue||839||1||Phosphoserine By similarity|
|Modified residue||842||1||Phosphothreonine By similarity|
|Modified residue||849||1||Phosphotyrosine By similarity|
|Modified residue||866||1||Phosphoserine By similarity|
|Modified residue||881||1||Phosphotyrosine By similarity|
|Alternative sequence||1 – 771||771||Missing in isoform 2.||VSP_004982|
|Alternative sequence||739 – 780||42||Missing in isoform 3.||VSP_004984|
|Alternative sequence||772 – 780||9||NVFKRHSMR → MGLIVLSSQ in isoform 2.||VSP_004983|
|Sequence conflict||205||1||E → A in BAA08290. Ref.2|
|Sequence conflict||807||1||V → F in AAC28340. Ref.3|
|||"Activation of a novel calcium-dependent protein-tyrosine kinase. Correlation with c-Jun N-terminal kinase but not mitogen-activated protein kinase activation."|
Yu H., Li X., Marchetto G.S., Dy R., Hunter D., Calvo B., Dawson T.L., Wilm M., Anderegg R.J., Graves L.M., Earp H.S.
J. Biol. Chem. 271:29993-29998(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 310-334; 553-572; 672-687 AND 989-998.
Tissue: Liver epithelium.
|||"Cloning and characterization of cell adhesion kinase beta, a novel protein-tyrosine kinase of the focal adhesion kinase subfamily."|
Sasaki H., Nagura K., Ishino M., Tobioka H., Kotani K., Sasaki T.
J. Biol. Chem. 270:21206-21219(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
|||"Expression and characterization of splice variants of PYK2, a focal adhesion kinase-related protein."|
Xiong W.-C., Macklem M., Parsons J.T.
J. Cell Sci. 111:1981-1991(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3), SUBCELLULAR LOCATION, DOMAIN FAT.
|||"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."|
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
|||"Protein tyrosine kinase PYK2 involved in Ca(2+)-induced regulation of ion channel and MAP kinase functions."|
Lev S., Moreno H., Martinez R., Canoll P., Peles E., Musacchio J.M., Plowman G.D., Rudy B., Schlessinger J.
Nature 376:737-745(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, PHOSPHORYLATION.
|||"A role for Pyk2 and Src in linking G-protein-coupled receptors with MAP kinase activation."|
Dikic I., Tokiwa G., Lev S., Courtneidge S.A., Schlessinger J.
Nature 383:547-550(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN G-PROTEIN COUPLED RECEPTOR SIGNALING AND PHOSPHORYLATION OF SRC, INTERACTION WITH SRC, PHOSPHORYLATION.
|||"Cell adhesion kinase beta forms a complex with a new member, Hic-5, of proteins localized at focal adhesions."|
Matsuya M., Sasaki H., Aoto H., Mitaka T., Nagura K., Ohba T., Ishino M., Takahashi S., Suzuki R., Sasaki T.
J. Biol. Chem. 273:1003-1014(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH TGFB1I1.
|||"Pyk2/CAKbeta tyrosine kinase activity-mediated angiogenesis of pulmonary vascular endothelial cells."|
Tang H., Hao Q., Fitzgerald T., Sasaki T., Landon E.J., Inagami T.
J. Biol. Chem. 277:5441-5447(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN ANGIOGENESIS; CELL MIGRATION; CELL SPREADING AND REORGANIZATION OF THE ACTIN CYTOSKELETON, TISSUE SPECIFICITY.
|||"Metabotropic glutamate receptor 1-induced upregulation of NMDA receptor current: mediation through the Pyk2/Src-family kinase pathway in cortical neurons."|
Heidinger V., Manzerra P., Wang X.Q., Strasser U., Yu S.P., Choi D.W., Behrens M.M.
J. Neurosci. 22:5452-5461(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN SRC-MEDIATED PHOSPHORYLATION OF NMDA RECEPTORS AND REGULATON OF NMDA RECEPTOR CHANNEL ACTIVITY.
|||"Differential regulation of Pyk2 phosphorylation at Tyr-402 and Tyr-580 in intestinal epithelial cells: roles of calcium, Src, Rho kinase, and the cytoskeleton."|
Wu S.S., Jacamo R.O., Vong S.K., Rozengurt E.
Cell. Signal. 18:1932-1940(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, PHOSPHORYLATION AT TYR-402 AND TYR-580, CATALYTIC ACTIVITY.
|||"Postsynaptic clustering and activation of Pyk2 by PSD-95."|
Bartos J.A., Ulrich J.D., Li H., Beazely M.A., Chen Y., Macdonald J.F., Hell J.W.
J. Neurosci. 30:449-463(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: AUTOPHOSPHORYLATION, INTERACTION WITH DLG4.
|||"PYK2 signaling is required for PDGF-dependent vascular smooth muscle cell proliferation."|
Perez J., Torres R.A., Rocic P., Cismowski M.J., Weber D.S., Darley-Usmar V.M., Lucchesi P.A.
Am. J. Physiol. 301:C242-C251(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
|||"The Pyk2 FERM regulates Pyk2 complex formation and phosphorylation."|
Riggs D., Yang Z., Kloss J., Loftus J.C.
Cell. Signal. 23:288-296(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT TYR-402; TYR-579 AND TYR-580, SUBUNIT.
|+||Additional computationally mapped references.|
|U69109 mRNA. Translation: AAC52895.1.|
D45854 mRNA. Translation: BAA08290.1.
AF063890 mRNA. Translation: AAC28340.1.
BC101921 mRNA. Translation: AAI01922.1.
|RefSeq||NP_059014.2. NM_017318.2. |
3D structure databases
|SMR||P70600. Positions 415-692, 869-999. |
Protein-protein interaction databases
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSRNOT00000030007; ENSRNOP00000031615; ENSRNOG00000027839. |
ENSRNOT00000030036; ENSRNOP00000036813; ENSRNOG00000027839.
|UCSC||RGD:628758. rat. |
|RGD||628758. Ptk2b. |
Enzyme and pathway databases
|BRENDA||22.214.171.124. 5301. |
Gene expression databases
Family and domain databases
|Gene3D||126.96.36.199. 1 hit. |
|InterPro||IPR019749. Band_41_domain. |
|Pfam||PF00373. FERM_M. 1 hit. |
PF03623. Focal_AT. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
|PRINTS||PR00109. TYRKINASE. |
|ProDom||PD006413. Focal_adhesion_target_reg. 1 hit. |
[Graphical view] [Entries sharing at least one domain]
|SMART||SM00295. B41. 1 hit. |
SM00219. TyrKc. 1 hit.
|SUPFAM||SSF47031. SSF47031. 1 hit. |
SSF56112. SSF56112. 1 hit.
SSF68993. SSF68993. 1 hit.
|PROSITE||PS00660. FERM_1. False negative. |
PS00661. FERM_2. False negative.
PS50057. FERM_3. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
|Accession||Primary (citable) accession number: P70600|
Secondary accession number(s): O88489, Q3T1H4, Q63201
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
Index of protein domains and families