O35346 (FAK1_RAT) Reviewed, UniProtKB/Swiss-Prot
Last modified February 19, 2014. Version 137. History...
Names and origin
|Protein names||Recommended name:|
Focal adhesion kinase 1
Short name=FADK 1
Focal adhesion kinase-related nonkinase
Protein-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||1055 AA.|
|Sequence processing||The displayed sequence is further processed into a mature form.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
Non-receptor protein-tyrosine kinase that plays an essential role in regulating cell migration, adhesion, spreading, reorganization of the actin cytoskeleton, formation and disassembly of focal adhesions and cell protrusions, cell cycle progression, cell proliferation and apoptosis. Required for early embryonic development and placenta development. Required for embryonic angiogenesis, normal cardiomyocyte migration and proliferation, and normal heart development. Regulates axon growth and neuronal cell migration, axon branching and synapse formation; required for normal development of the nervous system. Plays a role in osteogenesis and differentiation of osteoblasts. Functions in integrin signal transduction, but also in signaling downstream of numerous growth factor receptors, G-protein coupled receptors (GPCR), EPHA2, netrin receptors and LDL receptors. 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 the AKT1 signaling cascade. Promotes activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling cascade. Promotes localized and transient activation of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and thereby modulates the activity of Rho family GTPases. Signaling via CAS family members mediates activation of RAC1. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ACTN1, ARHGEF7, GRB7, RET and WASL. Promotes phosphorylation of PXN and STAT1; most likely PXN and STAT1 are phosphorylated by a SRC family kinase that is recruited to autophosphorylated PTK2/FAK1, rather than by PTK2/FAK1 itself. Promotes phosphorylation of BCAR1; GIT2 and SHC1; this requires both SRC and PTK2/FAK1. Promotes phosphorylation of BMX and PIK3R1. Isoform 2 (FRNK) does not contain a kinase domain and inhibits PTK2/FAK1 phosphorylation and signaling. Its enhanced expression can attenuate the nuclear accumulation of LPXN and limit its ability to enhance serum response factor (SRF)-dependent gene transcription By similarity. Ref.7
ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Subject to autoinhibition, mediated by interactions between the FERM domain and the kinase domain. Activated by autophosphorylation at Tyr-397. This promotes interaction with SRC and phosphorylation at Tyr-576 and Tyr-577 in the kinase activation loop by SRC. Phosphorylation at Tyr-397, Tyr-576 and Tyr-577 is required for maximal kinase activity.
Interacts with GIT1. Component of a complex that contains at least FER, CTTN and PTK2/FAK1. Interacts with BMX. Interacts with STEAP4. Interacts with ZFYVE21. Interacts with ESR1. Interacts with PIK3R1 or PIK3R2. Interacts with FGR, FLT4 and RET. Interacts with EPHA2 in resting cells; activation of EPHA2 recruits PTPN11, leading to dephosphorylation of PTK2/FAK1 and dissociation of the complex. Interacts with EPHA1 (kinase activity-dependent). Interacts with P53/TP53. Interacts (via first Pro-rich region) with CAS family members (via SH3 domain), including BCAR1, BCAR3, CASS4 and NEDD9. Interacts with TGFB1I1. Interacts with SRC, GRB2 and GRB7. Interacts with ARHGEF28. Interacts with SHB. Interacts with PXN and TLN1. Interacts with SORBS1. Interacts with STAT1. Interacts with WASL. Interacts with ARHGAP26 and SHC1. Interacts with RB1CC1; this inhibits PTK2/FAK1 activity and activation of downstream signaling pathways. Interacts with ARHGEF7. Interacts with MDM2 By similarity. Interacts with PIAS1. Interacts with DCC. Interacts with LPXN (via LD motif 3) By similarity. Interacts with MISP By similarity. Ref.3 Ref.5 Ref.6 Ref.7
Cell junction › focal adhesion. Cell membrane; Peripheral membrane protein; Cytoplasmic side. Cytoplasm › perinuclear region. Cytoplasm › cytoskeleton By similarity. Cytoplasm › cytoskeleton › microtubule organizing center › centrosome By similarity. Nucleus. Note: Constituent of focal adhesions. Detected at microtubules By similarity. Ref.4 Ref.6 Ref.8
The first Pro-rich domain interacts with the SH3 domain of CAS family members, such as BCAR1 and NEDD9 By similarity.
The carboxy-terminal region is the site of focal adhesion targeting (FAT) sequence which mediates the localization of FAK1 to focal adhesions.
Phosphorylated on tyrosine residues upon activation, e.g. upon integrin signaling. Tyr-397 is the major autophosphorylation site, but other kinases can also phosphorylate this residue. Phosphorylation at Tyr-397 promotes interaction with SRC and SRC family members, leading to phosphorylation at Tyr-576, Tyr-577 and at additional tyrosine residues. FGR promotes phosphorylation at Tyr-397 and Tyr-576. FER promotes phosphorylation at Tyr-577, Tyr-861 and Tyr-928, even when cells are not adherent. Tyr-397, Tyr-576 and Ser-722 are phosphorylated only when cells are adherent. Phosphorylation at Tyr-397 is important for interaction with BMX, PIK3R1 and SHC1. Phosphorylation at Tyr-928 is important for interaction with GRB2. Dephosphorylated by PTPN11; PTPN11 is recruited to PTK2 via EPHA2 (tyrosine phosphorylated). Microtubule-induced dephosphorylation at Tyr-397 is crucial for the induction of focal adhesion disassembly; this dephosphorylation could be catalyzed by PTPN11 and regulated by ZFYVE21 By similarity. Ref.4 Ref.6 Ref.8
Sumoylated; this enhances autophosphorylation. Ref.6
Contains 1 FERM domain.
Contains 1 protein kinase domain.
|This entry describes 2 isoforms produced by alternative promoter usage. [Align] [Select]|
|Isoform 1 (identifier: O35346-1) |
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: O35346-2) |
Also known as: FRNK;
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|
|Initiator methionine||1||1||Removed By similarity|
|Chain||2 – 1055||1054||Focal adhesion kinase 1||PRO_0000088079|
|Domain||35 – 355||321||FERM|
|Domain||422 – 680||259||Protein kinase|
|Nucleotide binding||428 – 434||7||ATP By similarity|
|Nucleotide binding||500 – 502||3||ATP By similarity|
|Region||707 – 1055||349||Interaction with TGFB1I1 By similarity|
|Region||915 – 1055||141||Interaction with ARHGEF28 By similarity|
|Compositional bias||712 – 733||22||Pro-rich|
|Compositional bias||863 – 916||54||Pro-rich|
|Active site||546||1||Proton acceptor By similarity|
|Binding site||454||1||ATP By similarity|
Amino acid modifications
|Modified residue||2||1||N-acetylalanine By similarity|
|Modified residue||5||1||Phosphotyrosine By similarity|
|Modified residue||13||1||Phosphothreonine By similarity|
|Modified residue||29||1||Phosphoserine By similarity|
|Modified residue||397||1||Phosphotyrosine; by autocatalysis Ref.6|
|Modified residue||407||1||Phosphotyrosine By similarity|
|Modified residue||570||1||Phosphotyrosine By similarity|
|Modified residue||576||1||Phosphotyrosine; by RET and SRC By similarity|
|Modified residue||577||1||Phosphotyrosine; by RET and SRC By similarity|
|Modified residue||580||1||Phosphoserine By similarity|
|Modified residue||722||1||Phosphoserine Ref.4|
|Modified residue||732||1||Phosphoserine; by CDK5 By similarity|
|Modified residue||861||1||Phosphotyrosine By similarity|
|Modified residue||913||1||Phosphoserine Ref.4|
|Modified residue||917||1||Phosphothreonine By similarity|
|Modified residue||928||1||Phosphotyrosine By similarity|
|Cross-link||152||Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) Ref.6|
|Alternative sequence||1 – 692||692||Missing in isoform 2.||VSP_042172|
|Mutagenesis||152||1||K → R: Abolishes sumoylation. Ref.6|
|||"Cloning of focal adhesion kinase, pp125FAK, from rat brain reveals multiple transcripts with different patterns of expression."|
Burgaya F., Girault J.A.
Brain Res. Mol. Brain Res. 37:63-73(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Tissue: Corpus striatum.
|||Sasaki T., Nagura K., Sasaki H.|
Submitted (DEC-1995) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 350-528 (ISOFORM 1).
|||"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.
|||"Subcellular redistribution of focal adhesion kinase and its related nonkinase in hypertrophic myocardium."|
Yi X.P., Wang X., Gerdes A.M., Li F.
Hypertension 41:1317-1323(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-722 AND SER-913, CHARACTERIZATION OF ISOFORM 2.
|||"Direct interaction of focal adhesion kinase with p190RhoGEF."|
Zhai J., Lin H., Nie Z., Wu J., Canete-Soler R., Schlaepfer W.W., Schlaepfer D.D.
J. Biol. Chem. 278:24865-24873(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ARHGEF28.
|||"PIAS1-mediated sumoylation of focal adhesion kinase activates its autophosphorylation."|
Kadare G., Toutant M., Formstecher E., Corvol J.C., Carnaud M., Boutterin M.C., Girault J.A.
J. Biol. Chem. 278:47434-47440(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: SUMOYLATION AT LYS-152, MUTAGENESIS OF LYS-152, INTERACTION WITH PIAS1, AUTOPHOSPHORYLATION, PHOSPHORYLATION AT TYR-397, SUBCELLULAR LOCATION.
|||"Focal adhesion kinase in netrin-1 signaling."|
Ren X.R., Ming G.L., Xie Y., Hong Y., Sun D.M., Zhao Z.Q., Feng Z., Wang Q., Shim S., Chen Z.F., Song H.J., Mei L., Xiong W.C.
Nat. Neurosci. 7:1204-1212(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH DCC.
|||"Nuclear compartmentalization of FAK and FRNK in cardiac myocytes."|
Yi X.P., Zhou J., Huber L., Qu J., Wang X., Gerdes A.M., Li F.
Am. J. Physiol. 290:H2509-H2515(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, PHOSPHORYLATION, CHARACTERIZATION OF ISOFORM 2.
|+||Additional computationally mapped references.|
|AF020777 mRNA. Translation: AAB72203.1.|
U43942 mRNA. Translation: AAA86280.1.
|RefSeq||NP_037213.1. NM_013081.2. |
3D structure databases
|SMR||O35346. Positions 33-686, 911-1052. |
Protein-protein interaction databases
|BioGrid||247643. 5 interactions.|
|IntAct||O35346. 3 interactions.|
Protocols and materials databases
Genome annotation databases
|UCSC||RGD:3443. rat. |
|RGD||3443. Ptk2. |
Enzyme and pathway databases
|BRENDA||184.108.40.206. 5301. |
|Reactome||REACT_114732. Cell-Cell communication. |
Gene expression databases
Family and domain databases
|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||PS00661. FERM_2. 1 hit. |
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: O35346|
Secondary accession number(s): Q62900
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
Index of protein domains and families