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PTK2
Available structures PDB Ortholog search: H0YB16 PDBe H0YB16 RCSB List of PDB id codes 4Q9S, 1K04, 1K05, 1MP8, 1OW6, 1OW7, 1OW8, 2ETM, 2IJM, 3B71, 3BZ3, 3PXK, 3S9O, 4EBV, 4EBW, 4GU6, 4GU9, 4I4E, 4I4F, 4K8A, 4K9Y, 4KAB, 4KAO, 4NY0
Identifiers
Aliases	PTK2, FADK, FAK, FAK1, FRNK, PPP1R71, p125FAK, pp125FAK, protein tyrosine kinase 2, Fak, Focal adhesion kinase, Dmel_CG10023, FAK65D, ptk2, DFAK, Fak56, DFak56, Dmel\CG10023, pFAK, CT28129, CG10023, Fak56D, DmFAK
External IDs	OMIM: 600758; MGI: 95481; HomoloGene: 7314; GeneCards: PTK2; OMA:PTK2 - orthologs
Gene location (Human) Chr. Chromosome 2 (human) Band 56D5-56D5|2-89 cM Start 19,430,659 bp End 19,437,259 bp
Gene location (Mouse) Chr. Chromosome 15 (mouse) Band 15 D3|15 33.94 cM Start 73,205,102 bp End 73,423,280 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in ovary testicle testicle ovary ovary antenna gut ovary antenna gut Top expressed in left lung lobe Gonadal ridge dermis medullary collecting duct tail of embryo dentate gyrus of hippocampal formation granule cell mandibular prominence human fetus maxillary prominence prefrontal cortex More reference expression data BioGPS 37233/ More reference expression data
Gene ontology Molecular function SH2 domain binding kinase activity signaling receptor binding ATP binding protein kinase activity JUN kinase binding non-membrane spanning protein tyrosine kinase activity transferase activity protein binding protein kinase binding nucleotide binding actin binding protein tyrosine kinase activity protein phosphatase binding Cellular component cytoplasm cytosol membrane focal adhesion extrinsic component of cytoplasmic side of plasma membrane microtubule organizing center cytoskeleton nucleus stress fiber apical plasma membrane lamellipodium plasma membrane cell cortex cell junction dendritic spine adherens junction Biological process regulation of protein phosphorylation positive regulation of protein phosphorylation regulation of cell adhesion mediated by integrin placenta development vasculogenesis protein phosphorylation vascular endothelial growth factor receptor signaling pathway growth hormone receptor signaling pathway blood vessel development regulation of osteoblast differentiation angiogenesis transforming growth factor beta receptor signaling pathway cellular response to transforming growth factor beta stimulus positive regulation of protein kinase B signaling Fc-gamma receptor signaling pathway involved in phagocytosis cell motility regulation of GTPase activity signal complex assembly regulation of epithelial cell migration negative regulation of axonogenesis regulation of endothelial cell migration establishment of cell polarity regulation of focal adhesion assembly phosphorylation netrin-activated signaling pathway negative regulation of synapse assembly extracellular matrix organization negative regulation of apoptotic process neuron migration positive regulation of ubiquitin-dependent protein catabolic process regulation of cell shape integrin-mediated signaling pathway regulation of substrate adhesion-dependent cell spreading negative regulation of organ growth microtubule cytoskeleton organization negative regulation of anoikis positive regulation of protein kinase activity negative regulation of cell-cell adhesion positive regulation of cell migration ephrin receptor signaling pathway heart morphogenesis MAPK cascade axon guidance positive regulation of phosphatidylinositol 3-kinase activity multicellular organism development regulation of cell population proliferation positive regulation of cell population proliferation positive regulation of phosphatidylinositol 3-kinase signaling regulation of cytoskeleton organization endothelial cell migration central nervous system neuron axonogenesis innate immune response peptidyl-tyrosine phosphorylation epidermal growth factor receptor signaling pathway protein autophosphorylation nuclear migration negative regulation of autophagy positive regulation of cardiac muscle hypertrophy peptidyl-tyrosine autophosphorylation cell differentiation regulation of cell adhesion Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 5747,37233 5747,37233 14083 Ensembl ENSG00000169398 FBgn0020440 ENSMUSG00000022607 UniProt Q05397 P34152 RefSeq (mRNA) NM_001199649 NM_005607 NM_153831 NM_001316342 NM_001144246 NM_001144247 NM_001169736 NM_079069 NM_166352 NM_166353 NM_001130409 NM_007982 NM_001358045 NM_001358046 RefSeq (protein) NP_001186578 NP_001303271 NP_005598 NP_722560 NP_001339623 NP_001339624 NP_001339625 NP_001339626 NP_001339627 NP_001339628 NP_001339629 NP_001339630 NP_001339631 NP_001339632 NP_001339633 NP_001339634 NP_001339635 NP_001339636 NP_001339637 NP_001339638 NP_001339639 NP_001339640 NP_001339641 NP_001339642 NP_001339643 NP_001339644 NP_001339645 NP_001339646 NP_001339647 NP_001339648 NP_001339649 NP_001339650 NP_001339651 NP_001339652 NP_001339653 NP_001339654 NP_001339655 NP_001339656 NP_001339657 NP_001339658 NP_001339659 NP_001339660 NP_001339661 NP_001339662 NP_001339663 NP_001339664 NP_001339665 NP_001339666 NP_001339667 NP_001339668 NP_001339669 NP_001339670 NP_001339671 NP_001339672 NP_001339673 NP_001339674 NP_001339675 NP_001339676 NP_001339677 NP_001339678 NP_001339679 NP_001339680 NP_001339681 NP_032008 NP_001344974 NP_001344975 Location (UCSC) Chr 2: 19.43 – 19.44 Mb Chr 15: 73.21 – 73.42 Mb PubMed search
Wikidata
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PTK2 protein tyrosine kinase 2 (PTK2), also known as focal adhesion kinase (FAK), is a protein that, in humans, is encoded by the PTK2 gene. PTK2 is a focal adhesion-associated protein kinase involved in cellular adhesion (how cells stick to each other and their surroundings) and spreading processes (how cells move around). It has been shown that when FAK was blocked, breast cancer cells became less metastatic due to decreased mobility.

Function

The PTK2 gene encodes a cytosolic protein tyrosine kinase that is found concentrated in the focal adhesions that form among cells attaching to extracellular matrix constituents. The encoded protein is a member of the FAK subfamily of protein tyrosine kinases that included PYK2, but lacks significant sequence similarity to kinases from other subfamilies. It also includes a large FERM domain.

With the exception of certain types of blood cells, most cells express FAK. FAK tyrosine kinase activity can be activated, which plays a key important early step in cell migration. FAK activity elicits intracellular signal transduction pathways that promote the turn-over of cell contacts with the extracellular matrix, promoting cell migration. FAK is required during development, with loss of FAK resulting in lethality. It seems to be a paradox that FAK is not absolutely required for cell migration, and may play other roles in the cell, including the regulation of the tumor suppressor p53. At least four transcript variants encoding four different isoforms have been found for this gene, but the full-length natures of only two of them have been determined.

FAK is a protein of 125 kD recruited as a participant in focal adhesion dynamics between cells, and has a role in motility and cell survival. FAK is a highly conserved, non-receptor tyrosine kinase originally identified as a substrate for the oncogene protein tyrosine kinase v-src. This cytosolic kinase has been implicated in diverse cellular roles including cell locomotion, mitogen response and cell survival. FAK is typically located at structures known as focal adhesions, which are multi-protein structures that link the extracellular matrix (ECM) to the cytoplasmic cytoskeleton. Additional components of focal adhesions include actin, filamin, vinculin, talin, paxillin, tensin and RSU-1.

Regulation

FAK is phosphorylated in response to integrin engagement, growth factor stimulation, and the action of mitogenic neuropeptides. Integrin receptors are heterodimeric transmembrane glycoproteins that cluster upon ECM engagement, leading to FAK phosphorylation and recruitment to focal adhesions. FAK activity can also be attenuated by expression of its endogenous inhibitor known as FAK-related nonkinase (FRNK). This is a truncated protein consisting of only the carboxyl-terminal noncatalytic domain of FAK.

Role in apoptosis

During early apoptotic signaling in human endothelial cells, FAK is cleaved by caspase 3 at Asp-772, generating two FAK fragments of approximately 90 and 130 kDa in length. The smaller FAK fragment is termed "killer FAT" and becomes the domain associated with death signaling. Throughout apoptosis, FAK is an important contributor to cell rounding, loss of focal contacts and apoptotic membrane formations such as blebbing, which involves contracting the cortical actin ring and is followed by chromatin condensation and nuclear fragmentation. Overexpression of FAK leads to inhibition of apoptosis and an increase in the prevalence of metastatic tumors.

Structure

Focal adhesion kinase has four defined regions, or tertiary structure domains. Two of these domains, the N-terminal FERM domain and the Kinase domain form an auto-inhibitory interaction. This interaction—thought to be the result of hydrophobic interactions between the two domains—prevents the activation of the Kinase domain, thereby preventing the signalling function of FAK. Release of this auto-inhibitory interaction has been shown to occur within focal adhesions—but not in the cytoplasm—and therefore is thought to require interaction with focal adhesion proteins, potentially as a result of mechanical forces transmitted through the focal adhesion.

C-terminus

A carboxy-terminal region of one hundred and fifty-nine amino acids, the focal adhesion targeting domain (FAT), has been shown to be responsible for targeting FAK to focal adhesions. This domain is composed of four alpha helices arranged in a bundle. The N-terminal helix contains a phosphorylatable tyrosine (Y925) implicated in signal transduction. Two hydrophobic patches between helices—one formed by the first and fourth helix, the other formed by the second and third helix—have been shown to bind short helical domains of Paxillin.

N-terminus

This section needs expansion. You can help by adding to it. (February 2019)

The function of the amino-terminal domain is less clear, but it has been shown to interact with the beta-1 integrin subunit in vitro and is thought to be involved in the transduction of signals from ECM-integrin clusters. However, a study has called into question the importance of this interaction and suggested that interaction with the cytoplasmic region of the beta-3 integrin subunit is important.

The amino-terminal domains of FAK share a significant sequence similarity with the band 4.1 domain first identified in erythrocytes. This 4.1 band domain binds to the cytoplasmic region of transmembrane proteins including glycophorin C, actin and spectrin. This suggests that the amino-terminal region of FAK may have a role in anchoring the cytoskeleton, the exact nature of this role has not been clarified as yet.

Catalytic/regulatory domain

Between the amino and the carboxy regions lies the catalytic domain. Phosphorylation of the activation loop within this kinase domain is important for the kinase activity of FAK.

Clinical significance

FAK mRNA levels are elevated in ~37% of serous ovarian tumors and ~26% of invasive breast cancers, and in several other malignancies.

As a drug target

FAK inhibitors

Because of the involvement of FAK in many cancers, drugs that inhibit FAK are being sought and evaluated, e.g. in 2012: PF-573,228 (PF-228), PF-562,271 (PF-271), NVP-226, Y15 (1,2,4,5-benzenetetraamine tetrahydrochloride), and PND-1186,

By 2013 GSK2256098 and PF-573,228 had completed at least one phase 1 trial.

Additional FAK inhibitors in clinical trials in 2014 were: VS-6062 (PF 562,271), VS-6063 (PF-04554878 defactinib) and VS-4718 (PND-1186) (all three are ATP-competitive kinase inhibitors). VS-6063 was in a phase II trial in patients with KRAS mutant non-small cell lung cancer (Trial ID: NCT01951690) to see how the response depends on tumor-associated INK4a/Arf and p53 mutations.

In 2015, a mesothelioma trial of VS-6063 was ended early due to 'poor performance'.

Interactions

PTK2 has been shown to interact with:

• BCAR1,
• BMX,
• CD61,
• CRK,
• DCC,
• FYN,
• GIT1,
• GRB7,
• Grb2,
• IRS1,
• ITGB5,
• JAK2,
• MAPK8IP3,
• NCK1,
• NCK2,
• NEDD9,
• NEO1,
• P53,
• PIK3R1,
• PTEN,
• PXN,
  
• RB1CC1,
• STAT1,
• Src,
• Syk,
• TGFB1I1,
• TLN1,
• TSC2,
• YAP1.

See also

• Tyrosine kinase

References

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Further reading

• Iwata S, Ohashi Y, Kamiguchi K, Morimoto C (June 2000). "Beta 1-integrin-mediated cell signaling in T lymphocytes". Journal of Dermatological Science. 23 (2): 75–86. doi:10.1016/S0923-1811(99)00096-1. PMID 10808124.
• Schaller MD (July 2001). "Biochemical signals and biological responses elicited by the focal adhesion kinase". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1540 (1): 1–21. doi:10.1016/S0167-4889(01)00123-9. PMID 11476890.
• Panetti TS (January 2002). "Tyrosine phosphorylation of paxillin, FAK, and p130CAS: effects on cell spreading and migration". Frontiers in Bioscience. 7 (1–3): d143–50. doi:10.2741/panetti. PMID 11779709. S2CID 35708933.
• Hauck CR, Hsia DA, Schlaepfer DD (February 2002). "The focal adhesion kinase--a regulator of cell migration and invasion". IUBMB Life. 53 (2): 115–9. doi:10.1080/15216540211470. PMID 12049193. S2CID 6904396.
• Hanks SK, Ryzhova L, Shin NY, Brábek J (May 2003). "Focal adhesion kinase signaling activities and their implications in the control of cell survival and motility". Frontiers in Bioscience. 8 (4): d982–96. doi:10.2741/1114. PMID 12700132.
• Gabarra-Niecko V, Schaller MD, Dunty JM (December 2003). "FAK regulates biological processes important for the pathogenesis of cancer". Cancer and Metastasis Reviews. 22 (4): 359–74. doi:10.1023/A:1023725029589. PMID 12884911. S2CID 25057260.

External links

• MBInfo: FAK
• FAK Info with links in the Cell Migration Gateway Archived 2014-12-11 at the Wayback Machine
• PTK2 protein, human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• "Breaking down cancer’s wall of resistance", by DR Nick Peel, Cancer Research UK, Science blog, August 2014
• Overview of all the structural information available in the PDB for UniProt: Q05397 (Human Focal adhesion kinase 1) at the PDBe-KB.
• Overview of all the structural information available in the PDB for UniProt: P34152 (Mouse Focal adhesion kinase 1) at the PDBe-KB.

• Biology

• Genes on human chromosome 2
• Tyrosine kinases
• Cancer research