PTK2




This article is about the protein. For the cell line, see Ptk2 cells.




























































PTK2
Protein PTK2 PDB 1k04.png







Available structures
PDB Ortholog search: PDBe RCSB



Identifiers
Aliases
PTK2, FADK, FAK, FAK1, FRNK, PPP1R71, p125FAK, pp125FAK, protein tyrosine kinase 2
External IDs OMIM: 600758 MGI: 95481 HomoloGene: 7314 GeneCards: PTK2























RNA expression pattern

PBB GE PTK2 208820 at fs.png

PBB GE PTK2 207821 s at fs.png
More reference expression data















Orthologs
Species Human Mouse
Entrez


5747


14083
Ensembl


n/a


ENSMUSG00000022607
UniProt


Q05397


P34152
RefSeq (mRNA)


NM_001199649
NM_005607
NM_153831
NM_001316342


NM_001130409
NM_007982
NM_001358045
NM_001358046
RefSeq (protein)





NP_001123881
NP_032008
NP_001344974
NP_001344975
Location (UCSC) n/a Chr 15: 73.21 – 73.42 Mb

PubMed search		 [2] [3]
Wikidata



View/Edit Human View/Edit Mouse

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.[4] 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).[5] It has been shown that when FAK was blocked, breast cancer cells became less metastatic due to decreased mobility.[6]




Contents






  • 1 Function


  • 2 Regulation


  • 3 Role in Apoptosis


  • 4 Structure


    • 4.1 C-terminus


    • 4.2 N-terminus


    • 4.3 Catalytic/regulatory domain




  • 5 Clinical significance


  • 6 As a drug target


    • 6.1 FAK inhibitors




  • 7 Interactions


  • 8 See also


  • 9 References


  • 10 Further reading


  • 11 External links





Function


This 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.[7][8]


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.[9]


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.[10] 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[11] and RSU-1.



Regulation


FAK is phosphorylated in response to integrin engagement, growth factor stimulation, and the action of mitogenic neuropeptides.[12][13]Integrin receptors are heterodimeric transmembrane glycoproteins that cluster upon ECM engagement, leading to FAK phosphorylation and recruitment to focal adhesions.[14][15] 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.[16]



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.[17] The smaller FAK fragment is termed "killer FAT" and becomes the domain associated with death signaling.[17] Throughout apoptosis, FAK is an important contributor to cell rounding, loss of focal contacts and apoptotic membrane formations such as blebbing,[18] which involves contracting the cortical actin ring and is followed by chromatin condensation and nuclear fragmentation.[19] Overexpression of FAK leads to inhibition of apoptosis and an increase in the prevalence of metastatic tumors.[18]



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[20]—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.[21] 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.[22]



N-terminus


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.[23] However, a recent 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.[24]


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.[25] 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.[26]



Clinical significance


FAK mRNA levels are elevated in ~37% of serous ovarian tumors and ~26% of invasive breast cancers, and in several other malignancies.[27]



As a drug target



FAK inhibitors






Because of the involvement of FAK in many cancers, drugs that inhibit FAK are being sought and evaluated,[28] 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,[28]


By 2013 GSK2256098 and PF-573,228 had completed at least one phase 1 trial.[28]


Additional FAK inhibitors in clinical trials in 2014 were:[27]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.[27]


In 2015 a mesothelioma trial of VS-6063 was ended early due to 'poor performance'.[29]



Interactions


PTK2 has been shown to interact with:





  • BCAR1,[30][31][32][33][34][35]


  • BMX,[36]


  • CD61,[37][38]


  • CRK,[31][39]


  • DCC,[40]


  • FYN,[41][42]


  • GIT1,[43][44][45]


  • GRB7,[46]


  • Grb2,[32][39][41][47][48]


  • IRS1[49] and


  • ITGB5,[37]


  • JAK2,[50][51]


  • MAPK8IP3,[52]


  • NCK1,[53][54]


  • NCK2,[54]


  • NEDD9,[55]


  • NEO1,[40]


  • P53,[56]


  • PIK3R1,[57]


  • PTEN,[58][59]


  • PXN,[35][60][61][62][63][64][65][66][67][68]


  • RB1CC1,[69]


  • STAT1,[70]


  • Src,[31][39][41][49][71][72]


  • Syk,[38][73]


  • TGFB1I1,[61][74][75]


  • TLN1,[60][76]


  • TSC2,[77] and


  • YAP1.[78]




See also


  • Tyrosine kinase


References





  1. ^ abc GRCm38: Ensembl release 89: ENSMUSG00000022607 - Ensembl, May 2017


  2. ^ "Human PubMed Reference:"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"""""""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("//upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("//upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("//upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}


  3. ^ "Mouse PubMed Reference:".


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  7. ^ SCOPe: Structural Classification of Proteins — extended. Release 2.06. Lineage for Protein: Focal adhesion kinase 1


  8. ^ Q00944


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  12. ^ Abedi H, Zachary I (June 1997). "Vascular endothelial growth factor stimulates tyrosine phosphorylation and recruitment to new focal adhesions of focal adhesion kinase and paxillin in endothelial cells". The Journal of Biological Chemistry. 272 (24): 15442–51. doi:10.1074/jbc.272.24.15442. PMID 9182576.


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  18. ^ ab Mehlen P, Puisieux A (June 2006). "Metastasis: a question of life or death". Nature Reviews. Cancer. 6 (6): 449–58. doi:10.1038/nrc1886. PMID 16723991.


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  22. ^ Hildebrand JD, Schaller MD, Parsons JT (June 1995). "Paxillin, a tyrosine phosphorylated focal adhesion-associated protein binds to the carboxyl terminal domain of focal adhesion kinase". Molecular Biology of the Cell. 6 (6): 637–47. doi:10.1091/mbc.6.6.637. PMC 301225. PMID 7579684.


  23. ^ Schaller MD, Otey CA, Hildebrand JD, Parsons JT (September 1995). "Focal adhesion kinase and paxillin bind to peptides mimicking beta integrin cytoplasmic domains". The Journal of Cell Biology. 130 (5): 1181–7. doi:10.1083/jcb.130.5.1181. PMC 2120552. PMID 7657702.


  24. ^ Tahiliani PD, Singh L, Auer KL, LaFlamme SE (March 1997). "The role of conserved amino acid motifs within the integrin beta3 cytoplasmic domain in triggering focal adhesion kinase phosphorylation". The Journal of Biological Chemistry. 272 (12): 7892–8. doi:10.1074/jbc.272.12.7892. PMID 9065456.


  25. ^ Girault JA, Labesse G, Mornon JP, Callebaut I (December 1998). "Janus kinases and focal adhesion kinases play in the 4.1 band: a superfamily of band 4.1 domains important for cell structure and signal transduction". Molecular Medicine. 4 (12): 751–69. PMC 2230389. PMID 9990861.


  26. ^ Calalb MB, Polte TR, Hanks SK (February 1995). "Tyrosine phosphorylation of focal adhesion kinase at sites in the catalytic domain regulates kinase activity: a role for Src family kinases". Molecular and Cellular Biology. 15 (2): 954–63. PMC 231984. PMID 7529876.


  27. ^ abc Sulzmaier FJ, Jean C, Schlaepfer DD (September 2014). "FAK in cancer: mechanistic findings and clinical applications". Nature Reviews. Cancer. 14 (9): 598–610. doi:10.1038/nrc3792. PMC 4365862. PMID 25098269.


  28. ^ abc Dunn KB, Heffler M, Golubovskaya VM (December 2010). "Evolving therapies and FAK inhibitors for the treatment of cancer". Anti-Cancer Agents in Medicinal Chemistry. 10 (10): 722–34. doi:10.2174/187152010794728657. PMC 3274818. PMID 21291406.


  29. ^ Researchers Stop Once-Promising Mesothelioma Clinical Trial. Oct 2015


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  32. ^ ab Hildebrand JD, Taylor JM, Parsons JT (June 1996). "An SH3 domain-containing GTPase-activating protein for Rho and Cdc42 associates with focal adhesion kinase". Molecular and Cellular Biology. 16 (6): 3169–78. PMC 231310. PMID 8649427.


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  35. ^ ab Wang JF, Park IW, Groopman JE (April 2000). "Stromal cell-derived factor-1alpha stimulates tyrosine phosphorylation of multiple focal adhesion proteins and induces migration of hematopoietic progenitor cells: roles of phosphoinositide-3 kinase and protein kinase C". Blood. 95 (8): 2505–13. PMID 10753828.


  36. ^ Chen R, Kim O, Li M, Xiong X, Guan JL, Kung HJ, Chen H, Shimizu Y, Qiu Y (May 2001). "Regulation of the PH-domain-containing tyrosine kinase Etk by focal adhesion kinase through the FERM domain". Nature Cell Biology. 3 (5): 439–44. doi:10.1038/35074500. PMID 11331870.


  37. ^ ab Eliceiri BP, Puente XS, Hood JD, Stupack DG, Schlaepfer DD, Huang XZ, Sheppard D, Cheresh DA (April 2002). "Src-mediated coupling of focal adhesion kinase to integrin alpha(v)beta5 in vascular endothelial growth factor signaling". The Journal of Cell Biology. 157 (1): 149–60. doi:10.1083/jcb.200109079. PMC 2173263. PMID 11927607.


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  49. ^ ab Lebrun P, Mothe-Satney I, Delahaye L, Van Obberghen E, Baron V (November 1998). "Insulin receptor substrate-1 as a signaling molecule for focal adhesion kinase pp125(FAK) and pp60(src)". The Journal of Biological Chemistry. 273 (48): 32244–53. doi:10.1074/jbc.273.48.32244. PMID 9822703.


  50. ^ Zhu T, Goh EL, Lobie PE (April 1998). "Growth hormone stimulates the tyrosine phosphorylation and association of p125 focal adhesion kinase (FAK) with JAK2. Fak is not required for stat-mediated transcription". The Journal of Biological Chemistry. 273 (17): 10682–9. doi:10.1074/jbc.273.17.10682. PMID 9553131.


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  53. ^ Minegishi M, Tachibana K, Sato T, Iwata S, Nojima Y, Morimoto C (October 1996). "Structure and function of Cas-L, a 105-kD Crk-associated substrate-related protein that is involved in beta 1 integrin-mediated signaling in lymphocytes". The Journal of Experimental Medicine. 184 (4): 1365–75. doi:10.1084/jem.184.4.1365. PMC 2192828. PMID 8879209.


  54. ^ ab Goicoechea SM, Tu Y, Hua Y, Chen K, Shen TL, Guan JL, Wu C (July 2002). "Nck-2 interacts with focal adhesion kinase and modulates cell motility". The International Journal of Biochemistry & Cell Biology. 34 (7): 791–805. doi:10.1016/s1357-2725(02)00002-x. PMID 11950595.


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  58. ^ Tamura M, Gu J, Danen EH, Takino T, Miyamoto S, Yamada KM (July 1999). "PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase/Akt cell survival pathway". The Journal of Biological Chemistry. 274 (29): 20693–703. doi:10.1074/jbc.274.29.20693. PMID 10400703.


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  76. ^ Chen HC, Appeddu PA, Parsons JT, Hildebrand JD, Schaller MD, Guan JL (July 1995). "Interaction of focal adhesion kinase with cytoskeletal protein talin". The Journal of Biological Chemistry. 270 (28): 16995–9. doi:10.1074/jbc.270.28.16995. PMID 7622520.


  77. ^ Gan B, Yoo Y, Guan JL (December 2006). "Association of focal adhesion kinase with tuberous sclerosis complex 2 in the regulation of s6 kinase activation and cell growth". The Journal of Biological Chemistry. 281 (49): 37321–9. doi:10.1074/jbc.M605241200. PMID 17043358.


  78. ^ Lachowski D, Cortes E, Robinson B, Rice A, Rombouts K, Del Río Hernández AE (October 2017). "FAK controls the mechanical activation of YAP, a transcriptional regulator required for durotaxis". FASEB Journal. 32: fj.201700721R. doi:10.1096/fj.201700721r. PMID 29070586.




Further reading


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  • 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. 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: d143–50. doi:10.2741/panetti. PMID 11779709.


  • 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.


  • 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: 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 Metastasis Reviews. 22 (4): 359–74. doi:10.1023/A:1023725029589. PMID 12884911.




External links



  • MBInfo: FAK


  • FAK Info with links in the Cell Migration Gateway


  • PTK2 protein, human at the US 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












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