関: FAK、focal adhesion protein-tyrosine kinase

WordNet

of or relating to a focus; "focal length"
having or localized centrally at a focus; "focal point"; "focal infection"
a fibrous band of scar tissue that binds together normally separate anatomical structures
abnormal union of bodily tissues; most common in the abdomen
an enzyme that catalyzes the conversion of a proenzyme to an active enzyme
the basic unit of money in Papua New Guinea

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/10/20 14:03:05」(JST)

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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.^[2] 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).^[3] It has been shown that when FAK was blocked, breast cancer cells became less metastatic due to decreased mobility.^[4]

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. 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.^[5]

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.^[6] 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^[7] and RSU-1.

Regulation

FAK is phosphorylated in response to integrin engagement, growth factor stimulation, and the action of mitogenic neuropeptides.^[8]^[9] Integrin receptors are heterodimeric transmembrane glycoproteins that cluster upon ECM engagement, leading to FAK phosphorylation and recruitment to focal adhesions.^[10]^[11]

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.^[12] The smaller FAK fragment is termed "killer FAT" and becomes the domain associated with death signaling.^[12] Throughout apoptosis, FAK is an important contributor to cell rounding, loss of focal contacts and apoptotic membrane formations such as blebbing,^[13] which involves contracting the cortical actin ring and is followed by chromatin condensation and nuclear fragmentation.^[14] Overexpression of FAK leads to inhibition of apoptosis and an increase in the prevalence of metastatic tumors.^[13]

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^[15]—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.^[16] 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.^[17]

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.^[18] 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.^[19]

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.^[20] 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.^[21]

Interactions

PTK2 has been shown to interact with:

BCAR1,^[22]^[23]^[24]^[25]^[26]^[27]
BMX,^[28]
CD61,^[29]^[30]
CRK,^[23]^[31]
DCC,^[32]
FYN,^[33]^[34]
GIT1,^[35]^[36]^[37]
GRB7,^[38]
Grb2,^[24]^[31]^[33]^[39]^[40]
IRS1^[41] and
ITGB5,^[29]
JAK2,^[42]^[43]
MAPK8IP3,^[44]
NCK1,^[45]^[46]
NCK2,^[46]
NEDD9,^[47]
NEO1,^[32]
P53,^[48]
PIK3R1,^[49]
PTEN,^[50]^[51]
PXN,^[27]^[52]^[53]^[54]^[55]^[56]^[57]^[58]^[59]^[60]
RB1CC1,^[61]
STAT1,^[62]
Src,^[23]^[31]^[33]^[41]^[63]^[64]
Syk,^[30]^[65]
TGFB1I1,^[53]^[66]^[67]
TLN1,^[52]^[68] and
TSC2.^[69]

References

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^ Physorg:When cancer cells can't let go
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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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Imipramine administration induces changes in the phosphorylation of FAK and PYK2 and modulates signaling pathways related to their activity.

Zalewska T1, Bielawski A2, Stanaszek L1, Wieczerzak K2, Ziemka-Nałęcz M1, Nalepa I3.
Biochimica et biophysica acta.Biochim Biophys Acta.2016 Feb;1860(2):424-33. doi: 10.1016/j.bbagen.2015.11.008. Epub 2015 Nov 24.
BACKGROUND: Antidepressants can modify neuronal functioning by affecting many levels of signal transduction pathways that are involved in neuroplasticity. We investigated whether the phosphorylation status of focal adhesion kinase (FAK/PTK2) and its homolog, PYK2/PTK2B, and their complex with the do
PMID 26620976

Uptake of Marasmius oreades agglutinin disrupts integrin-dependent cell adhesion.

Juillot S1, Cott C2, Madl J2, Claudinon J2, van der Velden NS3, Künzler M3, Thuenauer R2, Römer W4.
Biochimica et biophysica acta.Biochim Biophys Acta.2016 Feb;1860(2):392-401. doi: 10.1016/j.bbagen.2015.11.002. Epub 2015 Nov 10.
BACKGROUND: Fruiting body lectins have been proposed to act as effector proteins in the defense of fungi against parasites and predators. The Marasmius oreades agglutinin (MOA) is a lectin from the fairy ring mushroom with specificity for Galα1-3Gal containing carbohydrates. This lectin is composed
PMID 26546712

Substance P Enhances Keratocyte Migration and Neutrophil Recruitment through Interleukin-8.

Słoniecka M1, Le Roux S1, Zhou Q1, Danielson P2.
Molecular pharmacology.Mol Pharmacol.2016 Feb;89(2):215-25. doi: 10.1124/mol.115.101014. Epub 2015 Dec 8.
Keratocytes, the resident cells of the corneal stroma, are responsible for maintaining turnover of this tissue by synthesizing extracellular matrix components. When the cornea is injured, the keratocytes migrate to the wounded site and participate in the stromal wound healing. The neuropeptide subst
PMID 26646648

Japanese Journal

Sushi repeat-containing protein X-linked 2 promotes angiogenesis through the urokinase-type plasminogen activator receptor dependent integrin αvβ3/focal adhesion kinase pathways

Drug Discoveries & Therapeutics 11(4), 212-217, 2017
NAID 130006062958

Subcellular localization of proline-rich tyrosine kinase 2 during oocyte fertilization and early-embryo development in mice

Journal of Reproduction and Development 62(4), 351-358, 2016
NAID 130005406817

A novel angiogenic peptide, ΔADT: A truncated adrenotensin peptide revealed by secretory peptidome analysis of human retinal pericytes

BioScience Trends 10(6), 500-506, 2016
NAID 130005295790

「接着斑キナーゼ」

Protein tyrosine kinase 2
	PDB rendering of the C-terminal FAT domain based on 1k04.
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	1K04, 1K05, 1MP8, 1OW6, 1OW7, 1OW8, 2ETM, 2IJM, 2RA7, 3B71, 3BZ3, 3PXK, 3S9O, 4EBV, 4EBW, 4GU6, 4GU9, 4I4E, 4I4F, 4K8A, 4K9Y, 4KAB, 4KAO, 4NY0, 4Q9S
Identifiers
Symbols	PTK2 ; FADK; FAK; FAK1; FRNK; PPP1R71; p125FAK; pp125FAK
External IDs	OMIM: 600758 MGI: 95481 HomoloGene: 7314 ChEMBL: 2695 GeneCards: PTK2 Gene
EC number	2.7.10.2
Gene ontology
Molecular function	• actin binding; • protein kinase activity; • protein tyrosine kinase activity; • non-membrane spanning protein tyrosine kinase activity; • signal transducer activity; • receptor binding; • protein binding; • ATP binding; • JUN kinase binding; • protein kinase binding; • SH2 domain binding;
Cellular component	• stress fiber; • nucleus; • cytoplasm; • microtubule organizing center; • cytosol; • cytoskeleton; • plasma membrane; • focal adhesion; • cell cortex; • apical plasma membrane; • lamellipodium; • extrinsic component of cytoplasmic side of plasma membrane;
Biological process	• microtubule cytoskeleton organization; • angiogenesis; • vasculogenesis; • neuron migration; • placenta development; • regulation of protein phosphorylation; • positive regulation of protein phosphorylation; • heart morphogenesis; • apoptotic process; • cellular component disassembly involved in execution phase of apoptosis; • cytoskeleton organization; • cell adhesion; • signal complex assembly; • epidermal growth factor receptor signaling pathway; • transforming growth factor beta receptor signaling pathway; • integrin-mediated signaling pathway; • small GTPase mediated signal transduction; • axon guidance; • blood coagulation; • positive regulation of cell proliferation; • regulation of cell shape; • embryo development; • regulation of endothelial cell migration; • regulation of epithelial cell migration; • programmed cell death; • positive regulation of phosphatidylinositol 3-kinase signaling; • cell migration; • peptidyl-tyrosine phosphorylation; • central nervous system neuron axonogenesis; • negative regulation of cell-cell adhesion; • establishment of cell polarity; • cell differentiation; • platelet activation; • extracellular matrix organization; • positive regulation of cell migration; • regulation of cell adhesion mediated by integrin; • netrin-activated signaling pathway; • peptidyl-tyrosine autophosphorylation; • Fc-gamma receptor signaling pathway involved in phagocytosis; • establishment of nucleus localization; • regulation of cell proliferation; • negative regulation of apoptotic process; • regulation of GTPase activity; • endothelial cell migration; • positive regulation of phosphatidylinositol 3-kinase activity; • innate immune response; • regulation of osteoblast differentiation; • positive regulation of protein kinase activity; • negative regulation of organ growth; • protein autophosphorylation; • vascular endothelial growth factor receptor signaling pathway; • ephrin receptor signaling pathway; • cell motility; • negative regulation of axonogenesis; • regulation of cytoskeleton organization; • regulation of focal adhesion assembly; • positive regulation of protein kinase B signaling; • negative regulation of synapse assembly; • growth hormone receptor signaling pathway; • regulation of substrate adhesion-dependent cell spreading; • positive regulation of protein ubiquitination involved in ubiquitin-dependent protein catabolic process; • negative regulation of anoikis;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	v; t; e;

　　[★]

英: focal adhesion kinase、focal adhesion protein-tyrosine kinase、FAK
関: 局所接着キナーゼ、焦点接着キナーゼ、フォーカルアドヒージョンキナーゼ

「FAK」

　　[★]

接着斑キナーゼ、焦点接着キナーゼ、局所接着キナーゼ

関: focal adhesion kinase、focal adhesion protein-tyrosine kinase

「focal adhesion protein-tyrosine kinase」

　　[★]

接着斑キナーゼ、フォーカルアドヒージョンキナーゼ

関: FAK、focal adhesion kinase

「局所接着キナーゼ」

　　[★]

英: focal adhesion kinase、FAK
関: 焦点接着キナーゼ、接着斑キナーゼ

「焦点接着キナーゼ」

　　[★]

英: focal adhesion kinase、FAK
関: 局所接着キナーゼ、接着斑キナーゼ

「focal」

　　[★]

adj.

焦点の、焦点を通る
(病変が)限局性の、局所の、病巣の、巣状の

関: circumscribed、definite、focal point、focally、foci、focus、local、localized、locally、nidal、nidus、topical、topically

「adhesion」

　　[★]

n

接着、付着、粘着、粘着力、凝着、密着、溶着、癒着、支持、索状帯。固守、執着

「focal adhesion」

　　[★]

接着点、接着斑

関: adhesion plaque、desmosomal、desmosome、focal contact

「kinase」

　　[★] キナーゼカイネースリン酸化酵素 phosphoenzyme phosphotransferase 　

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[isbn0-12-432565-3-3] Blackshaw, S. E.; Dow, J. Kamal; Lackie, J. M. (1999). The dictionary of cell and molecular biology (3rd ed.). San Diego: Academic Press. ISBN 0-12-432565-3.

[4] Physorg:When cancer cells can't let go

[5] "Entrez Gene: PTK2 PTK2 protein tyrosine kinase 2".

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[pmid8682874-7] Chrzanowska-Wodnicka M, Burridge K (June 1996). "Rho-stimulated contractility drives the formation of stress fibers and focal adhesions". The Journal of Cell Biology 133 (6): 1403–15. doi:10.1083/jcb.133.6.1403. PMC 2120895. PMID 8682874.

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[pmid8649427-24] Hildebrand JD, Taylor JM, Parsons JT (June 1996). "An SH3 domain-containing GTPase-activating protein for Rho and Cdc42 associates with focal adhesion kinase". Mol. Cell. Biol. 16 (6): 3169–78. PMC 231310. PMID 8649427.

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リンク元	「接着斑キナーゼ」「FAK」「focal adhesion protein-tyrosine kinase」「局所接着キナーゼ」「焦点接着キナーゼ」
関連記事	「focal」「adhesion」「focal adhesion」「kinase」

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focal adhesion kinase