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PTK2 protein tyrosine kinase 2 (PTK2), also known as focal adhesion kinase (FAK), is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that, in humans, is encoded by the ''PTK2''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
. PTK2 is a
focal adhesion In cell biology, focal adhesions (also cell–matrix adhesions or FAs) are large macromolecular assemblies through which mechanical force and regulatory signals are transmitted between the extracellular matrix (ECM) and an interacting Cell (biolo ...
-associated protein
kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...
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 adhesion In cell biology, focal adhesions (also cell–matrix adhesions or FAs) are large macromolecular assemblies through which mechanical force and regulatory signals are transmitted between the extracellular matrix (ECM) and an interacting Cell (biolo ...
s that form among cells attaching to
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix (ICM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and bio ...
constituents. The encoded protein is a member of the FAK subfamily of protein
tyrosine kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...
s that included
PYK2 Protein tyrosine kinase 2 beta is an enzyme that in humans is encoded by the ''PTK2B'' gene. Function This gene encodes a cytoplasmic protein tyrosine kinase that is involved in calcium-induced regulation of ion channels and activation of the ...
, but lacks significant sequence similarity to kinases from other subfamilies. It also includes a large
FERM domain In molecular biology, the FERM domain (F for 4.1 protein, E for ezrin, R for radixin and M for moesin) is a widespread protein module involved in localising proteins to the plasma membrane. FERM domains are found in a number of cytoskeletal-ass ...
. With the exception of certain types of blood cells, most cells express FAK. FAK
tyrosine kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...
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 p53, also known as tumor protein p53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory transcription factor protein that is often mutated in human cancers. The p53 proteins (originally thou ...
. At least four
transcript variant Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative RNA splicing, splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene ma ...
s encoding four different
isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...
s 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 A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...
originally identified as a substrate for the
oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.
protein tyrosine kinase
v-src v-Src is a gene found in Rous sarcoma virus (RSV) that encodes a tyrosine kinase that causes a type of cancer in chickens. The src gene is oncogenic as it triggers uncontrolled growth in abnormal host cells. It was the first retroviral oncogen ...
. 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 The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell and ...
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...
. Additional components of focal adhesions include
actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ...
,
filamin Filamins are a class of proteins that hold two actin filaments at large angles. Filamin protein in mammals is made up of an actin-binding domain at its N-terminus that is followed by 24 immunoglobulin-like repeat modules of roughly 95 amino acids ...
,
vinculin In mammalian cells, vinculin is a membrane-cytoskeletal protein in focal adhesion plaques that is involved in linkage of integrin adhesion molecules to the actin cytoskeleton. Vinculin is a cytoskeletal protein associated with cell-cell and cell ...
,
talin Talin may refer to: Places * Talin, Armenia, a city * Tálín, a municipality and village in the Czech Republic *Tallinn, capital of Estonia * Talin, Iran, a village in West Azerbaijan Province * Talin, Syria, a village in Tartus Governorate Other ...
,
paxillin Paxillin is a protein that in humans is encoded by the ''PXN'' gene. Paxillin is expressed at focal adhesions of non-striated cells and at costameres of striated muscle cells, and it functions to adhere cells to the extracellular matrix. Mutati ...
,
tensin Tensin was first identified as a 220 kDa multi-domain protein localized to the specialized regions of plasma membrane called integrin-mediated focal adhesions (which are formed around a transmembrane core of an αβ integrin heterodimer). Genome se ...
and RSU-1.


Regulation

FAK is phosphorylated in response to
integrin Integrins are transmembrane receptors that help cell–cell and cell–extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, o ...
engagement,
growth factor A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for ...
stimulation, and the action of
mitogenic A mitogen is a small bioactive protein or peptide that induces a cell to begin cell division, or enhances the rate of division (mitosis). Mitogenesis is the induction (triggering) of mitosis, typically via a mitogen. The cell cycle Mitogens ac ...
neuropeptide Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like the ...
s.
Integrin receptor Integrins are transmembrane receptors that help cell–cell and cell–extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, or ...
s are heterodimeric
transmembrane A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently u ...
glycoproteins Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...
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 Caspase-3 is a caspase protein that interacts with caspase-8 and caspase-9. It is encoded by the ''CASP3'' gene. ''CASP3'' orthologs have been identified in numerous mammals for which complete genome data are available. Unique orthologs are als ...
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 In cell biology, a bleb (or snout) is a bulge of the plasma membrane of a cell, characterized by a spherical, "blister-like", bulky morphology. It is characterized by the decoupling of the cytoskeleton from the plasma membrane, degrading the inte ...
, 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 Protein tertiary structure is the three-dimensional shape of a protein. The tertiary structure will have a single polypeptide chain "backbone" with one or more protein secondary structures, the protein domains. Amino acid side chains and the ...
domains. Two of these domains, the N-terminal FERM domain and the
Kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...
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 The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...
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 An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix). The alpha helix is the most common structural arrangement in the secondary structure of proteins. It is also the most extreme type of l ...
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 Paxillin is a protein that in humans is encoded by the ''PXN'' gene. Paxillin is expressed at focal adhesions of non-striated cells and at costameres of striated muscle cells, and it functions to adhere cells to the extracellular matrix. Mutati ...
.


N-terminus

The function of the
amino-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...
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 In molecular biology, an intrinsically disordered protein (IDP) is a protein that lacks a fixed or ordered three-dimensional structure, typically in the absence of its macromolecular interaction partners, such as other proteins or RNA. IDPs ran ...
within this
kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...
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 cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...
s, 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 ''KRAS'' ( Kirsten rat sarcoma virus) is a gene that provides instructions for making a protein called K-Ras, a part of the RAS/MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the ce ...
mutant
non-small cell lung cancer Non-small-cell lung cancer (NSCLC), or non-small-cell lung carcinoma, is any type of epithelial lung cancer other than small-cell lung cancer (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitiv ...
(Trial ID: NCT01951690) to see how the response depends on tumor-associated INK4a/Arf and
p53 p53, also known as tumor protein p53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory transcription factor protein that is often mutated in human cancers. The p53 proteins (originally thou ...
mutations. In 2015, a
mesothelioma Mesothelioma is a type of cancer that develops from the thin layer of tissue that covers many of the internal organs (known as the mesothelium). The area most commonly affected is the lining of the lungs and chest wall. Less commonly the lini ...
trial of VS-6063 was ended early due to 'poor performance'.Researchers Stop Once-Promising Mesothelioma Clinical Trial. Oct 2015
/ref>


Interactions

PTK2 has been shown to
interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization advocating for the legal and human rights of children with intersex traits. The organization was founded in 2006 and fo ...
with: *
BCAR1 Breast cancer anti-estrogen resistance protein 1 is a protein that in humans is encoded by the ''BCAR1'' gene. Gene BCAR1 is localized on chromosome 16 on region q, on the negative strand and it consists of seven exons. Eight different gene i ...
, *
BMX BMX, an abbreviation for bicycle motocross or bike motocross, is a cycle sport performed on BMX bikes, either in competitive BMX racing or freestyle BMX, or else in general street or off-road recreation. History BMX began during the ea ...
, *
CD61 Integrin beta-3 (β3) or CD61 is a protein that in humans is encoded by the ''ITGB3'' gene. CD61 is a cluster of differentiation found on thrombocytes. Structure and function The ITGB3 protein product is the integrin beta chain beta 3. Integrin ...
, * CRK, *
DCC DCC may refer to: Biology * Netrin receptor DCC, human receptor protein, and the gene encoding it * Dosage compensation complex Business * Day Chocolate Company * DCC plc, an Irish holding company * Doppelmayr Cable Car, cable car company * D ...
, *
FYN Proto-oncogene tyrosine-protein kinase Fyn (p59-FYN, Slk, Syn, MGC45350, Gene ID 2534) is an enzyme that in humans is encoded by the ''FYN'' gene. Fyn is a 59-kDa member of the Src family of kinases typically associated with T-cell and neurona ...
, *
GIT1 ARF GTPase-activating protein GIT1 is an enzyme that in humans is encoded by the ''GIT1'' gene. GIT1 contains an ARFGAP domain, Anykrin repeats, and a GRK-interacting domain. The Arf-GAP domain, which enables it to act as a GTPase activating pr ...
, *
GRB7 Growth factor receptor-bound protein 7, also known as GRB7, is a protein that in humans is encoded by the ''GRB7'' gene. Function The product of this gene belongs to a small family of Signal transducing adaptor protein, adaptor proteins that a ...
, *
Grb2 Growth factor receptor-bound protein 2, also known as Grb2, is an adaptor protein involved in signal transduction/ cell communication. In humans, the GRB2 protein is encoded by the ''GRB2'' gene. The protein encoded by this gene binds recepto ...
, *
IRS1 Insulin receptor substrate 1 (IRS-1) is a signaling adapter protein that in humans is encoded by the ''IRS1'' gene. It is a 180 kDa protein with amino acid sequence of 1242 residues. It contains a single pleckstrin homology (PH) domain at the N-t ...
, * ITGB5, *
JAK2 Janus kinase 2 (commonly called JAK2) is a non-receptor tyrosine kinase. It is a member of the Janus kinase family and has been implicated in signaling by members of the type II cytokine receptor family (e.g. interferon receptors), the GM-CSF ...
, *
MAPK8IP3 C-jun-amino-terminal kinase-interacting protein 3 is an enzyme that in humans is encoded by the ''MAPK8IP3'' gene. The protein encoded by this gene shares similarity with the product of Drosophila syd gene, required for the functional interaction ...
, *
NCK1 Cytoplasmic protein NCK1 is a protein that in humans is encoded by the ''NCK1'' gene. Gene The Nck (non-catalytic region of tyrosine kinase adaptor protein 1) belongs to the adaptor family of proteins. The nck gene was initially isolated fro ...
, *
NCK2 Cytoplasmic protein NCK2 (also known as NCK-beta and Grb4) is a protein that in humans is encoded by the ''NCK2'' gene. Function NCK belongs to family of adaptor proteins. There are two mammalian NCK genes, NCK1 and NCK2. NCK1 is located in c ...
, *
NEDD9 Neural precursor cell expressed developmentally down-regulated protein 9 (NEDD-9) is a protein that in humans is encoded by the ''NEDD9'' gene. NEDD-9 is also known as enhancer of filamentation 1 (EF1), CRK-associated substrate-related protein (CA ...
, *
NEO1 Neogenin is a protein that in humans is encoded by the ''NEO1'' gene. Interactions NEO1 has been shown to interact with PTK2 PTK2 protein tyrosine kinase 2 (PTK2), also known as focal adhesion kinase (FAK), is a protein that, in humans, is ...
, *
P53 p53, also known as tumor protein p53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory transcription factor protein that is often mutated in human cancers. The p53 proteins (originally thou ...
, *
PIK3R1 Phosphatidylinositol 3-kinase regulatory subunit alpha is an enzyme that in humans is encoded by the ''PIK3R1'' gene. Function Phosphatidylinositol 3-kinase phosphorylates the inositol ring of phosphatidylinositol at the 3-prime position. ...
, * PTEN, * PXN,
*
RB1CC1 RB1-inducible coiled-coil protein 1 is a protein that in humans is encoded by the ''RB1CC1'' gene. Interactions RB1CC1 has been shown to interact with PTK2B, ASK1 and PTK2 PTK2 protein tyrosine kinase 2 (PTK2), also known as focal adhesio ...
, *
STAT1 Signal transducer and activator of transcription 1 (STAT1) is a transcription factor which in humans is encoded by the ''STAT1'' gene. It is a member of the STAT protein family. Function All STAT molecules are phosphorylated by receptor associ ...
, * Src, * Syk, *
TGFB1I1 Transforming growth factor beta-1-induced transcript 1 protein is a protein that in humans is encoded by the ''TGFB1I1'' gene. Often put together with and studied alongside TGFB1I1 is the mouse homologue HIC-5 ( Hydrogen Peroxide-Inducible Clone- ...
, *
TLN1 Talin-1 is a protein that in humans is encoded by the ''TLN1'' gene. Talin-1 is ubiquitously expressed, and is localized to costamere structures in cardiac muscle, cardiac and skeletal muscle cells, and to focal adhesions in smooth muscle and non ...
, *
TSC2 Tuberous sclerosis complex 2 (TSC2), also known as tuberin, is a protein that in humans is encoded by the ''TSC2'' gene. Function Mutations in this gene lead to tuberous sclerosis. Its gene product is believed to be a tumor suppressor and is ...
, *
YAP1 YAP1 (yes-associated protein 1), also known as YAP or YAP65, is a protein that acts as a transcription coregulator that promotes transcription of genes involved in cellular proliferation and suppressing apoptotic genes. YAP1 is a component in ...
.


See also

*
Tyrosine kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...


References


Further reading

* * * * * *


External links


MBInfo: FAK

FAK
Info with links in th
Cell Migration Gateway
*
"Breaking down cancer’s wall of resistance"
by DR Nick Peel, Cancer Research UK, Science blog, August 2014 * * {{DEFAULTSORT:Ptk2 Tyrosine kinases Cancer research