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A non-receptor tyrosine kinase (nRTK) is a
cytosolic The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrio ...
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
that is responsible for catalysing the transfer of a
phosphate In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid . The phosphate or orthophosphate ion is derived from phospho ...
group from a
nucleoside triphosphate A nucleoside triphosphate is a nucleoside containing a nitrogenous base bound to a 5-carbon sugar (either ribose or deoxyribose), with three phosphate groups bound to the sugar. They are the molecular precursors of both DNA and RNA, which are cha ...
donor, such as ATP, to tyrosine residues in
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s. Non-receptor tyrosine kinases are a subgroup of protein family
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, enzymes that can transfer the phosphate group from ATP to a tyrosine residue of a protein (phosphorylation). These enzymes regulate many cellular functions by switching on or switching off other enzymes in a cell. Unlike the
receptor tyrosine kinases Receptor tyrosine kinases (RTKs) are the high- affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinas ...
(RTKs), the second subgroup of tyrosine kinases, the non-receptor tyrosine kinases are cytosolic enzymes. Thirty-two non-receptor tyrosine kinases have been identified in human cells (). Non-receptor tyrosine kinases regulate cell growth, proliferation, differentiation, adhesion, migration and
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
, and they are critical components in the regulation of the
immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
.


Function

The main function of nRTKs is their involvement in
signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
in activated T- and
B-cell B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted o ...
s in the immune system. Signaling by many receptors is dependent on nRTKs including T-cell receptors ( TCR), B-cell receptors ( BCR), IL-2 receptors ( IL-2R), Ig receptors, erythropoietin ( EpoR) and
prolactin receptor The prolactin receptor (PRLR) is a type I cytokine receptor encoded in humans by the ''PRLR'' gene on chromosome 5p13-14. It is the receptor for prolactin (PRL). The PRLR can also bind to and be activated by growth hormone (GH) and human placental ...
s. CD4 and
CD8 CD8 (cluster of differentiation 8) is a transmembrane glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). Along with the TCR, the CD8 co-receptor plays a role in T cell signaling and aiding with cytotoxic T cell-antigen int ...
receptors on
T lymphocyte A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell rec ...
s require for their signaling the Src family member
Lck Lck (or lymphocyte-specific protein tyrosine kinase) is a 56 kDa protein that is found inside specialized cells of the immune system called lymphocytes. The Lck is a member of Src kinase family (SFK), it is important for the activation of the T ...
. When antigen binds to T-cell receptor, Lck becomes autophosphorylated and phosphorylates the zeta chain of the T-cell receptor, subsequently another nRTK,
Zap70 ZAP-70 (Zeta-chain-associated protein kinase 70) is a protein normally expressed near the surface membrane of lymphocytes (T cells, natural killer cells, and a subset of B cells). It is most prominently known to be recruited upon antigen binding to ...
, binds to this T-cell receptor and then participates in downstream signaling events that mediate transcriptional activation of
cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
genes. Another Src family member Lyn is involved in signaling mediated by B-cell receptor. Lyn is activated by stimulation of B-cell receptor, which leads to the recruitment and phosphorylation of Zap70-related nRTK,
Syk Tyrosine-protein kinase SYK, also known as spleen tyrosine kinase, is an enzyme which in humans is encoded by the ''SYK'' gene. Function SYK, along with ZAP70, is a member of the Syk family of tyrosine kinases. These cytoplasmic non-receptor t ...
. Another nRTK, Btk, is also involved in signaling mediated by the B-cell receptor. Mutations in the Btk gene are responsible for
X-linked agammaglobulinemia X-linked agammaglobulinemia (XLA) is a rare genetic disorder discovered in 1952 that affects the body's ability to fight infection. As the form of agammaglobulinemia that is X-linked, it is much more common in males. In people with XLA, the whit ...
, a disease characterized by the lack of mature B-cells.


Structure

Unlike receptor tyrosine kinases, nRTKs lack receptor-like features such as an extracellular
ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
-binding domain and a
transmembrane A transmembrane protein (TP) 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 frequentl ...
-spanning region. Most of the nRTKs are localized in the cytoplasm, but some nRTKs are anchored to the cell membrane through
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 ami ...
modification. These enzymes commonly have a modular construction and individual domains are joined together by flexible linker sequences. One of the important domain of nRTKs is the tyrosine kinase catalytic domain, which is about 275 residues in length. The structure of the catalytic domain can be divided into a small and a large lobe, where ATP binds to the small lobe and the protein substrate binds to the large lobe. Upon the binding of ATP and substrate to nRTKs, catalysis of phosphate transfer occurs in a cleft between these two lobes. It was found that nRTKs have some sequence preference around the target Tyr. For example, the Src preferred sequence is Glu–Glu/Asp–Ile–Tyr–Gly/Glu–Glu–Phe and Abl preferred sequence is Ile/Val–Tyr–Gly–Val–Leu/Val. Different preferred sequences around Tyr in Src and Abl suggest that these two types of nRTKs phosphorylates different targets. Non-receptor tyrosine kinases do not contain only a tyrosine kinase domain, nRTKs also possess domains that mediate protein-protein, protein-lipid, and protein- DNA interactions. One of the protein-protein interaction domains in nRTKs are the Src homology 2 ( SH2) and 3 ( SH3) domains. The longer SH2 domain (~100 residues) binds phosphotyrosine (P-Tyr) residues in a sequence-specific manner. The P-Tyr interacts with SH domain in a deep cleft, which cannot bind unphosphorylated Tyr. The SH3 domain is smaller (~60 residues) and binds proline-containing sequences capable of forming a polyproline type II helix. Some nRTKs without SH2 and SH3 domains possess some subfamily-specific domains used for protein-protein interactions. For example, specific domains that target enzymes to the cytoplasmic part of cytokine receptors ( Jak family) or two domains: an
integrin Integrins are transmembrane receptors that facilitate 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, ...
-binding domain and 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. More ...
-binding domain (Fak family). The nRTK Abl possess the SH2 and SH3 domains, but also possesses other domains for interactions: F actin–binding domain and a
DNA-binding domain A DNA-binding domain (DBD) is an independently folded protein domain that contains at least one structural motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence (a recognition sequence) or have a genera ...
contains a
nuclear localization signal A nuclear localization signal ''or'' sequence (NLS) is an amino acid sequence that 'tags' a protein for import into the cell nucleus by nuclear transport. Typically, this signal consists of one or more short sequences of positively charged lysines o ...
and is found in both the nucleus and the cytoplasm. In addition to SH2 and SH3 domains, Btk/Tec subfamily of nRTKs possess another modular domain, a pleckstrin homology (PH) domain. These PH domains bind to
phosphatidylinositol Phosphatidylinositol (or Inositol Phospholipid) consists of a family of lipids as illustrated on the right, where red is x, blue is y, and black is z, in the context of independent variation, a class of the phosphatidylglycerides. In such molecul ...
lipids that have been phosphorylated at particular positions on the head group. These enzymes can bind to activated signaling complexes at the membrane through PH domain interactions with phosphorylated phosphatidylinositol lipids.


Regulation

The most common theme in nRTKs and RTK regulation is tyrosine phosphorylation. With few exceptions, phosphorylation of tyrosines in 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 ...
of nRTKs leads to an increase in enzymatic activity. Activation loop
phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
occurs via trans-autophosphorylation or phosphorylation by different nRTKs. It is possible to negatively regulate kinase activity by the phosphorylation of tyrosines outside of the activation loop. Protein tyrosine phosphatases (PTPs) restore nRTKs to their basal state of activity. In some cases PTPs positively regulate nRTKs activity.


Src and Abl

Tyrosine kinases of Src family contain the same typical structure:
myristoylated Myristoylation is a lipidation modification where a myristoyl group, derived from myristic acid, is covalently attached by an amide bond to the alpha-amino group of an N-terminal glycine residue. Myristic acid is a 14-carbon saturated fatty ac ...
terminus, a region of positively charged residues, a short region with low sequence homology, SH3 and SH2 domains, a tyrosine kinase domain, and a short
carboxy-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal 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 the protein is ...
tail. There are two important regulatory tyrosine phosphorylation sites. To repress kinase activity it is possible by phosphorylation of Tyr-527 in the carboxy-terminal tail of Src by the nRTK Csk. By the experiment of v-Src, an oncogenic variant of Src, the importance of this phosphorylation site was confirmed. This oncogenic v-Src is a product of the Rous sarcoma virus and as a result of an carboxy-terminal truncation, v-Src lacks the negative regulatory site Tyr-527 leading this enzyme to be constitutively active that in turn causes uncontrolled growth of infected cells. Moreover, substitution of this tyrosine with phenylalanine in c-Src results in activation. A second regulatory phosphorylation site in Src is Tyr-416. This is an autophosphorylation site in the activation loop. It was found that a phosphorylation of Tyr-416 and Tyr-416 can suppressing the transforming ability of the activating Tyr-527→Phe mutation by Tyr-416→Phe mutation leads to maximal stimulation of kinase activity. Both the SH2 and SH3 domains are important for a negative regulation of Src activity. Mutations in the SH2 and SH3 domains that disrupt binding of phosphotyrosine lead to activation of kinase activity. Although the nRTK Abl contains SH3, SH2, and kinase domains in the same linear order as in Src, regulation of Abl is different. Abl lacks the negative regulatory phosphorylation site that is present in the carboxy terminus of Src, so the carboxy terminus of Abl does not have a functional role in the control of kinase activity. In a contrast to Src, mutations in the SH2 domain of Abl that abrogates phosphotyrosine binding do not activate Abl in vivo. For the repression of kinase activity of Abl is important the SH3 domain; mutations in the SH3 domain result in activation of Abl and cellular transformation.


ZAP70/Syk and JAKs

The kinase activity of Syk is regulated by the SH2 domains. Binding of the two SH2 domains to the tyrosine-phosphorylated ITAM (immunoreceptor tyrosine-based activation motif) sequences in the zeta chain of the T-cell receptor is thought to relieve an inhibitory restraint on the kinase domain, leading to stimulation of catalytic activity. Kinase activity of
Zap70 ZAP-70 (Zeta-chain-associated protein kinase 70) is a protein normally expressed near the surface membrane of lymphocytes (T cells, natural killer cells, and a subset of B cells). It is most prominently known to be recruited upon antigen binding to ...
can be increased by phosphorylation of Tyr-493 in the activation loop by Src family member Lck. Conversely the phosphorylation of Tyr-492 inhibit the kinase activity of Zap70; the mutation of Tyr-492 to phenylalanine results in Zap70 hyperactivity. Jak family members possess a fully functional tyrosine kinase domain and additionally pseudo-kinase domain in which substitution of several key catalytic residues leads to inactivation of kinase activity. This pseudo-kinase domain is enzymatically nonfunctional, but maybe it plays a role in the regulation of Jak activity. The experiments with a mutant of the Jak family member
Tyk2 Non-receptor tyrosine-protein kinase TYK2 is an enzyme that in humans is encoded by the ''TYK2'' gene. Tyk2 was the first member of the JAK family that was described (the other members are JAK1, JAK2, and JAK3). It has been implicated in IFN-α ...
, in which the pseudo-kinase domain is deleted, showed that these mutant enzyme lacks catalytic activity in vitro and is not capable of interferon-mediated signal transduction. In contrast, another mutant of the Jak family
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 rece ...
, also lacking the pseudo-kinase domain, was able to mediate growth hormone signaling. The role of the pseudo-kinase domain in Jak regulation is still not fully understood. There are two tyrosine phosphorylation sites within the activation loop. It is known that the autophosphorylation of the first of these tyrosines is important for stimulation of tyrosine kinase activity and biological function, but the role of the second tyrosine is not clear. JAKs are also regulated by
SOCS SOCS (suppressor of cytokine signaling proteins) refers to a family of genes involved in inhibiting the JAK-STAT signaling pathway. Genes * CISH * SOCS1 * SOCS2 * SOCS3 * SOCS4 * SOCS5 * SOCS6 * SOCS7 Suppressor of cytokine signaling 7 is a pro ...
(suppressor of cytokine signaling) proteins. These proteins contain a pseudo-substrate sequence thought to interfere with Jak substrate binding and phosphoryl transfer. In addition to a pseudo-substrate sequence, SOCS proteins possess an SH2 domain that binds to a phosphotyrosine in the Jak activation loop, which may facilitate interaction between the pseudosubstrate sequence and the kinase domain. Binding of the SH2 domain to the activation loop could also block substrate access directly or alter the conformation of the activation loop to repress catalytic activity.


Inhibitors

The mutation in a gene for non-receptor tyrosine kinase can results an aberrant activity of this enzyme. This pathologically increased activity of nRTK may be responsible for growth and progression of cancer cells, the induction of drug-resistance, formation of
metastasis Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
and tumor
neovascularization Neovascularization is the natural formation of new blood vessels ('' neo-'' + '' vascular'' + '' -ization''), usually in the form of functional microvascular networks, capable of perfusion by red blood cells, that form to serve as collateral circu ...
. The inhibition of nRTKs could help to a treatment of these tumors. Some of nRTKs inhibitors are already tested as an anti-cancer agents. This
targeted therapy Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks ...
blocks intracellular processes involved in the tumor transformation of cells and / or maintenance of malignant phenotype of tumor cells. Usually
monoclonal antibodies A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodies ca ...
are used for the targeted blockade of RTK, which block the extracellular domain of the receptor and prevent the binding of a ligand. For the specific blockade of nRTKs, however, low molecular weight substances called
Tyrosine-kinase inhibitor A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosph ...
(TKIs) are used, that block the transduction cascade either at the intracytosplasmatic level, or directly block the nRTKs.


Examples

Examples of non-receptor tyrosine kinases include: * ABL family **
ABL1 Tyrosine-protein kinase ABL1 also known as ABL1 is a protein that, in humans, is encoded by the ''ABL1'' gene (previous symbol ''ABL'') located on chromosome 9. c-Abl is sometimes used to refer to the version of the gene found within the mammalian ...
** ARG * ACK family ** ACK1 ** TNK1 * CSK family ** CSK ** MATK * FAK family ** FAK **
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 ...
*
FES Fez or Fes (; ar, فاس, fās; zgh, ⴼⵉⵣⴰⵣ, fizaz; french: Fès) is a city in northern inland Morocco and the capital of the Fès-Meknès administrative region. It is the second largest city in Morocco, with a population of 1.11 mi ...
family **
FES Fez or Fes (; ar, فاس, fās; zgh, ⴼⵉⵣⴰⵣ, fizaz; french: Fès) is a city in northern inland Morocco and the capital of the Fès-Meknès administrative region. It is the second largest city in Morocco, with a population of 1.11 mi ...
**
FER Fer (also known as Fer Servadou, Pinenc, Mansois and several other synonyms) is a red French wine grape variety that is grown primarily in South West France and is most notable for its role in the ''Appellation d'Origine Contrôlée'' (AOC) ...
* FRK family ** FRK **
BRK The 65xx family of microprocessors, consisting of the MOS Technology 6502 and its derivatives, the WDC 65C02, WDC 65C802 and WDC 65C816, and CSG 65CE02, all handle interrupts in a similar fashion. There are three hardware interrupt signals comm ...
** SRMS *
JAK Jak may refer to: Places * Ják, a village in Hungary People * Jak Alnwick (born 1993), English football goalkeeper * Jak Jones (born 1993), Welsh professional snooker player * Raymond Jackson ("JAK") (1927–1997), UK cartoonist * Jak Airport ( ...
family **
JAK1 JAK1 is a human tyrosine kinase protein essential for signaling for certain type I and type II cytokines. It interacts with the common gamma chain (γc) of type I cytokine receptors, to elicit signals from the IL-2 receptor family (e.g. IL-2R, I ...
**
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 rece ...
**
JAK3 Tyrosine-protein kinase JAK3 is a tyrosine kinase enzyme that in humans is encoded by the ''JAK3'' gene. Janus kinases Janus kinase 3 is a tyrosine kinase that belongs to the janus family of kinases. Other members of the Janus family include ...
**
TYK2 Non-receptor tyrosine-protein kinase TYK2 is an enzyme that in humans is encoded by the ''TYK2'' gene. Tyk2 was the first member of the JAK family that was described (the other members are JAK1, JAK2, and JAK3). It has been implicated in IFN-α ...
* SRC family ** SRC ** FGR **
FYN Funen ( da, Fyn, ), with an area of , is the third-largest island of Denmark, after Zealand and Vendsyssel-Thy. It is the 165th-largest island in the world. It is located in the central part of the country and has a population of 469,947 as ...
**
YES1 Proto-oncogene tyrosine-protein kinase Yes is a non-receptor tyrosine kinase that in humans is encoded by the ''YES1'' gene. This gene is the cellular homolog of the Yamaguchi sarcoma virus oncogene. The encoded protein has tyrosine kinase acti ...
** BLK **
HCK Tyrosine-protein kinase HCK is an enzyme that in humans is encoded by the ''HCK'' gene. Function The protein encoded by this gene is a protein-tyrosine kinase that is predominantly expressed in hemopoietic cell types, and belongs to the Src f ...
**
LCK Lck (or lymphocyte-specific protein tyrosine kinase) is a 56 kDa protein that is found inside specialized cells of the immune system called lymphocytes. The Lck is a member of Src kinase family (SFK), it is important for the activation of the T ...
** LYN *
SYK Tyrosine-protein kinase SYK, also known as spleen tyrosine kinase, is an enzyme which in humans is encoded by the ''SYK'' gene. Function SYK, along with ZAP70, is a member of the Syk family of tyrosine kinases. These cytoplasmic non-receptor t ...
family **
SYK Tyrosine-protein kinase SYK, also known as spleen tyrosine kinase, is an enzyme which in humans is encoded by the ''SYK'' gene. Function SYK, along with ZAP70, is a member of the Syk family of tyrosine kinases. These cytoplasmic non-receptor t ...
**
ZAP70 ZAP-70 (Zeta-chain-associated protein kinase 70) is a protein normally expressed near the surface membrane of lymphocytes (T cells, natural killer cells, and a subset of B cells). It is most prominently known to be recruited upon antigen binding to ...
* TEC family ** TEC ** BMX ** BTK **
ITK Itk is a framework for building mega-widgets using the Incr Tcl incr Tcl (commonly stylised as '' ncr Tcl/nowiki>'', and often abbreviated to ''itcl'') is a set of object-oriented extensions for the Tcl programming language. It is widely us ...
**
TXK TXK (Telephone eXchange Crossbar) was a range of Crossbar switch, Crossbar exchanges used by the British Post Office telephone network, subsequently BT, between 1964 and 1994. TXC was used as the designation at first, but this was later changed ...


References

{{Portal bar, Biology, border=no EC 2.7.10 Enzymes of known structure