Non-receptor tyrosine kinases (nRTKs) are cytoplasmic enzymes that catalyze the transfer of phosphate groups from ATP to tyrosine residues in proteins. Unlike receptor tyrosine kinases, nRTKs lack extracellular and transmembrane domains. nRTKs contain two domains - a catalytic domain consisting of two lobes that facilitate ATP transfer, and a protein-protein interaction domain containing SH2 and SH3 subdomains. There are several families of nRTKs including Src, Abl, Syk, Jak, and Zap70 that perform critical functions in immune cell signaling through T cell and B cell receptors. Inhibitors of overactive nRTKs show promise for cancer treatment by blocking intracellular tumor processes.

1. NON RECEPTOR
TYROSINE KINASE
By: Syed Kashif
1 M Pharm
AACP
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2. CONTENTS
1. INTRODUCTION
2. STRUCTURE
3. FAMLIES
4. INHIBITORS
5. FUNCTIONS
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3. INTRODUCTION
 Non receptor tyrosine kinases are cytoplasmic
enzymes that catalyse the transfer of a phosphate
group from a nucleoside triphosphate donor, such as
ATP, to tyrosine residues in proteins.
 Unlike the receptor tyrosine kinases (RTKs), the second
subgroup of tyrosine kinases, the non-receptor
tyrosine kinases are cytoplasmic enzymes.
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4. STRUCTURE
Unlike receptor tyrosine kinases, nRTKs lack receptor-
like features such as an extracellular ligand-binding
domain and a transmembrane-spanning region
LOCATION : cytoplasm
The nRTKs have 2 domains- domain 1 & 2
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5. DOMAIN-1
 Domain-1 : also called as catalytic domain or tyrosine kinase
domain
 It consists of 275 residues & 2 lobes(small & large)
 The small lobe consists of ATP & the large lobe consists of the
protein
 The ATP from the small lobe is transferred to the protein in the
large lobe thus bringing in its activation
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6.  small lobe large lobe
 ATP protein

 ADP protein P
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7. DOMAIN-2
 There are 3 sub domains
I. Protein-protein(D2a)
II. Protein-lipid(D2b)
III. Protein-DNA(D2c)
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8. Protein-protein domain(D2a)
 This has 2 sub domains i.e. src homologus domain 2 &
3 (SH-2 & SH-3)
 SH-2 is a long domain comprising of 100 residues &
binds to p-tyrosine residue
 SJ-3 is a small domain comprising of 60 residues &
binds to proline residue
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9. FAMILIES OF nRTKS
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10. Src family
 Src (pronounced "sarc" as it is short for sarcoma) is
a proto-oncogene encoding a tyrosine
kinase originally discovered byJ. Michael
Bishop and Harold E. Varmus, for which they were
awarded the 1989 Nobel Prize in Physiology or
Medicine.
 Tyrosine kinases of Src family contain the same typical
structure: myristoylated 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 tail which has a
negative regulatory phosphorylation site
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11.  SRC family
 SRC
 FGR
 FYN
 YES1
 BLK
 HCK
 LCK
 LYN
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12. Abl family
 Abelson murine leukemia viral oncogene homolog 1 also known
as ABL1 is a protein that, in humans, is encoded by
the ABL1 gene (previous symbol ABL) located on chromosome
9.
 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 it is the mutations in the SH-3 domain that brings about
activation
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13.  ABL family
 ABL1
 ARG
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14. Syk family
 Spleen tyrosine kinase, also known as Syk, is
an enzyme which in humans is encoded by
the SYK gene
 .
 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 ζ
chain of the T-cell receptor is thought to relieve an
inhibitory restraint on the kinase domain, leading to
stimulation of catalytic activity
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15. Zap70
 ZAP-70 (Zeta-chain-associated protein kinase
70) is a protein normally expressed near the
surface membrane of T cells and natural killer
cells
 Kinase activity of Zap70 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.
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16. Jak family
 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.[17] 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, 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, also
lacking the pseudo-kinase domain, was able to mediate
growth hormone signaling.
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17.  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,[19] but the role of the second
tyrosine is not clear.
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18.  JAK family
JAK1
JAK2
JAK3
TYK2
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19. INHIBITORS
 The pathologically increased activity of nRTK may be
responsible for growth and progression of cancer cells,
the induction of drug-resistance, formation
of metastasis and tumor neovascularization. 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 therapyblocks
intracellular processes involved in the tumor
transformation of cells and / or maintenance of malignant
phenotype of tumor cells. Usually monoclonal
antibodies 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 (TKIs) are used, that block
the transduction cascade either at the intracytosplasmatic
level, or directly block the nRTKs.
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20. FUNCTIONS
 The main function of nRTKs is their involvement
in signal transduction in activated T- and B-cells in the
immune system.[1] 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
receptors
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21. Action on T cells
 . CD4 and CD8 receptors on T lymphocytesrequire for
their signaling the Src family member Lck. When
antigen binds to T-cell receptor, Lck becomes
autophosphorylated and phosphorylates the zeta
chain of the T-cell receptor, subsequently another
nRTK, Zap70, binds to this T-cell receptor and then
participates in downstream signaling events that
mediate transcriptional activation of cytokine genes
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22. Action on B-cells
 . 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. Another nRTK, Btk, is also involved in
signaling mediated by the B-cell receptor. Mutations in
the Btk gene are responsible for X-
linkedagammaglobulinemia,[2][3] a disease
characterized by the lack of mature B-cells.
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23. REFENENCE
 https://en.wikipedia.org/wiki/Non-
receptor_tyrosine_kinase
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25. THANK YOU
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