NON RECEPTOR TYROSINE KINASE

By: Syed Kashif 1 M Pharm AACP

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CONTENTS

1. INTRODUCTION2. STRUCTURE3. FAMLIES4. INHIBITORS5. FUNCTIONS

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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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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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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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small lobe large lobe

ATP protein

ADP protein P

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DOMAIN-2

There are 3 sub domains I. Protein-protein(D2a)II. Protein-lipid(D2b)III. Protein-DNA(D2c)

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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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FAMILIES OF nRTKS

10Src 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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SRC familySRCFGRFYNYES1BLKHCKLCKLYN

12Abl 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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ABL family ABL1 ARG

14Syk 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

15Zap70

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. 

16Jak 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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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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JAK familyJAK1JAK2JAK3TYK2

19INHIBITORS

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.

20FUNCTIONS

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

21Action 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

22Action 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.

23REFENENCE

https://en.wikipedia.org/wiki/Non-receptor_tyrosine_kinase

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THANK YOU