Last edited by Shaktilar
Friday, November 27, 2020 | History

3 edition of Biochemical analysis of activating mutations of the Kit receptor tyrosine kinase found in the catalog.

Biochemical analysis of activating mutations of the Kit receptor tyrosine kinase

Johanna Shulman

Biochemical analysis of activating mutations of the Kit receptor tyrosine kinase

  • 393 Want to read
  • 22 Currently reading

Published by National Library of Canada in Ottawa .
Written in English


Edition Notes

Thesis (M.Sc.) -- University of Toronto, 1998.

SeriesCanadian theses = -- Thèses canadiennes
The Physical Object
FormatMicroform
Pagination2 microfiches : negative. --
ID Numbers
Open LibraryOL20234387M
ISBN 100612407942

Constitutive activation through oncogenic mutations of the KIT or platelet-derived growth factor receptor A (PDGFRA) receptor tyrosine kinase plays an important role in the pathogenesis of GISTs (1, 2). Imatinib mesylate (Gleevec, Novartis Pharmaceuticals) potently inhibits BCR-ABL, PDGFRA, PDGFRB, and KIT and has been the frontline therapy in. PathHunter receptor tyrosine and cytosolic tyrosine kinase assays are whole cell, high-throughput assays that utilize the enzyme fragment complementation technology based on a split β-galactosidase (β-gal) enzyme system to look at kinase activation. In this PathHunter assay approach, a small inactive peptide fragment of the β-galactosidase enzyme called ProLink™ (PK) is expressed. The Asp mutation probably was an activating mutation because the AspTyr, His, and Glu found in this study were constitutively tyrosine phosphorylated. 12 Iledel has also been shown to have strong autophosphorylation, 19 suggesting an association with the proliferation of leukemic cells because these mutations were detected in adult AML. Introduction. c-Kit, a type III receptor tyrosine kinase (RTK), plays a crucial role in cancer occurrence. 1 Currently, c-Kit is mainly considered a stem cell factor (SCF), which participates in vital functions of the human body, such as fertility, homeostasis, and melanogenesis; nevertheless, early studies on c-Kit introduced it as an oncogene. 2,3 Deregulation of c-Kit, including.


Share this book
You might also like
Coins and money tokens

Coins and money tokens

De locis solidus secunda divinatio geometrica in quinque libros iniuria temporum...

De locis solidus secunda divinatio geometrica in quinque libros iniuria temporum...

Hansel and Gretel

Hansel and Gretel

lifetime of positive thinking

lifetime of positive thinking

The MMPI

The MMPI

Observations and examples to assist magistrates in setting the assize of bread made of wheat, under the statute of the 31st George II

Observations and examples to assist magistrates in setting the assize of bread made of wheat, under the statute of the 31st George II

Managed Care Manual

Managed Care Manual

Kate M. Strange.

Kate M. Strange.

Outline history of the fine arts

Outline history of the fine arts

American Prisoners of the Bolsheviks 1917-1922

American Prisoners of the Bolsheviks 1917-1922

Commercial bank management

Commercial bank management

Corsages for milady.

Corsages for milady.

Global change

Global change

The American journal of psychiatry

The American journal of psychiatry

Durability Factor

Durability Factor

Biochemical analysis of activating mutations of the Kit receptor tyrosine kinase by Johanna Shulman Download PDF EPUB FB2

Constitutively activating mutations of c-kit receptor tyrosine kinase confer factor-independent growth and tumorigenicity of factor-dependent hematopoietic cell lines.

Kitayama H(1), Kanakura Y, Furitsu T, Tsujimura T, Oritani K, Ikeda H, Sugahara H, Mitsui H, Cited by: All of the mutations identified were missense muta-tions that localized to the tyrosine kinase domain of the Met receptor.

To investigate the possibility that these tumor-associated mutations caused constitutive activation of the Met receptor, we introduced the mutations into the met cDNA and examined their activity in biochemical and Cited by:   For example, point mutations and deletions that result in constitutive tyrosine kinase activation have been identified in the ALs of FLT3, 16,17 c-KIT, 18,19 or EGFR.

5,6 In addition, mutations in the JM domain of receptor tyrosine kinases, including internal tandem duplications in the case of FLT3 or KIT, 20 or point mutations, as has recently Cited by: The Kit receptor tyrosine kinase functions in hemato-poiesis, melanogenesis and gametogenesis. Kit receptor-mediated cellular responses include prolifera-tion, survival, adhesion, secretion and differentiation.

In mast cells, Kit-mediated recruitment and activation of phosphatidylinositol 3 -kinase (PI 3-kinase) pro-Cited by:   Autoinhibition of receptor tyrosine kinases is often accomplished by residues within the kinase domain or by immediately adjacent juxtamembrane or C-terminal sequences, with activating mutations in these regions identified in Kit, Flt-3, and EGFR (Furitsu et al.,Lynch et al.,Nakao et al.,Paez et al., ).

In contrast Cited by:   Activation of TKRs may occur through mutations but, by sequence analysis, no mutations were detected in 6 ovarian tumors with elevated immunoreactivity for each of the TKRs (c-kit, PDGFRα, and PDGFRβ).

Tyrosine kinase receptors could also be activated through autocrine or paracrine stimulation of receptor by its ligand. Receptor tyrosine kinases (RTKs) play an important role in a variety of cellular processes including growth, motility, differentiation, and metabolism.

As such, dysregulation of RTK signaling leads to an assortment of human diseases, most notably, cancers. Recent large-scale genomic studies have revealed the presence of various alterations in the genes encoding RTKs such as EGFR.

Mutations within the activation loop of members of the class III receptor tyrosine kinase (RTK) subfamily, which includes KIT, PDGFRA, and FLT3, have been observed in multiple human tumor types.

These mutations confer constitutive activation as well as resistance to the type II tyrosine kinase inhibitors (TKI) that are currently clinically.

Proto-oncogene c-KIT is the gene encoding the receptor tyrosine kinase protein known as tyrosine-protein kinase KIT, CD (cluster of differentiation ) or mast/stem cell growth factor receptor (SCFR).

Multiple transcript variants encoding different isoforms have been found for this gene. KIT was first described by the German biochemist Axel Ullrich in as the cellular homolog of the. The receptor tyrosine kinase KIT acts on a downstream signaling cascade leading to key intracellular signals controlling cellular proliferation and survival (7, 8).

Oncogenic KIT mutations resulting in ligand-independent kinase activity have been reported in 75% to 80% of gastrointestinal stromal tumors (GIST; ref. Imatinib mesylate. Kasamatsu et al. () stated that KIT is expressed as a kD glycosylated transmembrane protein with an extracellular domain, a transmembrane region, and a tyrosine kinase domain.

The extracellular domain consists of 5 Ig-like domains. A soluble form of KIT (sKIT) is released from membrane-bound KIT (mKIT) upon stimulation. sKIT is a glycoprotein of about kD.

The detected somatic mutations were grouped into the major RTK pathway, MAPK pathway, PI3K pathway, and others. Mutations that are known to be activating oncogenic mutations are shown in red. RTK gene mutations with unknown functions that were investigated in this study are shown in orange.

RTK, receptor tyrosine kinase. c-Kit, a receptor tyrosine kinase, is involved in intracellular signaling, and the mutated form of c-Kit plays a crucial role in occurrence of some cancers. Structural Basis for Activation of the Receptor Tyrosine Kinase KIT by Stem Cell Factor Satoru Yuzawa,1,2 Yarden Opatowsky,1,2 Zhongtao Zhang,1,3 Valsan Mandiyan,1 Irit Lax,1 and Joseph Schlessinger1,* 1Department of Pharmacology, Yale University School of Medicine, Cedar Street, New Haven, CTUSA 2These authors contributed equally to this work.

3Present address:. Recently, mutations in the Met tyrosine kinase receptor have been identified in both hereditary and sporadic forms of papillary renal carcinoma. We have introduced the corresponding mutations into the met cDNA and examined the effect of each mutation in biochemical and biological assays.

In contrast, our analysis of the phenotype of Kit YF /Kit YF mice was designed to investigate a specific subset of PI 3‐kinase functions, those mediated by Kit receptor activation. Another question concerns the downstream Kit/PI 3‐kinase signaling pathways, which are crucial in different cell types affected by the Kit YF mutation.

The Met tyrosine kinase is a high-affinity receptor for hepatocyte growth factor/scatter factor (HGF/SF) (1, 2).Both Met and HGF/SF are expressed in numerous tissues, although their expression is confined predominantly to cells of epithelial and mesenchymal origin, respectively (3, 4).Signaling via this receptor-ligand pair has been shown to affect a wide range of biological activities.

Location and biochemical properties of secondary KIT kinase mutations in TKI-resistant GIST. The location of primary KIT kinase mutations is shown on the left-most stick figure.

The protein domains are indicated to the left of this panel. The center of the figure has an exploded view of the kinase. Tyrosine kinases, both nonreceptor and receptor tyrosine kinases, are overexpressed in solid tumors and stimulate their growth and receptor tyrosine kinase that is overexpressed in most solid tumors is EGFR-TK (epidermal growth factor receptor tyrosine kinase).Overexpression results in autophosphorylation (of protein tyrosine residues) that stimulates signal transduction pathways.

Stem Cell Factor (SCF) initiates its multiple cellular responses by binding to the ectodomain of KIT, resulting in tyrosine kinase activation. We describe the crystal structure of the entire ectodomain of KIT before and after SCF stimulation.

The structures show that KIT dimerization is driven by SCF binding whose sole role is to bring two KIT molecules together. Biochemical studies for 81 clustering before or after receptor activation.

Somatic mutations in RTK-III ectodomains for activation of the receptor tyrosine kinase KIT. These observations suggest the hypothesis that activating mutations in tyrosine kinases are important in the pathogenesis of PV, ET, and MMM.

We used an internet-based clinical proto-col and high-throughput DNA sequence analysis to screen for tyrosine kinase mutations in PV, ET, and MMM.

JAK2 mutations in myeloproliferative disorders. KIT receptor tyrosine kinase mutations are implicated as a prognostic factor in adults with core binding factor (CBF) acute myeloid leukemia (AML).

Location of the KIT mutation and analysis by. Mutations in receptor tyrosine kinases are common in cancer, and a variety of kinase mutations can have oncogenic effects. Not all of these mutations are susceptible to existing kinase inhibitors, and many inhibitors are nonspecific, resulting in undesirable off-target effects.

Evans et al. developed BLU, an inhibitor that specifically targets the KIT and PDGFRA oncogenic kinases.

Somatic mutations in receptor tyrosine kinasopathies and developmental syndromes. Germline mutations underlie the majority of the DRTKs recognized to date (Table 1). However, there is an inherent bias for identification of germline mutations as they are readily detected in DNA extracted from blood, the DNA source used in most gene discovery.

The transmembrane domains of receptor tyrosine kinases have been shown to play a critical role in the regulation of receptor dimerisation and activation. 11 The mutation GR in human FGFR3 is found in individuals with achondroplasia and results in constitutive FGFR3 activation.

12, 13 Importantly, it has been reported that substitution of the. Sommer, G, Agosti, V, Ehlers, I, et al. Gastrointestinal stromal tumors in a mouse model by targeted mutation of the Kit receptor tyrosine kinase. Proc Natl Acad Sci USA ; –   Figure 1: Sequence conservation and structural features of the gatekeeper residue threonine in tyrosine kinases and activation of kinase activity by gatekeeper residue mutation.

Introduction. Receptor tyrosine kinases (RTKs) are involved in different steps of neoplastic development and progression. Their signaling influences the growth, differentiation, adhesion, motility, and death of cells. 1 RTKs are divided in 20 subfamilies including class III RTKs.

Mutations in class III RTKs have a major impact on leukemic transformation of acute myeloid leukemia (AML) cells. A large number of targeted agents, both receptor-tyrosine kinase inhibitors and monoclonal antibodies, have recently become front-line therapeutics, primarily for patients whose tumors express specific gene mutations, chromosomal aberrations, or activate specific pathways for continued growth.

Targeted inhibitory agents in selected subsets of. Mutations in the proto-oncogene c-kit, including point mutations, deletions, or duplications in the negative regulatory juxtamembrane (JM) domain or point mutations in the catalytic domain, have been observed in human and canine cancers and often result in constitutive activation of Kit in the absence of ligand identify a receptor tyrosine kinase (RTK) inhibitor capable of blocking.

Introduction. RET is a receptor tyrosine kinase (RTK) expressed and required during early development for the formation of neural crest-derived lineages and kidney organogenesis (Arighi et al., ; Plaza-Menacho et al., ).It has been reported, based on cell-based experimental models, that upon ligand and coreceptor binding to the extracellular domain, the catalytic and signaling activity.

KIT is a transmembrane class III receptor tyrosine kinase which is required for MC growth, differentiation, and functional activation. Mutations in codon of the KIT gene result in ligand-independent (constitutive) activation of KIT signaling and, thus, may play a central role in the pathogenesis of SM.

Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins.

Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the. Biochemical characterization of KIT/ML receptor. Given the frequency of the exon 10 mutation in our chordoma patients, we used site-directed mutagenesis to introduce ML substitution into a wild-type KIT-expressing vector and transiently transfected COS1 cells to assess the role of ML in KIT activation and, therefore, imatinib response.

All the mutations at exon 17 of c-KIT involved residues in the activating loop, D and/or N, that exhibit increased tyrosine kinase activity. 28, 29 The reported patterns of pediatric c-KIT. Targeting oncogenic mutations in receptor tyrosine kinases – an overview 1 Receptor tyrosine kinases (RTKs) 2 Regulation of RTK activity and cell signaling 3 Structural features of kinase domain 4 Cellular signaling mediated by the activated RTKs 5 Activating mutations.

Receptor tyrosine kinase KIT controls many signal transduction pathways and represents a typical allosterically regulated protein. The mutation-induced deregulation of KIT activity impairs cellular physiological functions and causes serious human diseases.

The impact of hotspots mutations (DH/Y/N/V and VG/D) localized in crucial regulatory segments, the juxtamembrane region. Activating mutations in KIT proto-oncogene receptor tyrosine kinase (KIT) (encodes KIT protein) (OMIM ) and less frequently in platelet-derived growth factor receptor α (PDGFRA) (encodes platelet-derived growth factor receptor α) (OMIM ) are considered the major molecular drivers of most GISTs.

9 The resulting aberrant receptor. Receptor tyrosine kinases (RTKs) are proteins on the surface of animal cells that transmit signals into the cell.

Binding of an extracellular signal protein to the RTK activates its intracellular enzyme (kinase). This process needs to be tightly controlled, as unwanted RTK activation can lead to disease.

The discoidin domain receptors, DDR1 and DDR2, are unusual RTKs that are activated by a. Activating mutations of receptor tyrosine kinases KIT or PDGFRA are key to the pathogenesis of most gastrointestinal stromal tumors (GIST).

More than 80% of GISTs express mutated, constitutively active KIT receptors, another 5% to 7% express mutated PDGFRA, and the remaining 10% to 15% are wild-type GISTs (WT) lacking mutations in either of.Incidence of mutations of class iii receptor tyrosine kinase (kit and flt3) in pediatric and adult acute leukaemic patients.

Biochemical analysis of activating mutations of the kit [email protected]{osti_, title = {Structural Basis for Activation of the Receptor Tyrosine Kinase KIT by Stem Cell Factor}, author = {Yuzawa, S and Opatowsky, Y and Zhang, Z and Mandiyan, V and Lax, I and Schlessinger, J}, abstractNote = {Stem Cell Factor (SCF) initiates its multiple cellular responses by binding to the ectodomain of KIT, resulting in tyrosine kinase activation.