Largest Commercially Available 93 Tyrosine Kinase Cell-Based Panel

Keywords: Tyrosine kinase, Cancer, Oncogenic activation, Inhibitor, Drug discovery
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Table 1. Mechanism of oncogenic activation of tyrosine kinase

The EGFR family of receptor tyrosine kinase comprises of four members – the EGFR/ Erb B1, HER-2/ Erb B2, HER-3/ Erb B3 and HER-4/ Erb B4. Members of the EGFR family are involved in some complex biological signal transduction network. Both EGFR and HER-2/ neu are amplified in tumor samples of breast, lung and colorectal tissues. Their overexpression leads to elevated MAP kinase and PI3 kinase recruitment and subsequent suppression of apoptosis, deregulation of cell cycle and proliferation.

Receptor tyrosine kinases - function, families and evolution [Video file].
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Table 2. Protein kinase inhibitors in clinical trials

54. Hamaguchi I, Iwama A, Yamaguchi N, Sakano S, Matsuda Y, Suda T. Characterization of mouse non-receptor tyrosine kinase gene, HYL. 1994;9:3371-4

Figure 5. Structure of some of the important protein kinase inhibitors.
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88. Takeuchi M, Kuramochi S, Fusaki N, Nada S, Kawamura-Tsuzuku J, Matsuda S. . Functional and physical interaction of protein-tyrosine kinases Fyn and Csk in the T-cell signaling system. 1993;268:27413-9

Figure 6. Schematic structure of different approaches for tyrosine kinase inhibition
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Src family kinase tyrosine phosphorylates Toll-like …

CML is a chronic myelodysplastic hematopoietic stem cell disorder syndrome (95% of the CML) resulting from a reciprocal translocation between chromosome-9 and chromosome-22, the Philadelphia chromosome. Break point cluster region (BCR) sequences of chromosome-22 on translocation juxtaposes with the c-ABL tyrosine kinase of chromosome-9. The fusion gene produces a 210 KDa mutant protein in which the first exon of c-ABL has been replaced by BCR sequences, encoding either 927 or 902 amino acid. Another BCR-ABL fusion protein of 185 KDa containing BCR sequences from exon 1fused to exon 2-11 of c-ABL, is found in 10% of adult ALL patients. The BCR-ABL chimeric gene product has a tyrosine kinase activity several fold higher than it's normal counterpart and correlates with the disease phenotype [,,,,] .

Mouse Tyrosine Kinases - SABiosciences

Figure 2. Mechanism of action of tyrosine kinase. 1. Receptor expression at membrane claveola 2. Ligand binding 3. Hetero/homodimerization leading to tyrosine kinase activation and tyrosine transphosphorylation 4. Signal transduction 5. Receptor internalization 6. Receptor degradation or re-expression.

Coactivation of Receptor Tyrosine Kinases ..

TEL-ABL tyrosine kinase like ABL-BCR is constitutively phosphorylated due to reciprocal translocation t(9,12) in case of ALL and with a complex karyotype t(9,12,14) in patients with CML. TEL which is a putative transcription factor is fused in-frame with exon-2 of the ABL proto-oncogene, producing a fusion protein product with elevated tyrosine kinase activity [,] . Other important translocations include t(5,12) in CMML producing TEL-PDGF receptor. The helix-loop-helix motif of TEL is believed to induce homodimerization and kinase activation of the TEL-ABL and TEL-PDGFRβ fusion proteins. NPM-ALK fusion products t(2,5) is constitutively activated in Anaplastic large cell lymphoma [,] .

Receptor Tyrosine Kinases: Legacy of the First Two …

Autocrine-paracrine stimulation serves as an important mechanism for the constitutive activation of tyrosine kinase specially receptor tyrosine kinases. This activation loop is stimulated when a receptor tyrosine kinase is abnormally expressed or overexpressed in presence of it's associated ligand or when there is an overexpression of the ligand in presence of it's cognate receptor. A role of autocrine-paracrine stimulation has been immanent in a variety of human cancers. Burning examples are being provided by EGFR, PDGFR and IGF receptors and their associated ligands [] .