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. 2004;1(2):101-115.
doi: 10.7150/ijms.1.101. Epub 2004 Jun 1.

Tyrosine kinase - Role and significance in Cancer

Manash K Paul  1 , Anup K Mukhopadhyay
Affiliations

Tyrosine kinase - Role and significance in Cancer

Manash K Paul et al. Int J Med Sci. 2004.

Abstract

Tyrosine kinases are important mediators of the signaling cascade, determining key roles in diverse biological processes like growth, differentiation, metabolism and apoptosis in response to external and internal stimuli. Recent advances have implicated the role of tyrosine kinases in the pathophysiology of cancer. Though their activity is tightly regulated in normal cells, they may acquire transforming functions due to mutation(s), overexpression and autocrine paracrine stimulation, leading to malignancy. Constitutive oncogenic activation in cancer cells can be blocked by selective tyrosine kinase inhibitors and thus considered as a promising approach for innovative genome based therapeutics. The modes of oncogenic activation and the different approaches for tyrosine kinase inhibition, like small molecule inhibitors, monoclonal antibodies, heat shock proteins, immunoconjugates, antisense and peptide drugs are reviewed in light of the important molecules. As angiogenesis is a major event in cancer growth and proliferation, tyrosine kinase inhibitors as a target for anti-angiogenesis can be aptly applied as a new mode of cancer therapy. The review concludes with a discussion on the application of modern techniques and knowledge of the kinome as means to gear up the tyrosine kinase drug discovery process.

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Conflict of interest statement

Conflict of interest: The authors have declared that no conflict of interest exists.

Figures

Figure 1
Figure 1
Schematic representation of the mode of action of tyrosine kinase. PK represents protein kinase and PP stands for protein phosphatase.
Figure 2
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.
Figure 3
Figure 3
Schematic view of different mechanisms leading to the constitutive activation of tyrosine kinase.
Figure 4
Figure 4
Model of the ATP-binding site of protein kinases. ATP is depicted in red, Sug1, Hyp1 & Hyc1 are residues lining the sugar region, hydrophobic pocket (Hyp), hydrophobic channel (Huc) and hinge region (Hin) respectively (redrawn) .
Figure 5
Figure 5
Structure of some of the important protein kinase inhibitors.
Figure 6
Figure 6
Schematic structure of different approaches for tyrosine kinase inhibition
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