Oncogenic Kinases in Cancer

Abstract

Oncogenesis involves the generation and transmission of signals that result in de‐regulation of cell proliferation, inhibition of apoptosis and morphological changes. Transmembrane or cytoplasmic tyrosine and serine/threonine kinases participate both directly and indirectly in cell transformation and tumorigenesis. Such kinases transfer phosphates to tyrosine residues or serine and threonine residues of other kinases or proteins that participate in various signalling pathways in the cell. Up to 20% of the 32 000 human genes sequenced by the Human Genome Project encode proteins that are involved in cellular signalling, and among these, more than 520 are protein kinases. Many of these kinases have been implicated in tumorigenesis involving transmembrane, cytoplasmic and nuclear signalling, cell‐cycle control and regulation of apoptosis. Screening and targeting oncogenic kinases are becoming rapidly part of a personalised strategy for the treatment of cancer.

Key Concepts

  • Oncogenic receptor kinases.
  • Cytoplasmic and nuclear signalling oncogenic kinases.
  • Oncogenic kinases involved in cell‐cycle control.
  • Kinases contribute to oncogenesis by regulating apoptosis.
  • Targeting kinases is a viable strategy for cancer therapy.

Keywords: tyrosine kinases; receptor kinases; serine/threonine kinases; cell cycle; apoptosis

Figure 1. Receptor tyrosine kinases mediate extra‐cellular growth signals that trigger a cascade of phosphorylation events in the cytoplasm, leading to the activation of gene transcription. RPTK, receptor protein tyrosine kinase; PI3K, phospho‐inositol‐3‐kinase; Akt, serine threonine kinase cloned from the AKT8 retrovirus; Bad, Bcl‐2‐related protein; Iκkα, IκB kinase α NIK, NfκB activating–interleukin1 receptor–induced kinase; IκB, inhibitor of NFκ B; RelA, subunit of Nfκ B, p50 nuclear factor κ B subunit; NFκB, nuclear factor κ B, TPL‐2 tumour progression locus 2; SEK, stress‐induced serine threonine kinase; JNK, c‐jun kinase; c‐jun, component of AP1 complex; c‐fos, component of AP1 complex; ERK1/2, extra‐cellular signal regulated kinase 1 and 2; MEK1, MEKK, kinase phosphorylating MEKs; Raf1, MSV retrovirus–induced serine threonine kinase; Src, simian retrovirus–induced tyrosine kinase; Abl, Abelson murine leukaemia virus–induced tyrosine kinase; SOS, GTP/GDP exchange factor; Grb2, GTP/GDP exchange factor; Ras, transforming gene of Harvey and Kirsten sarcoma viruses; Ap1, transcription factor complex.
Figure 2. Mechanisms of apoptosis induced by death receptors, or cellular stress, which are potentially inhibited by oncogenic kinases. Fas, CD95, APO1 death receptor; TNFR1, tumour necrosis factor receptor 1; FADD, Fas‐associated death domain; TRADD, TNF‐receptor‐associated death domain protein; TRAF2, TNF‐receptor‐associated factor 2; p38MAPK, 38 kDa‐mitogen‐activated protein kinase; Apaf‐1, apoptosis‐associated factor 1; CytoC, cytochrome c; IAP, inhibitor of apoptosis.
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References

Abrantes JL, Tornatore TF, Pelizzaro‐Rocha KJ, et al. (2014) Crosstalk between kinases, phosphatases and miRNAs in cancer. Biochimie 107 (Pt B): 167–187.

Bader AG, Kang S, Zhao L and Vogt PK (2005) Oncogenic PI3 K deregulates transcription and translation. Nature Reviews. Cancer 5: 921–929.

Blume‐Jensen P and Hunter T (2001) Oncogenic kinase signalling. Nature 411: 355–365.

Campbell J, Ryan CJ, Brough R, et al. (2016) Large‐scale profiling of kinase dependencies in cancer cell lines. Cell Reports 14 (10): 2490–2501.

Eiring AM and Deininger MW (2014) Individualizing kinase‐targeted cancer therapy: the paradigm of chronic myeloid leukemia. Genome Biology 15 (9): 461.

Fesik SW (2005) Promoting apoptosis as a strategy for cancer drug discovery. Nature Reviews. Cancer 5: 876–885.

Goldman JM and Melo JV (2003) Chronic myeloid leukemia–advances in biology and new approaches to treatment. New England Journal of Medicine 349: 1451–1464.

Hanahan D and Weinberg RA (2000) The hallmarks of cancer. Cell 100: 57–70.

Huang Y, Lu M and Wu H (2004) Antagonizing XIAP‐mediated caspase‐3 inhibition. Achilles' heel of cancers? Cancer Cell 5: 1–2.

Klein S, McCormick F and Levitzki A (2005) Killing time for cancer cells. Nature Reviews. Cancer 5: 573–580.

Levine AJ, Feng Z, Mak TW, You H and Jin S (2006) Coordination and communication between the p53 and IGF‐1‐AKT‐TOR signal transduction pathways. Genes & Development 20: 267–275.

Massague J (2004) G1 cell‐cycle control and cancer. Nature 432: 298–306.

McLean GW, Carragher NO, Avizienyte E, et al. (2005) The role of focal‐adhesion kinase in cancer – a new therapeutic opportunity. Nature Reviews. Cancer 5: 505–515.

Meuwissen R and Berns A (2005) Mouse models for human lung cancer. Genes & Development 19: 643–664.

Sabatini DM (2006) mTOR and cancer: insights into a complex relationship. Nature Reviews. Cancer 6: 729–734.

Tang A, Gao K, Chu L, et al. (2017) Aurora kinases: novel therapy targets in cancers. Oncotarget 8 (14): 23937–23954.

Thomas SJ, Snowden JA, Zeidler MP and Danson SJ (2015) The role of JAK/STAT signalling in the pathogenesis, prognosis and treatment of solid tumours. British Journal of Cancer 113 (3): 365–371.

Tsatsanis C (2006) Tpl2/Cot kinase. AfCS‐Nature Molecule Pages. doi:10.1038/mp.a000092.01, http://www.signaling‐gateway.org/molecule/query?afcsid=A000092.

Tsatsanis C and Spandidos DA (2000) The role of oncogenic kinases in human cancer. International Journal of Molecular Medicine 5: 583–590.

Zachos G and Spandidos DA (1997) Expression of ras proto‐oncogenes: regulation and implications in the development of human tumors. Critical Reviews in Oncology/Hematology 26: 65–75.

Further Reading

Ferrell JE (2000) Regulatory cascades: function and properties. In: Encyclopedia of Life Sciences. London: Nature Publishing Group. http://www.els.net.

Heldin C‐H (2000) Signal transduction: overview. In: Encyclopedia of Life Sciences. London: Nature Publishing Group. http://www.els.net.

Hunter T (2000) Signaling: 2000 and beyond. Cell 100: 113–127.

Sowadski JM and Epstein LF (2000) Protein kinases. In: Encyclopedia of Life Sciences. London: Nature Publishing Group. http://www.els.net.

Vallar L, Gullick WJ, Palmero I and Peters G (1996) Signalling subversion in cancer. In: Parker PJ and Pawson T (eds) Cell Signalling, pp. 324–367. London: Imperial Cancer Research Fund.

Web Links

Abl: http://www.signaling‐gateway.org/molecule/query?afcsid=A000161

Information on different signalling kinases can be retrieved at the ‘Alliance for Cellular Signaling/Nature (AfCS/Nature)’ at http://www.signaling‐gateway.org/molecule/

Tpl2: http://www.signaling‐gateway.org/molecule/query?afcsid=A000092

mTOR: http://www.signaling‐gateway.org/molecule/query?afcsid=A000094

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How to Cite close
Tsintarakis, Antonis, and Zafiropoulos, Alexandros(Sep 2017) Oncogenic Kinases in Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006051.pub3]