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Switching on kinases: oncogenic activation of BRAF and the PDGFR family

Abstract

The cytoplasmic serine/threonine kinase BRAF and receptor tyrosine kinases of the platelet-derived growth factor receptor (PDGFR) family are frequently activated in cancer by mutations of an equivalent amino acid. Structural studies have provided important insights into why these very different kinases share similar oncogenic hot spots and why the PDGFR juxtamembrane region is also a frequent oncogenic target. This research has implications for other kinases that are mutated in human tumours and for the treatment of cancer using kinase inhibitors.

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Figure 1: Signal transduction by PDGFR-family kinases and BRAF.
Figure 2: The BRAF and PDGFR-family kinases.
Figure 3: Oncogenic mutations in BRAF and PDGFR-family kinases.
Figure 4: Activation of CDK2.
Figure 5: Formation of the β6β9-sheet and movement of the C-helix during kinase activation.
Figure 6: Interaction between the activation segment and the P-loop in inactive BRAF.
Figure 7: Activation of KIT.
Figure 8: Oncogenic activation-segment mutations of kinases.

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Acknowledgements

This work was supported by the Biotechnology and Biological Sciences Research Council. We thank D. Barford, T. Gibson, R. Marais and J. Taylor for many helpful comments.

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DATABASES

Cancer.gov

acute myeloid leukaemia

breast cancer

chronic myeloid leukaemia

melanoma

Entrez Gene

ABL

AKT

ARAF

ARG

BCR

BRAF

CDK2

CSF1

FLT3

FMS

KIT

PDGFRα

PDGFRβ

RAF1

SCF

SRC

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Dibb, N., Dilworth, S. & Mol, C. Switching on kinases: oncogenic activation of BRAF and the PDGFR family. Nat Rev Cancer 4, 718–727 (2004). https://doi.org/10.1038/nrc1434

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