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The regulatory crosstalk between kinases and proteases in cancer

Nature Reviews Cancer volume 10, pages 278–292 (2010)Cite this article

Subjects

Key Points

  • Protein kinases and proteases are both major classes of cellular enzymes; the kinome and the degradome each include more than 500 genes.

  • Direct interactions between kinases and proteases are frequent, and more than 125 examples of kinases that undergo regulated processing by one or more proteases are currently known. Targets for proteases include kinases in all the major branches of the kinome, as well as atypical protein kinases. Conversely, approximately 150 proteases in all the main families in the degradome are known to be phosphorylated by one or more kinases.

  • Bidirectional kinase–protease interactions have an important role in many cellular processes, including transmembrane signalling, apoptosis and cell migration. Prominent examples include kinase–caspase crosstalk in apoptosis and interactions between deubiquitylases or γ-secretase and receptor tyrosine kinases in cell proliferation and invasion.

  • Kinase–protease interactions are implicated as causal events in disease, and have a particularly important role in cancer. Cell migration and invasion are hallmarks of metastatic cancer, and many kinase–protease interactions are involved in activating these processes in a dysregulated fashion in cancer cells.

  • Clinical implications of kinase–protease crosstalk are emerging. Interplay between ERBB family receptor tyrosine kinases and a disintegrin and metalloproteinase (ADAM) proteases results in the shedding of ERBB2 soluble forms that blunt the efficiency of ERBB2-specific monoclonal antibody therapy in breast cancer. A clinical trial in patients with breast cancer is underway using a combination of an ADAM10 and ADAM17 inhibitor with an ERBB2-specific antibody.

  • Kinase–protease connections are being uncovered at a rapid pace, and their roles in cancer will undoubtedly become increasingly important and offer new opportunities for clinical intervention.

Abstract

Kinases and proteases are responsible for two fundamental regulatory mechanisms — phosphorylation and proteolysis — that orchestrate the rhythms of life and death in all organisms. Recent studies have highlighted the elaborate interplay between both post-translational regulatory systems. Many intracellular or pericellular proteases are regulated by phosphorylation, whereas multiple kinases are activated or inactivated by proteolytic cleavage. The functional consequences of this regulatory crosstalk are especially relevant in the different stages of cancer progression. What are the clinical implications derived from the fertile dialogue between kinases and proteases in cancer?

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Figure 1: Global representation of the crosstalk between the human kinome and the human degradome.
Figure 2: Functional interplay between kinases and proteases.
Figure 3: Overview of the crosstalk between kinases and deubiquitylases (DUBs).
Figure 4: Interplay between kinases and apoptotic proteases.

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Acknowledgements

We thank all members of our laboratories for their helpful comments on the manuscript and apologize for the omission of relevant works owing to space constraints. C.L-O. is supported by grants from Ministerio de Ciencia e Innovación-Spain, European Union-Microenvimet and Fundación M. Botín. T.H. is supported by grants from the National Cancer Institute and is a Frank and Else Schilling American Cancer Society Research Professor. The Instituto Universitario de Oncología is supported by Obra Social Cajastur and Acción Transversal del Cáncer RTICC.

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Authors and Affiliations

  1. Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain and,

    Carlos López-Otín

  2. Molecular and Cell Biology Laboratory, Salk Institute, La Jolla, 92037, CA, USA

    Tony Hunter

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  1. Carlos López-Otín
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  2. Tony Hunter
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Correspondence to Carlos López-Otín.

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Supplementary information

Supplementary Information S1 (table)

Proteases phosphorylated by kinases (PDF 312 kb)

Supplementary information S2 (table)

Kinases targeted by proteases (PDF 525 kb)

Supplementary information S3 (figure)

Global representation of the crosstalk between the human kinome and the human degradome. (PDF 166 kb)

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DATABASES

ClinicalTrials.gov 

NCT00864175

National Cancer Institute Drug Dictionary 

bortezomib

perifosine

FURTHER INFORMATION

Carlos López-Otín's homepage

Incyte

The Human Kinome

The Mammalian Degradome Database

Glossary

Proteasome

Multimeric and multicatalytic protease that degrades multiple intracellular proteins in a ubiquitin- and ATP-dependent manner and has a key role in many events of cellular regulation mediated by protein degradation.

Shedding

Protease-mediated process that involves the release of the extracellular portion of a membrane protein.

RIPping

Protease-mediated process in which a receptor is cleaved in the transmembrane domain by intramembrane-cleaving proteases (I-CLiPs), a group of proteases including the presenilins that are part of a larger complex called γ-secretase.

Signalosome

Multi-subunit protease that promotes the activity of cullin-containing ubiquitin E3 ligases and has important roles in the cell cycle, DNA damage response, nuclear transport, gene transcription and kinase signalling.

Deubiquitylases

A large family of enzymes that comprises cysteine proteases and metalloproteinases, which remove conjugated ubiquitin from proteins and are linked to the regulation and termination of ubiquitin-mediated signalling.

E3 ligase

Enzyme that catalyses the final step of the process that activates and transfers ubiquitin and ubiquitin-like molecules to substrate proteins.

Isopeptidase

Enzyme that cleaves amide bonds that are not present in the main polypeptide chain of a protein, such as those formed between the ɛ-amino group of lysine side chains of ubiquitin-targeted proteins and the terminal carboxyl group of ubiquitin.

Dependence receptors

Structurally unrelated receptors that can induce cell death by apoptosis when unoccupied by ligand, and so create cellular dependence on their ligands. In the presence of ligand, these receptors mediate survival, differentiation and migration.

Apoptosome

Multiprotein complex that mediates the activation of initiator caspases at the onset of apoptosis.

Furin

Member of a group of propotein convertases that catalyse the maturation of precursors for many secreted and transmembrane proteins by cleavage at Arg-X-Lys/Arg-Arg sites.

Trastuzumab

Humanized monoclonal antibody that interferes with ERBB2 signalling and is currently used for the treatment of breast cancer.

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López-Otín, C., Hunter, T. The regulatory crosstalk between kinases and proteases in cancer. Nat Rev Cancer 10, 278–292 (2010). https://doi.org/10.1038/nrc2823

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