Protein family review

This in an extract of a protein family review which first appeared in GenomeBiology, and is reproduced by permission of the publisher, BioMedCentral Ltd.

Authors:

Aspasia Theodosiou¹ and Alan Ashworth²

¹Biomedical Sciences Research Centre 'Alexander Fleming', PO Box 74145, Varkiza 166-02, Athens, Greece
²The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, Fulham Road, London SW3 6JB, UK

Correspondence:

Alan Ashworth.

Email:

alana@icr.ac.uk

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Subscribers to GenomeBiology may view the full version of this review article online at genomebiology.com

Published:

26 June 2002

The MAP kinase phosphatases

Summary

Mitogen-activated protein MAP kinases are key signal-transducing enzymes that are activated by a wide range of extracellular stimuli. They are responsible for the induction of a number of cellular responses, such as changes in gene expression, proliferation, differentiation, cell cycle arrest and apoptosis. Although regulation of MAP kinases by a phosphorylation cascade has long been recognized as significant, their inactivation through the action of specific phosphatases has been less studied. An emerging family of structurally distinct dual-specificity serine, threonine and tyrosine phosphatases that act on MAP kinases consists of ten members in mammals, and members have been found in animals, plants and yeast. Three subgroups have been identified that differ in exon structure, sequence and substrate specificity.

Frontiers

MAP kinase activation has been implicated in oncogenic transformation, tumor formation and metastasis [57,58,59]. This suggests that the MKPs could have a role in tumorigenesis, perhaps as tumor suppressors. Several MKPs have been mapped to regions of the human genome altered in human cancer, but direct evidence for such a role is at present lacking. It will be interesting to see whether this family of genes plays a part in the development of cancer or other diseases.

The lack of relevant mammalian models makes it difficult to assign a physiological role to these phosphatases. Given the overlapping substrate specificity displayed by members of the various subgroups, in addition to the similar tissue distributions, it seems likely that there will be a certain degree of redundancy. This issue could be addressed by combined gene targeting of the members of each subgroup. Such an approach, in conjunction with further genetic biochemical and cell biological analyses of other model organisms should result in the elucidation of the precise biological roles of these enzymes in controlling key signaling pathways. Further insight into the regulation of these phosphatases by their substrates will be gained by determining the three-dimensional structures of representative members of each subgroup, both free and in complex with their targets.

Finally, the adoption by the community of a common nomenclature (such as the DUSP system used here and recommended by the Human Gene Nomenclature committee) will considerably facilitate progress in this important area.

Gene structure of the DUSPs

Three-dimensional structure of DUSP6