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PNAS 105 (28): 9680-9684

Copyright © 2008 by the National Academy of Sciences.

From the Cover


Evolution of the phospho-tyrosine signaling machinery in premetazoan lineages

David Pincus*, Ivica Letunic{dagger}, Peer Bork{dagger}, and Wendell A. Lim*,{ddagger}

*Department of Cellular and Molecular Pharmacology, University of California, 600 16th Street, San Francisco, CA 94158; and {dagger}European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany

Communicated by Henry R. Bourne, University of California, San Francisco, CA, April 3, 2008

Received for publication February 12, 2008.

Abstract: Multicellular animals use a three-part molecular toolkit to mediate phospho-tyrosine signaling: Tyrosine kinases (TyrK), protein tyrosine phosphatases (PTP), and Src Homology 2 (SH2) domains function, respectively, as "writers," "erasers," and "readers" of phospho-tyrosine modifications. How did this system of three components evolve, given their interdependent function? Here, we examine the usage of these components in 41 eukaryotic genomes, including the newly sequenced genome of the choanoflagellate, Monosiga brevicollis, the closest known unicellular relative to metazoans. This analysis indicates that SH2 and PTP domains likely evolved earliest—a handful of these domains are found in premetazoan eukaryotes lacking tyrosine kinases, most likely to deal with limited tyrosine phosphorylation cross-catalyzed by promiscuous Ser/Thr kinases. Modern TyrK proteins, however, are only observed in two lineages, metazoans and choanoflagellates. These two lineages show a dramatic coexpansion of all three domain families. Concurrent expansion of the three domain families is consistent with a stepwise evolutionary model in which preexisting SH2 and PTP domains were of limited utility until the appearance of the TyrK domain in the last common ancestor of metazoans and choanoflagellates. The emergence of the full three-component signaling system, with its dramatically increased encoding potential, may have contributed to the advent of metazoan multicellularity.

Key Words: choanoflagellates • encoding potential • tyrosine kinase • src homology 2 • protein tyrosine phosphatase

Freely available online through the PNAS open access option.

Author contributions: P.B. and W.A.L. designed research; D.P. and I.L. performed research; I.L. and P.B. contributed new reagents/analytic tools; D.P. and W.A.L. analyzed data; and D.P. and W.A.L. wrote the paper.

The authors declare no conflict of interest.

See Commentary on page 9453.

This article contains supporting information online at

{ddagger}To whom correspondence should be addressed. E-mail: lim{at}

© 2008 by The National Academy of Sciences of the USA

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