Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

PNAS 105 (28): 9674-9679

Copyright © 2008 by the National Academy of Sciences.

From the Cover


The protist, Monosiga brevicollis, has a tyrosine kinase signaling network more elaborate and diverse than found in any known metazoan

Gerard Manning*,{dagger}, Susan L. Young{ddagger}, W. Todd Miller§, and Yufeng Zhai*

*Razavi Newman Center for Bioinformatics, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037; {ddagger}Department of Molecular and Cell Biology and Center for Integrative Genomics, University of California, Berkeley, CA 94720; and §Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794

Edited by Tony Hunter, Salk Institute for Biological Studies, La Jolla, CA, and approved April 28, 2008

Received for publication February 11, 2008.

Abstract: Tyrosine kinase signaling has long been considered a hallmark of intercellular communication, unique to multicellular animals. Our genomic analysis of the unicellular choanoflagellate Monosiga brevicollis discovers a remarkable count of 128 tyrosine kinases, 38 tyrosine phosphatases, and 123 phosphotyrosine (pTyr)-binding SH2 proteins, all higher counts than seen in any metazoan. This elaborate signaling network shows little orthology to metazoan counterparts yet displays many innovations reminiscent of metazoans. These include extracellular domains structurally related to those of metazoan receptor kinases, alternative methods for membrane anchoring and phosphotyrosine interaction in cytoplasmic kinases, and domain combinations that link kinases to small GTPase signaling and transcription. These proteins also display a wealth of combinations of known signaling domains. This uniquely divergent and elaborate signaling network illuminates the early evolution of pTyr signaling, explores innovative ways to traverse the cellular signaling circuitry, and shows extensive convergent evolution, highlighting pervasive constraints on pTyr signaling.

Key Words: choanoflagellate • evolution • genome • kinome • phosphotyrosine

Freely available online through the PNAS open access option.

Author contributions: G.M., S.L.Y., and W.T.M. designed research; G.M., S.L.Y., W.T.M., and Y.Z. performed research; G.M., W.T.M., and Y.Z. contributed new reagents/analytic tools; G.M., S.L.Y., W.T.M., and Y.Z. analyzed data; and G.M., S.L.Y., W.T.M., and Y.Z. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

Data deposition: The sequences reported in this paper have been deposited in the datbase, (accession nos. Mbre0001Mbre0128).

See Commentary on page 9453.

This article contains supporting information online at

{dagger}To whom correspondence should be addressed. E-mail: manning{at}

© 2008 by The National Academy of Sciences of the USA

The Evolution of the GPCR Signaling System in Eukaryotes: Modularity, Conservation, and the Transition to Metazoan Multicellularity.
A. de Mendoza, A. Sebe-Pedros, and I. Ruiz-Trillo (2014)
Genome Biol Evol 6, 606-619
   Abstract »    Full Text »    PDF »
Earliest Holozoan Expansion of Phosphotyrosine Signaling.
H. Suga, G. Torruella, G. Burger, M. W. Brown, and I. Ruiz-Trillo (2014)
Mol. Biol. Evol. 31, 517-528
   Abstract »    Full Text »    PDF »
Evolution and Classification of Myosins, a Paneukaryotic Whole-Genome Approach.
A. Sebe-Pedros, X. Grau-Bove, T. A. Richards, and I. Ruiz-Trillo (2014)
Genome Biol Evol 6, 290-305
   Abstract »    Full Text »    PDF »
Kinannote, a computer program to identify and classify members of the eukaryotic protein kinase superfamily.
J. M. Goldberg, A. D. Griggs, J. L. Smith, B. J. Haas, J. R. Wortman, and Q. Zeng (2013)
Bioinformatics 29, 2387-2394
   Abstract »    Full Text »    PDF »
Mutational properties of amino acid residues: implications for evolvability of phosphorylatable residues.
P. Creixell, E. M. Schoof, C. S. H. Tan, and R. Linding (2012)
Phil Trans R Soc B 367, 2584-2593
   Abstract »    Full Text »    PDF »
Evolution of SH2 domains and phosphotyrosine signalling networks.
B. A. Liu and P. D. Nash (2012)
Phil Trans R Soc B 367, 2556-2573
   Abstract »    Full Text »    PDF »
The human phosphotyrosine signaling network: Evolution and hotspots of hijacking in cancer.
L. Li, C. Tibiche, C. Fu, T. Kaneko, M. F. Moran, M. R. Schiller, S. S.-C. Li, and E. Wang (2012)
Genome Res. 22, 1222-1230
   Abstract »    Full Text »    PDF »
Genomic Survey of Premetazoans Shows Deep Conservation of Cytoplasmic Tyrosine Kinases and Multiple Radiations of Receptor Tyrosine Kinases.
H. Suga, M. Dacre, A. de Mendoza, K. Shalchian-Tabrizi, G. Manning, and I. Ruiz-Trillo (2012)
Science Signaling 5, ra35
   Abstract »    Full Text »    PDF »
An Inside Job: Hacking into Janus Kinase/Signal Transducer and Activator of Transcription Signaling Cascades by the Intracellular Protozoan Toxoplasma gondii.
E. Y. Denkers, D. J. Bzik, B. A. Fox, and B. A. Butcher (2012)
Infect. Immun. 80, 476-482
   Abstract »    Full Text »    PDF »
The SH2 Domain-Containing Proteins in 21 Species Establish the Provenance and Scope of Phosphotyrosine Signaling in Eukaryotes.
B. A. Liu, E. Shah, K. Jablonowski, A. Stergachis, B. Engelmann, and P. D. Nash (2011)
Science Signaling 4, ra83
   Abstract »    Full Text »    PDF »
Comment on "Positive Selection of Tyrosine Loss in Metazoan Evolution".
Z. Su, W. Huang, and X. Gu (2011)
Science 332, 917
   Abstract »    Full Text »    PDF »
Response to Comment on "Positive Selection of Tyrosine Loss in Metazoan Evolution".
C. S. H. Tan, E. M. Schoof, P. Creixell, A. Pasculescu, W. A. Lim, T. Pawson, G. D. Bader, and R. Linding (2011)
Science 332, 917
   Abstract »    Full Text »    PDF »
Unexpected Repertoire of Metazoan Transcription Factors in the Unicellular Holozoan Capsaspora owczarzaki.
A. Sebe-Pedros, A. de Mendoza, B. F. Lang, B. M. Degnan, and I. Ruiz-Trillo (2011)
Mol. Biol. Evol. 28, 1241-1254
   Abstract »    Full Text »    PDF »
Tandem BRCT Domains: DNA's Praetorian Guard.
R. D. Mesquita, N. T. Woods, E. S. Seabra-Junior, and A. N. A. Monteiro (2010)
Genes & Cancer 1, 1140-1146
   Abstract »    Full Text »    PDF »
SH2 Domains Recognize Contextual Peptide Sequence Information to Determine Selectivity.
B. A. Liu, K. Jablonowski, E. E. Shah, B. W. Engelmann, R. B. Jones, and P. D. Nash (2010)
Mol. Cell. Proteomics 9, 2391-2404
   Abstract »    Full Text »    PDF »
Ancient origin of the integrin-mediated adhesion and signaling machinery.
A. Sebe-Pedros, A. J. Roger, F. B. Lang, N. King, and I. Ruiz-Trillo (2010)
PNAS 107, 10142-10147
   Abstract »    Full Text »    PDF »
Evolution: like any other science it is predictable.
S. Conway Morris (2010)
Phil Trans R Soc B 365, 133-145
   Abstract »    Full Text »    PDF »
Eukaryotic Protein Domains as Functional Units of Cellular Evolution.
J. Jin, X. Xie, C. Chen, J. G. Park, C. Stark, D. A. James, M. Olhovsky, R. Linding, Y. Mao, and T. Pawson (2009)
Science Signaling 2, ra76
   Abstract »    Full Text »    PDF »
The Dawn of Developmental Signaling in the Metazoa.
G.S. Richards and B.M. Degnan (2009)
Cold Spring Harb Symp Quant Biol
   Abstract »    PDF »
Positive Selection of Tyrosine Loss in Metazoan Evolution.
C. S. H. Tan, A. Pasculescu, W. A. Lim, T. Pawson, G. D. Bader, and R. Linding (2009)
Science 325, 1686-1688
   Abstract »    Full Text »    PDF »
Evolutionary roots of iodine and thyroid hormones in cell-cell signaling.
S. J. Crockford (2009)
Integr. Comp. Biol. 49, 155-166
   Abstract »    Full Text »    PDF »
2008: Signaling Breakthroughs of the Year.
E. M. Adler (2009)
Science Signaling 2, eg1
   Abstract »    Full Text »    PDF »
Clues to the evolution of complex signaling machinery.
B. J. Mayer (2008)
PNAS 105, 9453-9454
   Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882