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Science 317 (5835): 251-256

Copyright © 2007 by the American Association for the Advancement of Science

Combinatorial ShcA Docking Interactions Support Diversity in Tissue Morphogenesis

W. Rod Hardy,1,2 Lingying Li,3 Zhi Wang,3 Jiri Sedy,4 James Fawcett,1 Eric Frank,3 Jan Kucera,5,6* Tony Pawson1,2*

Abstract: Changes in protein-protein interactions may allow polypeptides to perform unexpected regulatory functions. Mammalian ShcA docking proteins have amino-terminal phosphotyrosine (pTyr) binding (PTB) and carboxyl-terminal Src homology 2 (SH2) domains, which recognize specific pTyr sites on activated receptors, and a central region with two phosphorylated tyrosine-X-asparagine (pYXN) motifs (where X represents any amino acid) that each bind the growth factor receptor–bound protein 2 (Grb2) adaptor. Phylogenetic analysis indicates that ShcA may signal through both pYXN-dependent and -independent pathways. We show that, in mice, cardiomyocyte-expressed ShcA directs mid-gestational heart development by a PTB-dependent mechanism that does not require the pYXN motifs. In contrast, the pYXN motifs are required with PTB and SH2 domains in the same ShcA molecule for the formation of muscle spindles, skeletal muscle sensory organs that regulate motor behavior. Thus, combinatorial differences in ShcA docking interactions may yield multiple signaling mechanisms to support diversity in tissue morphogenesis.

1 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
2 Department of Molecular and Medical Genetics, 4388 Medical Sciences Building, 1 King's College Circle, University of Toronto, Ontario M5S 1A8, Canada.
3 Department of Physiology, Tufts University School of Medicine, Boston, MA 02111, USA.
4 Institute of Anatomy, Charles University, First Faculty of Medicine, Prague 12000, Czech Republic.
5 Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA.
6 Veterans Administration Medical Center, Boston, MA 02130, USA.

* To whom correspondence should be addressed. E-mail: pawson{at} (T.P.); jfkucera{at} (J.K.)

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