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Published online 29 November 2004. doi:10.1083/jcb.200404108
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 167, Number 5, 945-952
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Article

 The neuronal scaffold protein Shank3 mediates signaling and biological function of the receptor tyrosine kinase Ret in epithelial cells

Gunnar Schuetz1, Marta Rosário1, Jan Grimm1, Tobias M. Boeckers2, Eckart D. Gundelfinger3, and Walter Birchmeier1

1 Max-Delbrück-Center for Molecular Medicine, 13092 Berlin, Germany
2 Department of Anatomy and Cell Biology, University of Ulm, D-89081 Ulm, Germany
3 Leibniz Institute for Neurobiology, 39118 Magdeburg, Germany

Correspondence to W. Birchmeier: wbirch{at}mdc-berlin.de

Shank proteins, initially also described as ProSAP proteins, are scaffolding adaptors that have been previously shown to integrate neurotransmitter receptors into the cortical cytoskeleton at postsynaptic densities. We show here that Shank proteins are also crucial in receptor tyrosine kinase signaling. The PDZ domain–containing Shank3 protein was found to represent a novel interaction partner of the receptor tyrosine kinase Ret, which binds specifically to a PDZ-binding motif present in the Ret9 but not in the Ret51 isoform. Furthermore, we show that Ret9 but not Ret51 induces epithelial cells to form branched tubular structures in three-dimensional cultures in a Shank3-dependent manner. Ret9 but not Ret51 has been previously shown to be required for kidney development. Shank3 protein mediates sustained Erk–MAPK and PI3K signaling, which is crucial for tubule formation, through recruitment of the adaptor protein Grb2. These results demonstrate that the Shank3 adaptor protein can mediate cellular signaling, and provide a molecular mechanism for the biological divergence between the Ret9 and Ret51 isoform.

J. Grimm's present address is Rinat Neuroscience Corporation, Palo Alto, CA 94304.

Abbreviations used in this paper: GDNF, glial cell line-derived neurotrophic factor; HGF/SF, hepatocyte growth factor/scatter factor; MEN, multiple endocrine neoplasia; PI3K, phosphatidylinositol-3-kinase; sGFR{alpha}1, soluble coreceptor GFR{alpha}1.


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