The tyrosine phosphatase Shp2 (PTPN11) directs Neuregulin-1/ErbB signaling throughout Schwann cell development
- Katja S. Grossmanna,b,
- Hagen Wendea,
- Florian E. Paulc,
- Cyril Chereta,
- Alistair N. Garratta,
- Sandra Zurborgd,
- Konstantin Feinberge,
- Daniel Besserb,
- Herbert Schulzc,
- Elior Pelese,
- Matthias Selbachc,
- Walter Birchmeierb,1 and
- Carmen Birchmeiera,2,1
- aNeuroscience Department,
- bDepartment of Cancer Research,
- cDepartment of Cardiovascular Research, Max-Delbrück-Centrum for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany;
- dEMBL Monterotondo, Adriano Buzzati-Traverso Campus, Via Ramarini 32, 00016 Monterotondo, Italy; and
- eWeizmann Institute of Science, PO Box 26, Rehovot 76100, Israel
-
Edited by Joseph Schlessinger, Yale University School of Medicine, New Haven, CT, and approved July 24, 2009
-
↵1W.B. and C.B. contributed equally to this work. (received for review April 20, 2009)
Abstract
The nonreceptor tyrosine phosphatase Shp2 (PTPN11) has been implicated in tyrosine kinase, cytokine, and integrin receptor signaling. We show here that conditional mutation of Shp2 in neural crest cells and in myelinating Schwann cells resulted in deficits in glial development that are remarkably similar to those observed in mice mutant for Neuregulin-1 (Nrg1) or the Nrg1 receptors, ErbB2 and ErbB3. In cultured Shp2 mutant Schwann cells, Nrg1-evoked cellular responses like proliferation and migration were virtually abolished, and Nrg1-dependent intracellular signaling was altered. Pharmacological inhibition of Src family kinases mimicked all cellular and biochemical effects of the Shp2 mutation, implicating Src as a primary Shp2 target during Nrg1 signaling. Together, our genetic and biochemical analyses demonstrate that Shp2 is an essential component in the transduction of Nrg1/ErbB signals.
Footnotes
- 2To whom correspondence should be addressed. E-mail: cbirch{at}mdc-berlin.de
-
Author contributions: K.S.G., A.N.G., W.B., and C.B. designed research; K.S.G., H.W., F.E.P., C.C., and S.Z. performed research; K.F. and E.P. contributed new reagents/analytic tools; D.B., H.S., and M.S. analyzed data; and K.S.G., W.B., and C.B. wrote the paper.
-
The authors declare no conflict of interest.
-
This article is a PNAS Direct Submission.
-
This article contains supporting information online at www.pnas.org/cgi/content/full/0904336106/DCSupplemental.
