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J. Biol. Chem., Vol. 281, Issue 10, 6785-6792, March 10, 2006

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PTPN11 (Shp2) Mutations in LEOPARD Syndrome Have Dominant Negative, Not Activating, Effects^*

Maria I. Kontaridis¹, Kenneth D. Swanson, Frank S. David², David Barford^¶, and Benjamin G. Neel³

From the Cancer Biology Program, Division of Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, and ^¶Section of Structural Biology, Institute of Cancer Research, Chester Beatty Labs, 237 Fulham Rd., London, SW3 6JB, United Kingdom

Multiple lentigines/LEOPARD syndrome (LS) is a rare, autosomal dominant disorder characterized by Lentigines, Electrocardiogram abnormalities, Ocular hypertelorism, Pulmonic valvular stenosis, Abnormalities of genitalia, Retardation of growth, and Deafness. Like the more common Noonan syndrome (NS), LS is caused by germ line missense mutations in PTPN11, encoding the protein-tyrosine phosphatase Shp2. Enzymologic, structural, cell biological, and mouse genetic studies indicate that NS is caused by gain-of-function PTPN11 mutations. Because NS and LS share several features, LS has been viewed as an NS variant. We examined a panel of LS mutants, including the two most common alleles. Surprisingly, we found that in marked contrast to NS, LS mutants are catalytically defective and act as dominant negative mutations that interfere with growth factor/Erk-mitogen-activated protein kinasemediated signaling. Molecular modeling and biochemical studies suggest that LS mutations contort the Shp2 catalytic domain and result in open, inactive forms of Shp2. Our results establish that the pathogenesis of LS and NS is distinct and suggest that these disorders should be distinguished by mutational analysis rather than clinical presentation.

Received for publication, October 16, 2005

^* This work was supported in part by National Institutes of Health Grant R37 49152 (to B. G. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains 20 supplemental equations.

¹ Supported by institutional National Research Service Award T32-CA081156 and by a Postdoctoral Fellowship from the American Heart Association.

² Supported by institutional National Research Service Award T32-HL07627.

³ To whom correspondence should be addressed: Cancer Biology Program, Dept. of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215. Tel.: 617-667-2823; Fax: 617-667-0610; E-mail: bneel{at}bidmc.harvard.edu.

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