Reduced phosphatase activity of SHP‐2 in LEOPARD syndrome: Consequences for PI3K binding on Gab1

LEOPARD (LS) and Noonan (NS) are overlapping syndromes associated with distinct mutations of SHP‐2. Whereas NS mutations enhance SHP‐2 catalytic activity, we show that the activity of three representative LS mutants is undetectable when assayed using a standard protein tyrosine phosphatase (PTP) substrate. A different assay using a specific SHP‐2 substrate confirms their decreased PTP activity, but also reveals a significant activity of the T468M mutant. In transfected cells stimulated with epidermal growth factor, the least active LS mutants promote Gab1/PI3K binding, validating our in vitro data. LS mutants thus display a reduced PTP activity both in vitro and in transfected cells.