STRUCTURAL DETERMINANTS OF SHP-2 FUNCTION AND SPECIFICITY IN XENOPUS MESODERM INDUCTION

SHP-2 is a positive component of many receptor tyrosine kinase signali ng pathways. The related proteintyrosine phosphatase (PTP) SHP-1 usual ly acts as a negative regulator. The precise domains utilized by SHP-2 to transmit positive signals in vivo and the basis for specificity be tween SHP-1 and SHP-2 are not clear. In Xenopus, SHP-2 is required for mesoderm induction and completion of gastrulation. We investigated th e effects of SHP-2 mutants and SHP-2/SHP-1 chimeras on basic fibroblas t growth factor-induced mesoderm induction. Both SH2 domains and the P TP domain are required for normal SHP-2 function in this pathway. The N-terminal SH2 domain is absolutely required, whereas the C-terminal S H2 contributes to wild-type function. The C-terminal tyrosyl phosphory lation sites and proline-rich region are dispensable, arguing against adapter models of SHP-2 function. Although the SH2 domains contribute to SHP-2 specificity, studies of SHP chimeras reveal that substantial specificity resides in the PTP domain. Thus, PTP domains exhibit biolo gically relevant specificity in vivo, and noncatalytic and catalytic d omains of PTPs contribute to specificity in a combinatorial fashion.