The role of the protein tyrosine phosphatase SHP-2 inbFGF signaling in Xenopus animal caps.

摘要

Protein tyrosine phosphorylation is well recognized as a major signaling mechanism for control of growth, differentiation, and movement. Coordination of these processes is essential for such complex events as embryonic development. Protein tyrosine kinases (PTKs) have been implicated in many signaling pathways required for normal embryonic development. More recently, it has become clear that protein tyrosine phosphatase (PTP) function also is crucial in developmental events. The roles of the SH2 domain-containing PTPs SHP-1 and SHP-2 in developmental signaling pathways have been well studied. The motheaten mouse, which lacks SHP-1, has multiple hematopoeitic abnormalities. SHP-1 functions predominantly as a negative regulator of hematopoeitic signaling pathways. In contrast, SHP-2 functions as a positive signaling component of multiple developmental pathways in Drosophila, C. elegans, Xenopus, and mice.;This thesis focuses on the role of SHP-2 during bFGF signaling in Xenopus animal caps. The studies presented herein contribute three major findings to our understanding of SHP-2 signaling pathways and basic mechanisms of embryonic development. First, the functional domains of SHP-2 required for bFGF signaling in animal caps were mapped. Both SH2 domains are required, but, consistent with its role in PTP activation, the NSH2 is more critical. We were unable to find a role for either the C-terminal tyrosine sites or the proline-rich region using this system, but these overexpression experiments cannot exclude a modulatory or negative regulatory role for these sites. The second, striking result was the finding that the PTP domain of SHP-2 is a major determinant of specificity in vivo. This result suggests that substrate recognition is intrinsic to the PTP domain and will enable us to further define PTP domain residues involved in recognition of specific SWP-2 targets. Finally, SHP-2 predominantly activates a pathway leading to morphogenetic movements in animal caps, and, to a lesser degree, contributes to expression of mesodermal genes. The activated SHP-2 mutants separate mesoderm induction from gastrulation movements and provide an experimental mechanism for elucidating pathways leading to cell movement in animal caps, and, by inference in embryos.