Oncogenic Met receptor induces ectopic structures in Xenopus embryos

Abstract

When aberrantly expressed or activated, the Met receptor tyrosine kinase is involved in tumor invasiveness and metastasis. In this study, we have used the Xenopus embryonic system to define the role of various Met proximal-binding partners and downstream signaling pathways in regulating an induced morphogenetic event. We show that expression of an oncogenic derivative of the Met receptor (Tpr-Met) induces ectopic morphogenetic structures during Xenopus embryogenesis. Using variant forms of Tpr-Met that are engineered to recruit a specific signaling molecule of choice, we demonstrate that the sole recruitment of either the Grb2 or the Shc adaptor protein is sufficient to induce ectopic structures and anterior reduction, while the recruitment of PI-3Kinase (PI-3K) is necessary but not sufficient for this effect. In contrast, the recruitment of PLCc can initiate the induction, but fails to maintain or elongate supernumerary structures. Finally, evidence indicates that the Ras/Raf/MAPK pathway is necessary, but not sufficient to induce these structures. This study also emphasizes the importance of examining signaling molecules in the regulatory context that is provided by receptor/effector interactions when assessing a role in cell growth and differentiation.

Reversible optogenetic control of kinase activity during differentiation and embryonic development

“…As a potent mesoderm inducer, overexpressed Raf1 can induce ectopic mesoderm during germ layer specification, which occurs during blastula and early gastrula stages, and result in the formation of ectopic tail-like structures later on. Alternatively, overexpressed Raf1 may trigger an epithelialmesenchymal transition (EMT)-like event after germ layer specification is completed, and directly transform ectoderm to neural and mesoderm lineages, followed by proliferation and extension of these structures (Ishimura et al, 2006). Although these two mechanisms are not mutually exclusive, it was very difficult for Ishimura et al to determine whether Raf1 could function through the second mechanism.…”

Light-mediated Reversible Modulation of the Mitogen-activated Protein Kinase Pathway during Cell Differentiation and <em>Xenopus</em> Embryonic Development

“…Alternatively, overexpressed Raf1 may trigger an epithelial-mesenchymal transition (EMT)-like event after germ-layer specification has completed and can directly transform ectoderm to neural and mesoderm lineages. This is followed by the proliferation and extension of these structures 43 . In these experiments, RNAs encoding MET receptor, Ras, and Raf1 were injected into embryos at the two-cell stage.…”

“…Previous work discovered that the activation of the Raf/MEK/ERK pathway leads to a cell fate change, resulting in the formation of an ectopic tail-like structure at the tailbud stage 43 . As a potent mesoderm inducer, overexpressed Raf1 can induce ectopic mesoderm during germ-layer specification, which occurs during the blastula and early gastrula stages, and result in the formation of ectopic tail-like structures later on.…”

Met receptor-induced Grb2 or Shc signals both promote transformation of intestinal epithelial cells, albeit they are required for distinct oncogenic functions

“…Interaction of the C-terminal Grb2 SH3 domain with Grb2-associated binding (Gab) scaffold protein family members couples RTKs to the PI3K/Akt survival pathway and to the Ras/MAPK cascade by an alternate route [ 14 ]. As such, the recruitment of Grb2 or Shc to RTKs has been shown to promote biologically redundant processes [ 7 , 8 , 15 , 16 ]. However, Shc proteins interact with diverse signaling molecules in addition to Grb2, thereby engage Grb2-independent pathways and biological functions [ 9 - 13 , 17 - 19 ].…”