The Eph family of receptor tyrosine kinases and their membrane-bound ligands, the ephrins, have been implicated in regulating cell adhesion and migration during development by mediating cell-to-cell signaling events. We have shown that ectopic expression of XLerk, a Xenopus homologue of the murine Lerk-2 (ephrin-B1) transmembrane ligand, causes dissociation of Xenopus embryonic blastomeres by the mid-blastula transition. Moreover, a mutant which lacks the extracellular receptor binding domain can induce this phenotype. Basic fibroblast growth factor (bFGF), but not activin, can rescue both the loss of cell adhesion and mesoderm induction in ectodermal explants expressing XLerk. Genetic evidence from other laboratories suggests that ephrins may transduce signals, and become tyrosine phosphorylated during embryogenesis. However, the induction and functional significance of ephrin phosphorylation is not yet clear. Our studies reveal that an activated fibroblast growth factor (FGF) receptor associates with and phosphorylates ephrinB1 on tyrosine. Moreover, this phosphorylation is a regulatory event that alters ephrinB1 function in cell adhesion. In addition, we identify a region in the cytoplasmic tail of ephrinB1 that is critical for direct interaction with the FGF receptor. We also find that FGF treatment of neural tissue expressing ephrinB1 reduces cell binding to a cognate Eph receptor substrate. This is the first demonstration of direct communication between the FGF receptor family and the Eph ligand family and implicates crosstalk between these two cell surface molecules in regulating cell adhesion.My laboratory is also currently studying a novel homeobox protein, Meis 1, that has some homology to the human oncogene product, pbx-1, discovered in human pre- B cell leukemias. The Xenopus homologue of Meis1 (Xmeis1) was isolated and its expression was predominantly found in tissues of neural cell fate, such as midbrain, hindbrain, as well as the neural crest derived branchial arches. Misexpression of Xmeis1b, an alternatively spliced form of Xmeis1a, induced tumor-like accumulations of ectopic pigmented cells in ventral regions of the developing embryo. RT-PCR analysis revealed that Xmeis1b induced ectopic expression of N-tubulin a neuronal marker, Xap2, a neural crest cell marker, and Krox-20, a hindbrain marker encoding a factor that regulates neural crest gene expression. Furthermore, in ectodermal explants, Xmeis1b induced neuronal and neural crest cell markers in the absence of any mesoderm, indicating that Xmeis1b is involved in the neural cell fate specification during embryogenesis.This project has been transferred from BRL to RCGL. - Development, EPH, Receptor Tyrosine Kinase, Xenopus, Homeobox Genes, XMeis,

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010006-04
Application #
6289281
Study Section
Special Emphasis Panel (RCGL)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Lee, Hyun-Shik; Nishanian, Tagvor G; Mood, Kathleen et al. (2008) EphrinB1 controls cell-cell junctions through the Par polarity complex. Nat Cell Biol 10:979-86
Bong, Yong-Sik; Lee, Hyun-Shik; Carim-Todd, Laura et al. (2007) ephrinB1 signals from the cell surface to the nucleus by recruitment of STAT3. Proc Natl Acad Sci U S A 104:17305-10
Lee, Hyun-Shik; Bong, Yong-Sik; Moore, Kathryn B et al. (2006) Dishevelled mediates ephrinB1 signalling in the eye field through the planar cell polarity pathway. Nat Cell Biol 8:55-63
Ishimura, A; Lee, H-S; Bong, Y-S et al. (2006) Oncogenic Met receptor induces ectopic structures in Xenopus embryos. Oncogene 25:4286-99
Mood, Kathleen; Saucier, Caroline; Bong, Yong-Sik et al. (2006) Gab1 is required for cell cycle transition, cell proliferation, and transformation induced by an oncogenic met receptor. Mol Biol Cell 17:3717-28
Mood, Kathleen; Saucier, Caroline; Ishimura, Akihiko et al. (2006) Oncogenic Met receptor induces cell-cycle progression in Xenopus oocytes independent of direct Grb2 and Shc binding or Mos synthesis, but requires phosphatidylinositol 3-kinase and Raf signaling. J Cell Physiol 207:271-85
Murakami, Monica S; Moody, Sally A; Daar, Ira O et al. (2004) Morphogenesis during Xenopus gastrulation requires Wee1-mediated inhibition of cell proliferation. Development 131:571-80
Mood, Kathleen; Bong, Yong-Sik; Lee, Hyun-Shik et al. (2004) Contribution of JNK, Mek, Mos and PI-3K signaling to GVBD in Xenopus oocytes. Cell Signal 16:631-42
Park, Eui Kyun; Warner, Neil; Bong, Yong-Sik et al. (2004) Ectopic EphA4 receptor induces posterior protrusions via FGF signaling in Xenopus embryos. Mol Biol Cell 15:1647-55
Bong, Yong-Sik; Park, Yeon-Hwa; Lee, Hyun-Shik et al. (2004) Tyr-298 in ephrinB1 is critical for an interaction with the Grb4 adaptor protein. Biochem J 377:499-507

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