The investigators have isolated and cloned a novel receptor tyrosine kinase expressed in Monocytes as well as Epithelial and Reproductive tissues, hence the name Mer. The sequencing of the human and mouse cDNAs have shown Mer to be one of 4 members of the axl receptor family, a family characterized by extracellular Ig- and Fibronectin-like domains. Mer is highly related to a newly discovered transforming chicken retroviral oncogene, v-eyk, and is either the mammalian homologue of v-eyk or its closest relative. Mer's closest human homologue, the receptor axl, is expressed in myeloid but not lymphoid leukemias and can, like v-eyk, transform fibroblasts when overexpressed. To obtain clues to the function of Mer, they have studied its expression pattern in normal and neoplastic cells. Mer is one of only a few receptor tyrosine kinases expressed widely in epithelial cell types as well as in hematopoietic lineages. While Mer is expressed in all monocytes and in bone marrow cells, transcripts are not detected in normal lymphocytes or in proliferating, activated T cells. However Mer is expressed in neoplastic T cell lines and in up to 2/3 of acute T cell leukemias obtained from untreated patients. Thus, in contrast to axl, Mer is ectopically expressed in human lymphoid neoplasia. In the mouse, Mer is widely expressed and can be detected in the very early, undifferentiated stages of the embryo (morula and blastocyst). In the proposed experiments they will assess the function of the newest member of a new class of receptor tyrosine kinases; a family in which two of 4 members have already been shown to transform cells.
Aim 1 will complete studies of Mer expression.
Aim 2 will ascribe biologic function to the Mer kinase. They have created a chimeric receptor combining the EGF receptor extracellular and transmembrane domains with the tyrosine kinase - containing cytoplasmic domain of Mer; when expressed in cells this fusion protein is an EGF activated Mer tyrosine kinase. They will use selected tissue culture models, the chiMera, and a full length Mer cDNA expression vector to study the giologic function and transforming capacity of Mer. The Mer kinase will be activated either by ligand (the chiMera) or by overexpression (the full length Mer cDNA).
Aim 3 will study Mer signal transduction using cells stably transfected with the Mer chiMera to determine whether the axl/Mer receptor family has unique or selective down stream signaling functions that differ from those of the well studied EGF receptor.
Aim 4 will approach Mer function in vivo by using gene targeted mice. They have targeted ES cells and made heterozygote Mer kinase knockout mice. Homozygous mice should provide insight into the importance and selective function of Mer. Strategies are proposed to advance these studies if the Mer knockout proves to be embryonic lethal.
| Graham, Douglas K; Salzberg, Dana B; Kurtzberg, Joanne et al. (2006) Ectopic expression of the proto-oncogene Mer in pediatric T-cell acute lymphoblastic leukemia. Clin Cancer Res 12:2662-9 |
| Guttridge, Katherine L; Luft, J Christopher; Dawson, Thomas L et al. (2002) Mer receptor tyrosine kinase signaling: prevention of apoptosis and alteration of cytoskeletal architecture without stimulation or proliferation. J Biol Chem 277:24057-66 |
| Camenisch, T D; Koller, B H; Earp, H S et al. (1999) A novel receptor tyrosine kinase, Mer, inhibits TNF-alpha production and lipopolysaccharide-induced endotoxic shock. J Immunol 162:3498-503 |
