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Blood, Vol. 95 No. 2 (January 15), 2000:
pp. 633-638
Transforming activity of receptor tyrosine kinase Tyro3 is
mediated, at least in part, by the PI3 kinase-signaling pathway
Zhengdao Lan,
Huiyun Wu,
Wenqing Li,
Shechao Wu,
Luo Lu,
Ming Xu, and
Wei Dai
From the Departments of Internal Medicine and Cell Biology,
Neurobiology, and Anatomy, University of Cincinnati College of
Medicine, Cincinnati, OH; and the Department of Physiology and
Biophysics, Wright State University, Dayton, OH.
Protein tyrosine phosphorylation is an integral part of
cytokine-induced proliferation and differentiation of hematopoietic cells. The authors previously reported cloning and characterization of
the receptor tyrosine kinase Tif, also termed Tyro3. Using the yeast
2-hybrid technology, they recently identified that the p85 subunit of
phosphatidylinositol 3-kinase (PI3 kinase) interacted with the
cytoplasmic domain of Tyro3. On treatment with epidermal growth factor
(EGF), NIH3T3 cells expressed EGFR/Tyro3 (a fusion receptor
with the extracellular domain from epidermal growth factor receptor and
the transmembrane and cytoplasmic domains from Tyro3), and EGFR/Tyro3
was rapidly phosphorylated on tyrosine residues. The
interaction between Tyro3 and p85 was also confirmed by glutathione S-transferase (GST) pull-down experiments. Co-immunoprecipitation followed by Western blot analysis revealed that PI3 kinase was associated with and phosphorylated by the activated Tyro3.
Tyro3-associated PI3 kinase exhibited an enhanced kinase activity. In
addition, EGF treatment of EGFR/Tyro3-expressing cells led to enhanced
phosphorylation of Akt, a downstream component of PI3 kinase. Treatment
of NIH3T3 cells expressing a full length of rat Tyro-3, but not NIH3T3
cells, with protein S also resulted in phosphorylation of Akt. Soft
agar colony assays showed that the addition of EGF to
EGFR/Tyro3-transfected cells, but not to the parental NIH3T3 cells,
resulted in a concentration-dependent increase in the formation of
anchorage-independent colonies. Tyro3-mediated transformation of NIH3T3
cells was significantly blocked by wortmannin, a PI3
kinase-specific inhibitor. Results of these combined studies strongly
suggested that the oncogenic transforming ability of Tyro3 was mediated
at least in part by the PI3 kinase pathway.
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