ECK receptor protein-tyrosine kinase: signal transduction and functions

Eck belongs to the Eph subfamily of receptor protein-tyrosine kinases (RPTKs) which is the largest subfamily of RPTKs. We have previously shown that B61, the ligand for the Eck RPTK, mediates the angiogenic effects of tumor necrosis factor-α (TNF-α). In order to elucidate the signaling mechanisms utilized by the Eck RPTK, a yeast two-hybrid screen was employed. One of the molecules isolated from this screen was the p85 subunit of PI 3-kinase which contains two SH2 domains. The p85 subunit bound to activated Eck in vivo, and in vitro binding studies suggested that this binding occurred via its C-terminal SH2 domain. Activation of Eck by its ligand, B61, resulted in stimulation of PI 3- kinase activity. Additionally, a novel molecule containing Src-like SH3 and SH2 domains was isolated in this screen. We have designated this molecule Src-like adapter protein (SLAP) based on its striking similarity to the Src family of non-receptor tyrosine kinases and the absence of a tyrosine kinase catalytic domain. SLAP binds to Eck as well as other RPTKs including epidermal growth factor receptor and platelet derived growth factor receptor through its SH2 domain. Unlike other adapter proteins such as Grb2 and Shc, overexpression of SLAP induces growth arrest in fibroblasts.