| Receptor tyrosine kinases of the Eph and epidermal growth factor (EGF) families are critical regulators of cell shape and motility. While Eph receptors typically transduce signals that result in cell repulsion, the EGF receptor triggers attractive responses. Here we characterize the role of two different molecules, the SHEP1 adaptor protein and the R-Ras GTPase, which act downstream of receptor tyrosine kinases to modulate cell morphology and migration. We show that SHEP1, through its association with Cas, plays a role in membrane extension and cell motility towards EGF. In addition, we present data suggesting that negative regulation of R-Ras mediates the repulsive effects of Eph receptors, including cell retraction, growth cone collapse and impaired cell migration. Although SHEP1 can bind R-Ras, the role of SHEP1 in the repulsive responses of Eph receptors remains unknown. This work delineates signal transduction mechanisms that contribute to our understanding of receptor tyrosine kinase biology. Growing evidence suggests Eph and EGF receptors also play a role in tumor progression, thus the data presented here may also aid in the design of new cancer therapies. |
