Quantification of short term signaling by the epidermal growth factor receptor

During the past decade, our knowledge of molecular mechanisms involved in g rowth factor signaling has proliferated almost explosively. However, the ki netics and control of information transfer through signaling networks remai n poorly understood. This paper combines experimental kinetic analysis and computational modeling of the short term pattern of cellular responses to e pidermal growth factor (EGF) in isolated hepatocytes. The experimental data show transient tyrosine phosphorylation of the EGF receptor (EGFR) and tra nsient or sustained response patterns in multiple signaling proteins target ed by EGFR. Transient responses exhibit pronounced maxima, reached within 1 5-30 s of EGF stimulation and followed by a decline to relatively low (quas i-steady-state) levels. In contrast to earlier suggestions, we demonstrate that the experimentally observed transients can be accounted for without re quiring receptor-mediated activation of specific tyrosine phosphatases, fol lowing EGF stimulation. The kinetic model predicts how the cellular respons e is controlled by the relative levels and activity states of signaling pro teins and under what conditions activation patterns are transient or sustai ned. EGFR. signaling patterns appear to be robust with respect to variation s in many elemental rate constants within the range of experimentally measu red values. On the other hand, we specify which changes in the kinetic sche me, rate constants, and total amounts of molecular factors involved are inc ompatible with the experimentally observed kinetics of signal transfer. Qua ntitation of signaling network responses to growth factors allows us to ass ess how cells process information controlling their growth and differentiat ion.