Signalling Kinetics

Modulation of signalling kinetics, namely the duration and/or strength of activation, elicits distinct cellular responses. The classic example of this mechanism can be found in the neuronal cell line PC12 (pheochromocytoma). PC12 cells proliferate in response to EGF, while nerve growth factor (NGF) induces differentiation (Marshall 1995). Although very different, both sequelae are mediated via the MEK/ERK pathway (Tan and Kim 1999). Further investigation has shown that EGF-dependant MAPK signalling is transient, lasting minutes, while NGF-dependant signalling is sustained, continuing for hours (Marshall 1995). Through stimulation of the TrkA receptor, NGF activates the MAPK cascade by two mechanisms, the Grb2/SOS pathway and the Rap1 pathway (York et al. 1998). Rap1, a member of the Ras family, modulates integrin-mediated cell adhesion and cadherin-mediated cell junction formation by regulating several effectors, including B-Raf (Bos 2005). In response to NGF, Grb2/SOS produces a transient signal due to a negative feedback mechanism, while Rap 1-dependant signalling produces sustained activation of B-Raf. However, EGF can activate only the Grb2/SOS pathway, resulting in a transient activation of MAPK (York et al. 1998). Consequently, these two growth factors induce distinct kinetics of MAPK signalling, culminating in disparate cellular outcomes. Despite the progress in our understanding, why or how these differences in signalling kinetics bring about such divergent cell behaviour is not known.

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