Functions of protein tyrosine phosphatases in neuronal signaling and development: insights from RPTPα

Reversible and specific phosphorylation of proteins on tyrosine is a major mechanism of intracellular signal transduction, that is particularly important in multicellular organisms. The number of protein tyrosine phosphatases (PTPs) in the genome rivals that of tyrosine kinases. Members of the PTP superfamily are increasingly found to be medically relevant e.g. as tumor suppressors, oncogenes, and mediators of host-pathogen interactions. This indicates that PTPs perform critical regulatory roles, and may constitute attractive pharmacological targets; yet, they remain much less well understood than the tyrosine kinases.

We will illustrate some of the complex biological functions of PTPs based mostly on our studies with a ubiquitous PTP, RPTPα. RPTPα is a physiological and endogenous activator of tyrosine kinases of the Src-family (SFKs), by dephosphorylating the C-terminal inhibitory site in these kinases, and thus controls signaling by integrins. Interestingly, RPTPα can also control signaling by growth factors in both positive and negative ways, through mechanisms that remain less well understood. Taken together, these findings illustrate how even a single PTP simultaneously exerts multiple effects on cellular signaling pathways. Tyrosine phosphorylation of RPTPα itself plays a key role in controlling these multiple functions. Analysis of RPTPα-deficient mice reveals how these molecular functions of RPTPα have important consequences for nervous system development (radial neuronal migration, and neurite outgrowth) and function (synaptic plasticity).