Switching Phosphatase Inhibitor to Kinase Inhibitor

Science's STKE  14 Dec 1999:
Vol. 1999, Issue 12, pp. tw4
DOI: 10.1126/stke.1999.12.tw4

The protein DARPP-32 (for dopamine and cyclic AMP-regulated phosphoprotein) participates in dopaminergic signaling in neurons. When DARPP-32 becomes phosphorylated on Thr34 by cAMP-dependent protein kinase (PKA), it becomes an inhibitor of protein phosphatase1 (PP1). Bibb et al. now report that DARPP-32 appears to be part of a more complicated regulatory loop. Phosphorylation of DARPP-32 at a different threonine residue (Thr75) by another kinase --cyclin-dependent kinase 5 (Cdk5) -- causes DARPP-32 to become an inhibitor of PKA. This should reduce phosphorylation of DARPP-32 by PKA and thus relieve DARPP-32's inhibition of PP1 activity. This reciprocal regulation of PKA and PP1 activities would synergistically affect phosphorylation of substrates that are targets for both of these enzymes. Such regulation through Cdk5 appears to be important in vivo: Inhibition of Cdk5 enhanced dopamine signaling in striatal slices from wild-type mice, but not that in slices from animals lacking DARPP-32. Modulation of DARPP-32's inhibitory activity through such phosphorylation-dependent switching may be an important mechanism for interaction of neuronal signaling pathways.

Bibb, J.A., Snyder, G.L., Nishi, A., Zhen, Y., Meijer, L., Fienberg, A.A., Tsai, L.-H., Kwon, Y.T., Girault, J.-A., Czernik, A.J., Huganir, R.L., Hemmings Jr., H.C., Nairn, A.C., and Greengard, P. (1999) Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons. Nature 402: 669-671. [Online Journal]