Inhibitor-1 (l-1) and DARPP-32, which share sequence homology in the amino-terminal region, are endogenous regulators of protein phosphatase-1 (PP-1). l-1 is expressed in a wide variety of tissues, while DARPP-32 is highly enriched in caudate nucleus and striatum in mammalian brain. When a homologous site in each protein is phosphorylated by cAMP-dependent protein kinase, l-1 and DARPP-32 are converted to potent inhibitors of PP-1. Additional phosphorylation sites in DARPP-32 can regulate the functional state of DARPP-32. Phosphorylation at Ser-102 by casein kinase II regulates the ability of DARPP-32 to serve as a substrate for cAMP-dependent protein kinase. Phosphorylation of Ser-137 by casein kinase I inhibits the dephosphorylation of Thr-34 by the calcium/calmodulin-dependent protein phosphatase, calcineurin. Thus, a complex regulatory pathway for the control of PP-1 activity converges on a single molecule, DARPP-32, by way of multi-site phosphorylation by distinct cla sses of protein kinase. As described above for synapsin II, we have recently found that DARPP-32 and l-1 can serve as in vitro substrates for MAP kinase, cdc2 kinase and cdk5. We wish to identify these novel phosphorylation sites, determine the functional effects of these specific phosphorylations on phosphatase inhibition, and then prepare phospho-specific antibodies to these sites in order to study the physiological regulation of the state of phosphorylation.
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