DARPP-32: from neurotransmission to cancer

Abstract

Dopamine and cAMP-regulated phosphoprotein Mr 32,000 (DARPP-32), also known as phosphoprotein phosphatase-1 regulatory subunit 1B (PPP1R1B), was initially discovered as a substrate of dopamine-activated protein kinase A (PKA) in the neostriatum in the brain. While phosphorylation at Thr-34 by PKA converts DARPP-32 into a potent inhibitor of protein phosphatase 1 (PP1), phosphorylation at Thr-75 transforms DARPP-32 into an inhibitor of PKA. Through regulation of DARPP-32 phosphorylation and modulation of protein phosphatase and kinase activities, DARPP-32 plays a critical role in mediating the biochemical, electrophysiological, and behavioral effects controlled by dopamine and other neurotransmitters in response to drugs of abuse and psychostimulants. Altered expression of DARPP-32 and its truncated isoform (t-DARPP), specifically in the prefrontal cortex, has been associated with schizophrenia and bipolar disorder. Moreover, cleavage of DARPP-32 by calpain has been implicated in Alzheimer's disease. Amplification of the genomic locus of DARPP-32 at 17q12 has been described in several cancers. DARPP-32 and t-DARPP are frequently overexpressed at the mRNA and protein levels in adenocarcinomas of the breast, prostate, colon, and stomach. Several studies demonstrated the pro-survival, pro-invasion, and pro-angiogenic functions of DARPP-32 in cancer. Overexpression of DARPP-32 and t-DARPP also promotes chemotherapeutic drug resistance and cell proliferation in gastric and breast cancers through regulation of pro-oncogenic signal transduction pathways. The expansion of DARPP-32 research from neurotransmission to cancer underscores the broad scope and implication of this protein in disparate human diseases.

Keywords: DARPP-32; PPP1R1B; cancer; neurotransmission; t-DARPP.

Figure 1. Regulation of PP1 and PKA by multisite phosphorylation of DARPP-32

Phosphorylation of DARPP-32 by protein kinases is indicated by green arrows, whereas dephosphorylation of DARPP-32 by protein phosphatases is depicted by red arrows. Phosphorylation of DARPP-32 at Thr-34 by PKA converts it into a potent inhibitor of PP1. However, phosphorylation of DARPP-32 at Thr-75 by CDK5 transforms it into an inhibitor of PKA. Dephosphorylation of Ser-137 by PP2C facilitates dephosphorylation of Thr-34 by PP2B, thereby removing the PKA-induced inhibition of PP1. Phosphorylation of Ser-45 and Ser-102 has no effect on the potency of DARPP-32 as an inhibitor of PP1. The scheme is based on [29].

Figure 2. Genomic structure of DARPP-32 and its truncated isoform, t-DARPP

DARPP-32 and t-DARPP share identical sequence from exon 2 to the 3′ end. Of note, exon 1 of t-DARPP is spliced from the intron 1 of DARPP-32. DARPP-32 (1,983 bp) encodes 204 amino acids, whereas t-DARPP (1,502 bp) encodes 168-amino-acids protein. The major phosphorylation sites on the proteins are indicated by T, threonine, and S, serine. DARPP-32 contains five phosphorylation sites at T34, S45, T75, S102, and S137, whereas t-DARPP lacks the T34 phosphorylation site of DARPP-32. The scheme is based on [39].

Figure 3. DARPP-32-regulated cancer signaling pathways

Based on the published data, DARPP-32 constitutes a signaling hub that regulates multiple pathways important for carcinogenesis and tumor progression. Activation is depicted by green arrows and negative regulation is indicated by red T-lines.

Figure 4. DARPP-32 regulates major hallmarks of tumorigenesis

Accumulating published reports strongly suggest that DARPP-32 promotes cancer cell proliferation, survival, invasion and metastasis, and angiogenesis. Each DARPP-32-mediated function involves regulation of corresponding signaling pathways depicted in the schematic diagram.