Darpp-32 and t-Darpp protein products of PPP1R1B: Old dogs with new tricks

Abstract

The PPP1R1B gene is located on chromosome 17q12 (39,626,636,626[GRCh38/hg38]), which codes for multiple transcripts and two experimentally-documented proteins Darpp-32 and t-Darpp. Darpp-32 (Dopamine and cAMP Regulated Phosphoprotein), discovered in the early 1980s, is a protein whose phosphorylation is upregulated in response to cAMP in dopamineresponsive tissues in the brain. It's phosphorylation profile modulates its ability to bind and inhibit Protein Phosphatase 1 activity, which, in turn, controls the activity of hundreds of phosphorylated proteins. PPP1R1B knockout mice exhibit subtle learning defects. In 2002, the second protein product of PPP1R1B was discovered in gastric cancers: t-Darpp (truncated Darpp-32). The start codon of t-Darpp is amino acid residue 37 of Darpp-32 and it lacks the domain responsible for modulating Protein Phosphatase 1. Aside from gastric cancers, t-Darpp and/or Darpp-32 is overexpressed in tumor cells from breast, colon, esophagus, lung and prostate tissues. More than one research team has demonstrated that these proteins, through mechanisms that to date remain cloudy, activate AKT, a protein whose phosphorylation leads to cell survival and blocks apoptosis. Furthermore, in Her2 positive breast cancers (an aggressive form of breast cancer), t-Darpp/ Darpp-32 overexpression causes resistance to the frequently-administered anti-Her2 drug, trastuzumab (Herceptin), likely through AKT activation. Here we briefly describe how Darpp-32 and t-Darpp were discovered and report on the current state of knowledge of their involvement in cancers. We present a case for the development of an anti-t-Darpp therapeutic agent and outline the unique challenges this endeavor will likely encounter.

ASCL1-regulated DARPP-32 and t-DARPP stimulate small cell lung cancer growth and neuroendocrine tumor cell survival

“…While growing evidence supports the oncogenic role of DARPP-32 and t-DARPP in a wide variety of adenocarcinomas 28,34 , we are the first to report that DARPP-32 isoforms promote neuroendocrine oncogenesis, as we observe DARPP-32 and t-DARPP drive SCLC growth through anti-apoptotic mechanisms and pro-survival signaling via Akt and Erk. Neuroendocrine tumors arise from cells of endocrine and neural origin and have been reported in the pancreas 43,44 , gastrointestinal tract 43,44 , lung 45,46 , breast 47 , genitourinary tract 48 , liver 49 , gall bladder 50 , and glands including thymus 51 .…”

“…Given the primary function of DARPP-32 proteins in neurons and their oncogenic role in non-brain cancers 28 , we hypothesized that DARPP-32 and t-DARPP contribute to neuroendocrine tumor growth in SCLCs. Paul Greengard discovered DARPP-32 as a neuronal phosphoprotein that inhibits PP-1 by mediating dopamine signaling through dopamine D1 and D2 receptors and glutamate signaling through N-methyl-D-aspartate receptor (NMDAR) 19,[54][55][56] .…”

“…Numerous studies have reported the oncogenic role of DARPP-32 isoforms in breast and gastric malignancies 28,34 . Recently, we demonstrated overexpression of DARPP-32 isoforms in NSCLC promote tumor growth 8 .…”

“…Given that DARPP-32 ablation reduces tumor growth in mouse models of human SCLC, we aimed to elucidate the clinical relevance of DARPP-32 in SCLC patients. Based on published reports that indicate upregulation of DARPP-32 and t-DARPP have been associated with breast, gastric, colorectal and non-small cell lung cancer 28,34 , we sought to assess DARPP-32 and t-DARPP protein expression in SCLC patients. Immunohistochemistry was performed to detect DARPP-32 isoforms in tissue specimens obtained from small cell lung carcinoma patients.…”

“…Given the multifaceted role of DARPP-32 and t-DARPP proteins in the oncogenesis of numerous cancer types 28 , including NSCLC 8 , we sought to determine whether DARPP-32 isoforms promote SCLC growth. Here, we demonstrate for the first time that DARPP-32 isoforms are regulated by Notch signaling to drive SCLC oncogenesis.…”