PP1, PKA and DARPP‐32 in breast cancer: A retrospective assessment of protein and mRNA expression

Saidy, Behnaz; Kotecha, Shreeya; Butler, A P; Rakha, Emad A.; Ellis, Ian O.; Green, Andrew; Martin, Stewart G.; Storr, Sarah J.

doi:10.1111/jcmm.16447

Cited by 10 publications

(9 citation statements)

References 30 publications

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“…RPS21 ’s role in breast cancer is not clear now, but one transcript of RPS, AA-RPS21 , is differentially expressed in cancerous tissues, indicating its potential driver role in breast cancer [34]. PPP1CA together with PRKACG and PRKAR1B were found to be the most strongly associated with breast cancer–specific survival [35]. Study found that inhibition of TXNIP via Myc drove Triple-negative breast cancers aggressiveness and was associated with decreased metastasis-free survival and decreased overall survival in breast cancer [36].…”

Section: Resultsmentioning

confidence: 99%

“…PPP1CA together with PRKACG and PRKAR1B were found to be the most strongly associated with breast cancer-specific survival [35]. Study found that inhibition of TXNIP via Myc drove Triple-negative breast cancers aggressiveness and was associated with decreased metastasis-free survival and decreased overall survival in breast cancer [36].…”

Section: Human Breast Cancer Data (Bc23209_c1_stdata)mentioning

confidence: 93%

See 1 more Smart Citation

SPRI: Spatial Pattern Recognition using Information based method for spatial gene expression data

Yuan

Shen

2022

Preprint

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The rapid development of spatially resolved transcriptomics has made it possible to analyze spatial gene expression patterns in complex biological tissues. To identify such genes, we propose a novel and robust nonparametric information-based approach, SPRI, to recognize their spatial patterns. SPRI directly models spatial transcriptome raw count data without model assumptions, which transforms the problem of spatial expression pattern recognition into the detection of dependencies between spatial coordinate pairs with gene read count as the observed frequencies. SPRI was used to analyze four recent published spatially resolved transcriptome data, and all results showed that SPRI outperforms prior methods, by robustly detecting more genes with significant spatial expression patterns, and revealing biological insights that cannot be identified by other methods.

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Section: Resultsmentioning

confidence: 99%

Section: Human Breast Cancer Data (Bc23209_c1_stdata)mentioning

confidence: 93%

SPRI: Spatial Pattern Recognition using Information based method for spatial gene expression data

Yuan

Shen

2022

Preprint

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“…Recently, it was shown that breast cancer patients with elevated DARPP-32 expression but low PP1 expression have worse overall survival than those with low expression of DARPP-32 52 , suggesting a strong inverse correlation between PP1 and DARPP-32 proteins in patient outcome. This supports the notion that DARPP-32–mediated inactivation of PP1 functions via phosphorylation leads to increased activation of kinases involved in oncogenic signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

IKKα promotes lung adenocarcinoma growth through ERK signaling activation via DARPP-32-mediated inhibition of PP1 activity

et al. 2023

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Non-small cell lung cancer (NSCLC) accounts for 80–85% cases of lung cancer cases. Diagnosis at advanced stages is common, after which therapy-refractory disease progression frequently occurs. Therefore, a better understanding of the molecular mechanisms that control NSCLC progression is necessary to develop new therapies. Overexpression of IκB kinase α (IKKα) in NSCLC correlates with poor patient survival. IKKα is an NF-κB-activating kinase that is important in cell survival and differentiation, but its regulation of oncogenic signaling is not well understood. We recently demonstrated that IKKα promotes NSCLC cell migration by physically interacting with dopamine- and cyclic AMP-regulated phosphoprotein, Mr 32000 (DARPP-32), and its truncated splice variant, t-DARPP. Here, we show that IKKα phosphorylates DARPP-32 at threonine 34, resulting in DARPP-32-mediated inhibition of protein phosphatase 1 (PP1), subsequent inhibition of PP1-mediated dephosphorylation of ERK, and activation of ERK signaling to promote lung oncogenesis. Correspondingly, IKKα ablation in human lung adenocarcinoma cells reduced their anchorage-independent growth in soft agar. Mice challenged with IKKα-ablated HCC827 cells exhibited less lung tumor growth than mice orthotopically administered control HCC827 cells. Our findings suggest that IKKα drives NSCLC growth through the activation of ERK signaling via DARPP-32-mediated inhibition of PP1 activity.

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“…In agreement with the previous finding showing DARPP-32 is phosphorylated by PKA, Hansen and colleagues showed that Wnt-5A-mediated phosphorylation of DARPP-32 Thr-34 reduces breast cancer cell migration, and DARPP-32 phosphorylation is tightly regulated by intracellular cAMP levels and subsequent PKA activation 39 . Recently, it was shown that breast cancer patients with elevated DARPP-32 expression but low PP1 expression have worse overall survival than those with low expression of DARPP-32 52 , suggesting a strong inverse correlation between PP1 and DARPP-32 proteins in patient outcome. This supports the notion that DARPP-32-mediated inactivation of PP1 functions via phosphorylation leads to increased activation of kinases involved in oncogenic signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

“…This supports the notion that DARPP-32-mediated inactivation of PP1 functions via phosphorylation leads to increased activation of kinases involved in oncogenic signaling pathways. Moreover, PKA protein expression in breast tumor tissues shows a strong correlation with DARPP-32 and PP1 protein expression, warranting further investigation to understand their molecular role in regulating breast tumorigenesis 52 . In a separate study, Hansen et al reported that PKA protein activated by Wnt-5a ligands regulates breast cancer cell migration by phosphorylating DARPP-32 at Thr-34 in a PP1/CREB-dependent manner 39 .…”

Section: Discussionmentioning

confidence: 99%

IKKα promotes lung adenocarcinoma growth through activation of ERK signaling via DARPP-32-mediated inhibition of PP1 activity

Alam

Wang

Zhu

et al. 2022

Preprint

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Non-small cell lung cancer (NSCLC) accounts for 80-85% cases of lung cancer cases. Diagnosis at advanced stages is common, after which therapy-refractory disease progression frequently occurs. Therefore, a better understanding of the molecular mechanisms that control NSCLC progression is necessary to develop new therapies. Overexpression of IκB kinase α (IKKα) in NSCLC correlates with poor patient survival. IKKα is an NF-κB-activating kinase that is important in cell survival and differentiation, but its regulation of oncogenic signaling is not well understood. We recently demonstrated that IKKα promotes NSCLC cell migration by physically interacting with dopamine- and cyclic AMP-regulated phosphoprotein, Mr 32000 (DARPP-32), and its truncated splice variant, t-DARPP. Here, we show that IKKα phosphorylates DARPP-32 at threonine 34, resulting in DARPP-32-mediated inhibition of protein phosphatase 1 (PP1), subsequent PP1-mediated dephosphorylation of ERK, and activation of ERK signaling to promote lung oncogenesis. Correspondingly, DARPP-32 ablation in human lung adenocarcinoma cells reduced their anchorage-independent growth in soft agar. Mice challenged with IKKα-ablated HCC827 cells exhibited less lung tumor growth than mice orthotopically administered control HCC827 cells. Our findings suggest that IKKα drives NSCLC growth through activation of ERK signaling via DARPP-32-mediated inhibition of PP1 activity.

show abstract

PP1, PKA and DARPP‐32 in breast cancer: A retrospective assessment of protein and mRNA expression

Cited by 10 publications

References 30 publications

SPRI: Spatial Pattern Recognition using Information based method for spatial gene expression data

SPRI: Spatial Pattern Recognition using Information based method for spatial gene expression data

IKKα promotes lung adenocarcinoma growth through ERK signaling activation via DARPP-32-mediated inhibition of PP1 activity

IKKα promotes lung adenocarcinoma growth through activation of ERK signaling via DARPP-32-mediated inhibition of PP1 activity

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