Protein phosphatase 1 in tumorigenesis: is it worth a closer look?

Felgueiras, Juliana; Jerónimo, Carmen; Fardilha, Margarida

doi:10.1016/j.bbcan.2020.188433

Cited by 29 publications

(29 citation statements)

References 222 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In mammals, three genes ( PPP1CA , PPP1CB , and PPP1CC ) encode four isoforms of the catalytic subunit of PP1: PP1α, PP1β, PP1γ1, and PP1γ2. These four isoforms are expressed in all tissues and compartments, although PP1γ2 is only expressed in testes [ 10 , 57 , 58 , 64 , 67 , 68 , 69 , 70 , 71 ]. In addition, all isoforms are found in the nucleus, but PP1β and PP1γ present a special accumulation in the nucleolus [ 57 ].…”

Section: Protein Phosphatase 1 (Pp1)mentioning

confidence: 99%

“…RIPPOs direct PP1 towards specific substrates to perform specific functions, preventing the dephosphorylation of substrates by occupying the PP1 binding site or promoting the dephosphorylation by directing PP1 to specific cell locations. Additionally, some RIPPOs can be PP1 substrates [ 57 , 58 , 64 , 71 , 72 , 73 , 74 , 75 ]. Currently, approximately 200 regulatory proteins of PP1 are known, and most of them do not show similarity in their sequence [ 57 , 62 , 64 , 65 , 74 ].…”

Section: Protein Phosphatase 1 (Pp1)mentioning

confidence: 99%

“…The regulation of PP1 is complex and is controlled by both phosphorylation by different kinases and the action of inhibitors and regulatory proteins that modulate its substrate specificity and activity [ 3 , 4 , 5 , 67 , 71 , 79 , 81 , 82 ]. On the one hand, PP1 is phosphorylated and inactivated during the cell cycle by CDK2/cyclin E, CDK2/cyclin A, CDK1/cyclin A and CDK1/cyclin B to avoid pRB dephosphorylation.…”

Section: Protein Phosphatase 1 (Pp1)mentioning

confidence: 99%

“…On the one hand, PP1 is phosphorylated and inactivated during the cell cycle by CDK2/cyclin E, CDK2/cyclin A, CDK1/cyclin A and CDK1/cyclin B to avoid pRB dephosphorylation. Specifically, the phosphorylation of PP1 at the T320 residue plays an important role in the G1/S transition and during mitosis [ 3 , 71 , 83 , 84 ]. On the other hand, CDK1/cyclin B phosphorylates and inactivates PP1 with the help of the PP1 Inhibitor-2 (I2) during the onset and the middle of mitosis [ 4 , 85 ].…”

Section: Protein Phosphatase 1 (Pp1)mentioning

confidence: 99%

See 3 more Smart Citations

Role of the Holoenzyme PP1-SPN in the Dephosphorylation of the RB Family of Tumor Suppressors During Cell Cycle

Verdugo‐Sivianes

Carnero

2021

Cancers

View full text Add to dashboard Cite

Cell cycle progression is highly regulated by modulating the phosphorylation status of the retinoblastoma protein (pRB) and the other two members of the RB family, p107 and p130. This process is controlled by a balance in the action of kinases, such as the complexes formed by cyclin-dependent kinases (CDKs) and cyclins, and phosphatases, mainly the protein phosphatase 1 (PP1). However, while the phosphorylation of the RB family has been largely studied, its dephosphorylation is less known. Phosphatases are holoenzymes formed by a catalytic subunit and a regulatory protein with substrate specificity. Recently, the PP1-Spinophilin (SPN) holoenzyme has been described as the main phosphatase responsible for the dephosphorylation of RB proteins during the G0/G1 transition and at the end of G1. Moreover, SPN has been described as a tumor suppressor dependent on PP1 in lung and breast tumors, where it promotes tumorigenesis by increasing the cancer stem cell pool. Therefore, a connection between the cell cycle and stem cell biology has also been proposed via SPN/PP1/RB proteins.

show abstract

Section: Protein Phosphatase 1 (Pp1)mentioning

confidence: 99%

Section: Protein Phosphatase 1 (Pp1)mentioning

confidence: 99%

Section: Protein Phosphatase 1 (Pp1)mentioning

confidence: 99%

Section: Protein Phosphatase 1 (Pp1)mentioning

confidence: 99%

See 2 more Smart Citations

Role of the Holoenzyme PP1-SPN in the Dephosphorylation of the RB Family of Tumor Suppressors During Cell Cycle

Verdugo‐Sivianes

Carnero

2021

Cancers

View full text Add to dashboard Cite

show abstract

“…PPP1R14C is a powerful inhibitor for PP1, a major phosphatase responsible for modulating the phospho-and dephospho-balance of numerous substrate proteins [24]. To identify whether GSK3β is the exact substrate protein affected by the PPP1R14C and PP1 interaction in TNBC cells, we screened a collection of PP1 substrates [25][26][27][28][29][30].…”

Section: Ppp1r14c Interacts With Pp1 To Constantly Inhibit Gsk3β Activitymentioning

confidence: 99%

Protein phosphatase 1 regulatory inhibitor subunit 14C promotes triple-negative breast cancer progression via sustaining inactive glycogen synthase kinase 3 beta

Jian

Kong

et al. 2021

Preprint

View full text Add to dashboard Cite

The majority of clinical deaths among patients with triple-negative breast cancer (TNBC) are caused by uncontrolled cell proliferation and aggressive metastases, which is regulated by hyperactive glycogen synthase kinase 3 beta (GSK3β); however, the underlying mechanisms remain largely unknown. In the present study, we found that protein phosphatase 1 regulatory inhibitor subunit 14C (PPP1R14C) was specifically upregulated in TNBC, compared with that in normal tissues and non-TNBC. High PPP1R14C expression correlated significantly with shorter 5-year relapse-free survival and overall survival in patients with TNBC. Overexpressing PPP1R14C promoted, while suppression of PPP1R14C decreased the cell proliferation and the aggressive phenotype of TNBC cells, in vitro and in vivo. Importantly, we revealed that PPP1R14C interacted with and inactivated type 1 Ser/Thr protein phosphatase (PP1) to sustain GSK3β phosphorylation at S9, and induced the ubiquitylation and degradation of non-phosphorylated GSK3β (S9A) via recruiting E3 ligase, TRIM25. Furthermore, treating with C2 ceramide (C2), which recovered kinase activity of GSK3β, resulted in tumor growth inhibition in PPP1R14C-overexpressing TNBC cells. Our findings reveal a novel mechanism whereby PPP1R14C sustains inactive GSK3β, which might lead to targeted therapy for TNBC.

show abstract

Protein phosphatase 1 regulatory inhibitor subunit 14C promotes triple‐negative breast cancer progression via sustaining inactive glycogen synthase kinase 3 beta

Jian

Kong

et al. 2022

Clinical & Translational Med

View full text Add to dashboard Cite

Triple‐negative breast cancer (TNBC) is fast‐growing and highly metastatic with the poorest prognosis among the breast cancer subtypes. Inactivation of glycogen synthase kinase 3 beta (GSK3β) plays a vital role in the aggressiveness of TNBC; however, the underlying mechanism for sustained GSK3β inhibition remains largely unknown. Here, we find that protein phosphatase 1 regulatory inhibitor subunit 14C (PPP1R14C) is upregulated in TNBC and relevant to poor prognosis in patients. Overexpression of PPP1R14C facilitates cell proliferation and the aggressive phenotype of TNBC cells, whereas the depletion of PPP1R14C elicits opposite effects. Moreover, PPP1R14C is phosphorylated and activated by protein kinase C iota (PRKCI) at Thr73. p‐PPP1R14C then represses Ser/Thr protein phosphatase type 1 (PP1) to retain GSK3β phosphorylation at high levels. Furthermore, p‐PPP1R14C recruits E3 ligase, TRIM25, toward the ubiquitylation and degradation of non‐phosphorylated GSK3β. Importantly, the blockade of PPP1R14C phosphorylation inhibits xenograft tumorigenesis and lung metastasis of TNBC cells. These findings provide a novel mechanism for sustained GSK3β inactivation in TNBC and suggest that PPP1R14C might be a potential therapeutic target.

show abstract

Protein phosphatase 1 in tumorigenesis: is it worth a closer look?

Cited by 29 publications

References 222 publications

Role of the Holoenzyme PP1-SPN in the Dephosphorylation of the RB Family of Tumor Suppressors During Cell Cycle

Role of the Holoenzyme PP1-SPN in the Dephosphorylation of the RB Family of Tumor Suppressors During Cell Cycle

Protein phosphatase 1 regulatory inhibitor subunit 14C promotes triple-negative breast cancer progression via sustaining inactive glycogen synthase kinase 3 beta

Protein phosphatase 1 regulatory inhibitor subunit 14C promotes triple‐negative breast cancer progression via sustaining inactive glycogen synthase kinase 3 beta

Contact Info

Product

Resources

About