蛋白磷酸酶1结构和生物学功能及其与肿瘤发生发展关系的研究进展

doi:10.13481/j.1671-587X.20250329

Abstract

Abstract:

Protein phosphatase 1 （PP1） is a widely expressed and highly conserved serine/threonine phosphatase in organisms. It regulates cellular signaling pathways by catalyzing the dephosphorylation of various proteins， thereby influencing biological processes such as cell proliferation， apoptosis， migration， and transcription. In vivo， PP1 does not exist as a free catalytic subunit but instead forms distinct PP1 holoenzymes by binding with at least one PP1-interacting protein （PIP）. The interaction between PP1’s catalytic subunit and its specific regulatory proteins is central to PP1’s function. Under normal conditions， PP1 stably performs its dephosphorylation role in vivo； however， in tumors， PP1 function is aberrantly regulated， leading to either increased or decreased PP1 activity. PP1 exerts a dual influence on tumorigenesis and progression， acting as a suppressor in some cancers while promoting oncogenesis in others. Based on domestic and international research findings on PP1， this review summarizes the structure and biological functions of PP1， as well as the impact of its various subunits on the development and progression of different cancers， including breast cancer， lung cancer， ovarian cancer， pancreatic adenocarcinoma （PAAD）， liver cancer， endometrial cancer， esophageal cancer （EC）， colorectal cancer， and glioblastoma （GBM）. This review aims to provide the insights for developing highly efficient and environmentally friendly anticancer drugs and therapeutic approaches targeting PP1 holoenzymes.

Key words: Protein phosphatase 1, Serine-threonine phosphatase, Protein phosphatase 1 regulatory proteins, Biological function, Dephosphorylation

CLC Number:

R730.2

Wengxiu GUO,Huiling ZHANG,Jun MENG. Research progress in structure and biological function of protein phosphatase 1 and its relationship with occurence and development of tumor[J].Journal of Jilin University(Medicine Edition), 2025, 51(3): 822-830.

References 50

[1]	SCHMID P， ABRAHAM J， CHAN S， et al. Capivasertib plus paclitaxel versus placebo plus paclitaxel As first-line therapy for metastatic triple-negative breast cancer： the PAKT trial［J］. J Clin Oncol， 2020， 38（5）： 423-433.
[2]	MOURA M， CONDE C. Phosphatases in mitosis： roles and regulation［J］. Biomolecules， 2019， 9（2）： 55.
[3]	GUZMAN F， FAZELI Y， KHUU M， et al. Retinoblastoma tumor suppressor protein roles in epigenetic regulation［J］. Cancers （Basel）， 2020， 12（10）： 2807.
[4]	FELGUEIRAS J， JERÓNIMO C， FARDILHA M. Protein phosphatase 1 in tumorigenesis： is it worth a closer look？［J］. Biochim Biophys Acta Rev Cancer， 2020， 1874（2）： 188433.
[5]	LIU Y S， CHANG Y C， KUO W W， et al. Inhibition of protein phosphatase 1 stimulates noncanonical ER stress eIF2α activation to enhance fisetin-induced chemosensitivity in HDAC inhibitor-resistant hepatocellular carcinoma cells［J］. Cancers （Basel）， 2019， 11（7）： 918.
[6]	JIAN Y T， KONG L Z， XU H Y， et al. Protein phosphatase 1 regulatory inhibitor subunit ¹⁴C promotes triple-negative breast cancer progression via sustaining inactive glycogen synthase kinase 3 beta［J］. Clin Transl Med， 2022， 12（1）： e725.
[7]	CHEN S P， YANG M， YANG H K， et al. Identification and validation of a 9-gene signature for the prognosis of ovarian cancer by integrated bioinformatical analysis［J］. Ann Transl Med， 2022， 10（19）： 1059.
[8]	XU H K， MAO J Y， YANG X D， et al. AMP-activated protein kinase family member 5 is an independent prognostic indicator of pancreatic adenocarcinoma： a study based on The Cancer Genome Atlas［J］. Mol Med Rep， 2020， 22（5）： 4329-4339.
[9]	YANG L J， GAO L， GUO Y N， et al. Upregulation of microRNA miR-141-3p and its prospective targets in endometrial carcinoma： a comprehensive study［J］. Bioengineered， 2021， 12（1）： 2941-2956.
[10]	ZOU Z H， LIU R， LIANG Y K， et al. Identification and validation of a PPP1R12A-related five-gene signature associated with metabolism to predict the prognosis of patients with prostate cancer［J］. Front Genet， 2021， 12： 703210.
[11]	DI FIORE R， D’ANNEO A， TESORIERE G， et al. RB1 in cancer： different mechanisms of RB1 inactivation and alterations of pRb pathway in tumorigenesis［J］. J Cell Physiol， 2013， 228（8）： 1676-1687.
[12]	FERREIRA M， BEULLENS M， BOLLEN M， et al. Functions and therapeutic potential of protein phosphatase 1： Insights from mouse genetics［J］. Biochim Biophys Acta Mol Cell Res， 2019， 1866（1）： 16-30.
[13]	TERRAK M， KERFF F， LANGSETMO K， et al. Structural basis of protein phosphatase 1 regulation［J］. Nature， 2004， 429（6993）： 780-784.
[14]	MARTIN S G， ZHANG S W， YANG S， et al. Dopamine and cAMP-regulated phosphoprotein 32kDa （DARPP-32）， protein phosphatase-1 and cyclin-dependent kinase 5 expression in ovarian cancer［J］. J Cell Mol Med， 2020， 24（16）： 9165-9175.
[15]	OHKURA H， YANAGIDA M. S. Pombe gene sds22+ essential for a midmitotic transition encodes a leucine-rich repeat protein that positively modulates protein phosphatase-1［J］. Cell， 1991， 64（1）： 149-157.
[16]	JIANG Y， SCOTT K L， KWAK S J， et al. Sds22/PP1 links epithelial integrity and tumor suppression via regulation of myosin Ⅱ and JNK signaling［J］. Oncogene， 2011， 30（29）： 3248-3260.
[17]	PAUL D， BARGALE A B， RAPOLE S， et al. Protein phosphatase 1 regulatory subunit SDS22 inhibits breast cancer cell tumorigenesis by functioning as a negative regulator of the AKT signaling pathway［J］. Neoplasia， 2019， 21（1）： 30-40.
[18]	SAINI K S， LOI S， DE AZAMBUJA E， et al. Targeting the PI3K/AKT/mTOR and Raf/MEK/ERK pathways in the treatment of breast cancer［J］. Cancer Treat Rev， 2013， 39（8）： 935-946.
[19]	LIAO L， ZHANG Y L， DENG L， et al. Protein phosphatase 1 subunit PPP1R14B stabilizes STMN1 to promote progression and paclitaxel resistance in triple-negative breast cancer［J］. Cancer Res， 2023， 83（3）： 471-484.
[20]	HORVÁTH D， TAMÁS I， SIPOS A， et al. Correction： Myosin phosphatase and RhoA-activated kinase modulate neurotransmitter release by regulating SNAP-25 of SNARE complex［J］. PLoS One， 2017， 12（6）： e0179296.
[21]	李菁，彭生，翁浩. 经皮自控电刺激耳神门穴对乳腺癌术后疼痛及恶心、呕吐的影响［J］. 同济大学学报（医学版）， 2024， 45（1）： 100-105.
[22]	SUN H Z， OU B C， ZHAO S L， et al. USP11 promotes growth and metastasis of colorectal cancer via PPP1CA-mediated activation of ERK/MAPK signaling pathway［J］. EBioMedicine， 2019， 48： 236-247.
[23]	KOTECHA S， LEBOT M N， SUKKARN B， et al. Dopamine and cAMP-regulated phosphoprotein 32 kDa （DARPP-32） and survival in breast cancer： a retrospective analysis of protein and mRNA expression［J］. Sci Rep， 2019， 9： 16987.
[24]	ZHANG Y X， ZHEN F， SUN Y， et al. Single-cell RNA sequencing reveals small extracellular vesicles derived from malignant cells that contribute to angiogenesis in human breast cancers［J］. J Transl Med， 2023， 21（1）： 570.
[25]	BEAVER C M， AHMED A， MASTERS J R. Clonogenicity： holoclones and meroclones contain stem cells［J］. PLoS One， 2014， 9（2）： e89834.
[26]	VERDUGO-SIVIANES E M， CARNERO A. SPINOPHILIN： a multiplayer tumor suppressor［J］. Genes Dis， 2022， 10（1）： 187-198.
[27]	ZHANG W， SHANG S， YANG Y Y， et al. Identification of DNA methylation-driven genes by integrative analysis of DNA methylation and transcriptome data in pancreatic adenocarcinoma［J］. Exp Ther Med， 2020， 19（4）： 2963-2972.
[28]	DANG M， ARMBRUSTER N， MILLER M A， et al. Regulated ADAM17-dependent EGF family ligand release by substrate-selecting signaling pathways［J］. Proc Natl Acad Sci USA， 2013， 110（24）： 9776-9781.
[29]	CAO H J， WANG Z Q， WANG Y， et al. PPP1R14D promotes the proliferation， migration and invasion of lung adenocarcinoma via the PKCα/BRAF/MEK/ERK signaling pathway［J］. Int J Oncol， 2022， 61（6）： 153.
[30]	BOLLEN M， PETI W， RAGUSA M J， et al. The extended PP1 toolkit： designed to create specificity［J］. Trends Biochem Sci， 2010， 35（8）： 450-458.
[31]	ZHUO X L， CHEN L， LAI Z W， et al. Protein phosphatase 1 regulatory subunit 3G （PPP1R3G） correlates with poor prognosis and immune infiltration in lung adenocarcinoma［J］. Bioengineered， 2021， 12（1）： 8336-8346.
[32]	ZHOU N N， LUO P， WEN Y， et al. Immune cell infiltration is a strong prognostic indicator in surgical resection of SCLC［J］. J Thorac Oncol， 2019， 14（10）： e242-e243.
[33]	BARRA F， EVANGELISTI G， FERRO DESIDERI L， et al. Investigational PI3K/AKT/mTOR inhibitors in development for endometrial cancer［J］. Expert Opin Investig Drugs， 2019， 28（2）： 131-142.
[34]	ALAM S K， WANG L， ZHU Z， et al. IKKα promotes lung adenocarcinoma growth through ERK signaling activation via DARPP-32-mediated inhibition of PP1 activity［J］. NPJ Precis Oncol， 2023， 7（1）： 33.
[35]	QIAO Y N， HE W Q， CHEN C P， et al. Myosin phosphatase target subunit 1 （MYPT1） regulates the contraction and relaxation of vascular smooth muscle and maintains blood pressure［J］. J Biol Chem， 2014， 289（32）： 22512-22523.
[36]	MUÑOZ-GALVÁN S， FELIPE-ABRIO B， VERDUGO-SIVIANES E M， et al. Downregulation of MYPT1 increases tumor resistance in ovarian cancer by targeting the Hippo pathway and increasing the stemness［J］. Mol Cancer， 2020， 19（1）： 7.
[37]	WU H， ZHAO X B， WANG J， et al. Circular RNA CDR1as alleviates cisplatin-based chemoresistance by suppressing miR-1299 in ovarian cancer［J］. Front Genet， 2022， 12： 815448.
[38]	ZHAO Y S， ZHENG R Y， CHEN J， et al. CircRNA CDR1as/miR-641/HOXA9 pathway regulated stemness contributes to cisplatin resistance in non-small cell lung cancer （NSCLC）［J］. Cancer Cell Int， 2020， 20： 289.
[39]	TIWARI A， TASHIRO K， DIXIT A， et al. Loss of HIF1A from pancreatic cancer cells increases expression of PPP1R1B and degradation of p53 to promote invasion and metastasis［J］. Gastroenterology， 2020， 159（5）： 1882-1897.e5.
[40]	ZHU Y X， KOSMACEK E A， CHATTERJEE A， et al. MnTE-2-PyP suppresses prostate cancer cell growth via H₂O₂ production［J］. Antioxidants （Basel）， 2020， 9（6）： 490.
[41]	HU L Y， XU H K， WANG X G， et al. The expression and clinical prognostic value of protein phosphatase 1 catalytic subunit beta in pancreatic cancer［J］. Bioengineered， 2021， 12（1）： 2763-2778.
[42]	VERBINNEN I， BOENS S， FERREIRA M， et al. Enhanced DNA-repair capacity and resistance to chemically induced carcinogenesis upon deletion of the phosphatase regulator NIPP1［J］. Oncogenesis， 2020， 9（3）： 30.
[43]	DENG M X， PENG L， LI J M， et al. PPP1R14B is a prognostic and immunological biomarker in pan-cancer［J］. Front Genet， 2021， 12： 763561.
[44]	XIANG N， CHEN T， ZHAO X L， et al. In vitro assessment of roles of PPP1R14B in cervical and endometrial cancer［J］. Tissue Cell， 2022， 77： 101845.
[45]	HE K， WANG T W， HUANG X M， et al. PPP1R14B is a diagnostic prognostic marker in patients with uterine corpus endometrial carcinoma［J］. J Cell Mol Med， 2023， 27（6）： 846-863.
[46]	CHEN Z， TANG W J， YE W W， et al. ADAMTS9-AS2 regulates PPP1R12B by adsorbing miR-196b-5p and affects cell cycle-related signaling pathways inhibiting the malignant process of esophageal cancer［J］. Cell Cycle， 2022， 21（16）： 1710-1725.
[47]	DING C B， TANG W D， WU H L， et al. The PEAK1-PPP1R12B axis inhibits tumor growth and metastasis by regulating Grb2/PI3K/Akt signalling in colorectal cancer［J］. Cancer Lett， 2019， 442： 383-395.
[48]	YANG J， ZHANG Q R， YANG Z Y， et al. KIF18A interacts with PPP1CA to promote the malignant development of glioblastoma［J］. Exp Ther Med， 2023， 25（4）： 154.
[49]	YU Y H， ZHANG Y H， DING Y Q， et al. microRNA-99b-3p promotes angiotensin Ⅱ-induced cardiac fibrosis in mice by targeting GSK-3β［J］. Acta Pharmacol Sin， 2021， 42（5）： 715-725.
[50]	KIRKBRIDE J A， NILSSON G Y， KIM J I， et al. PHI-1， an endogenous inhibitor protein for protein phosphatase-1 and a pan-cancer marker， regulates raf-1 proteostasis［J］. Biomolecules， 2023， 13（12）： 1741.

Research progress in structure and biological function of protein phosphatase 1 and its relationship with occurence and development of tumor

RichHTML

PDF (PC)

Like

Knowledge

Abstract

Cite this article

share this article

References 50

Related Articles 3

Metrics

Comments

Recommended 0

[1]	Xin ZHANG,Fei WANG,Bingjie CUI,Jing DU. Research progress in effect of phosphorylation modification of Hedgehog signaling pathway on occurrence and development of tumor [J]. Journal of Jilin University(Medicine Edition), 2025, 51(2): 526-533.
[2]	Congcong BAI,Xianlei ZHOU,Zhi ZHANG,Shuang GAO,Xuemei ZHANG. Expression of CSPG4P12 gene in small cell lung cancer tissue and its effect on behaviors of cell biology [J]. Journal of Jilin University(Medicine Edition), 2025, 51(2): 392-402.
[3]	Shaoru WANG,Yungang LUO. Research progress in biological function of chitooligosaccharide and its application in biomedical field [J]. Journal of Jilin University(Medicine Edition), 2024, 50(4): 1164-1172.