PMID- 34638419
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20211016
IS  - 2072-6694 (Print)
IS  - 2072-6694 (Electronic)
IS  - 2072-6694 (Linking)
VI  - 13
IP  - 19
DP  - 2021 Sep 30
TI  - PMEPA1/TMEPAI Is a Unique Tumorigenic Activator of AKT Promoting Proteasomal 
      Degradation of PHLPP1 in Triple-Negative Breast Cancer Cells.
LID - 10.3390/cancers13194934 [doi]
LID - 4934
AB  - Transmembrane prostate androgen-induced protein (TMEPAI), also known as PMEPA1, 
      is highly expressed in many types of cancer and promotes oncogenic abilities. 
      However, the mechanisms whereby TMEPAI facilitates tumorigenesis are not fully 
      understood. We previously established TMEPAI-knockout (KO) cells from human 
      triple-negative breast cancer (TNBC) cell lines and found that TMEPAI-KO cells 
      showed reduced tumorigenic abilities. Here, we report that TMEPAI-KO cells 
      upregulated the expression of pleckstrin homology (PH) domain and leucine-rich 
      repeat protein phosphatase 1 (PHLPP1) and suppressed AKT Ser473 phosphorylation, 
      which was consistent with TCGA dataset analysis. Additionally, the knockdown (KD) 
      of PHLPP1 in TMEPAI-KO cells partially but significantly rescued AKT Ser473 
      phosphorylation, as well as in vitro and in vivo tumorigenic activities, thus 
      showing that TMEPAI functions as an oncogenic protein through the regulation of 
      PHLPP1 subsequent to AKT activation. Furthermore, we demonstrated that TMEPAI 
      PPxY (PY) motifs are essential for binding to NEDD4-2, an E3 ubiquitin ligase, 
      and PHLPP1-downregulatory ability. Moreover, TMEPAI enhanced the complex 
      formation of PHLPP1 with NEDD4-2 and PHLPP1 polyubiquitination, which leads to 
      its proteasomal degradation. These findings indicate that the PY motifs of TMEPAI 
      suppress the amount of PHLPP1 and maintain AKT Ser473 phosphorylation at high 
      levels to enhance the tumorigenic potentiality of TNBC.
FAU - Haque, Md Anwarul
AU  - Haque MA
AUID- ORCID: 0000-0001-6785-4121
AD  - Department of Experimental Pathology, Graduate School of Comprehensive Human 
      Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.
AD  - Department of Pharmacy, Faculty of Science, University of Rajshahi, Rajshahi 
      6205, Bangladesh.
FAU - Abdelaziz, Mohammed
AU  - Abdelaziz M
AD  - Department of Experimental Pathology, Graduate School of Comprehensive Human 
      Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.
AD  - Department of Pathology, Faculty of Medicine, Sohag University, Sohag 82524, 
      Egypt.
FAU - Puteri, Meidi Utami
AU  - Puteri MU
AUID- ORCID: 0000-0003-1550-8627
AD  - Department of Experimental Pathology, Graduate School of Comprehensive Human 
      Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.
FAU - Vo Nguyen, Thanh Thao
AU  - Vo Nguyen TT
AD  - Department of Experimental Pathology, Graduate School of Comprehensive Human 
      Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.
AD  - Department of Medical Biotechnology, Biotechnology Center of Ho Chi Minh City, Ho 
      Chi Minh City 700000, Vietnam.
FAU - Kudo, Kosei
AU  - Kudo K
AD  - Department of Experimental Pathology, Graduate School of Comprehensive Human 
      Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.
FAU - Watanabe, Yukihide
AU  - Watanabe Y
AD  - Department of Experimental Pathology, Graduate School of Comprehensive Human 
      Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.
FAU - Kato, Mitsuyasu
AU  - Kato M
AUID- ORCID: 0000-0001-9905-2473
AD  - Department of Experimental Pathology, Graduate School of Comprehensive Human 
      Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.
AD  - Transborder Medical Research Center, Faculty of Medicine, University of Tsukuba, 
      Tsukuba 305-8575, Japan.
LA  - eng
GR  - JP18K06682/Japan Society for the Promotion of Science/
GR  - JP16K19100/Japan Society for the Promotion of Science/
GR  - JP25870093/Japan Society for the Promotion of Science/
GR  - JP21K06942/Japan Society for the Promotion of Science/
GR  - JP18H02676/Japan Society for the Promotion of Science/
GR  - JP25293092/Japan Society for the Promotion of Science/
GR  - JP20K20597/Japan Society for the Promotion of Science/
PT  - Journal Article
DEP - 20210930
PL  - Switzerland
TA  - Cancers (Basel)
JT  - Cancers
JID - 101526829
PMC - PMC8508116
OTO - NOTNLM
OT  - AKT signaling
OT  - PHLPP1
OT  - TMEPAI
OT  - TNBC
OT  - ubiquitination
COIS- The authors declare no conflict of interest. The funders had no role in the 
      design of the study; in the collection, analyses, or interpretation of data; in 
      the writing of the manuscript, or in the decision to publish the results.
EDAT- 2021/10/14 06:00
MHDA- 2021/10/14 06:01
PMCR- 2021/09/30
CRDT- 2021/10/13 01:01
PHST- 2021/08/18 00:00 [received]
PHST- 2021/09/18 00:00 [revised]
PHST- 2021/09/23 00:00 [accepted]
PHST- 2021/10/13 01:01 [entrez]
PHST- 2021/10/14 06:00 [pubmed]
PHST- 2021/10/14 06:01 [medline]
PHST- 2021/09/30 00:00 [pmc-release]
AID - cancers13194934 [pii]
AID - cancers-13-04934 [pii]
AID - 10.3390/cancers13194934 [doi]
PST - epublish
SO  - Cancers (Basel). 2021 Sep 30;13(19):4934. doi: 10.3390/cancers13194934.