WWOX Controls Cell Survival, Immune Response and Disease Progression by pY33 to pS14 Transition to Alternate Signaling Partners

Tsung-Yun Liu; Ganesan Nagarajan; Ming-Fu Chiang; Shenq-Shyang Huang; Tzu-Chia Lin; Yu-An Chen; Chun-I Sze; Nan-Shan Chang

doi:10.3390/cells11142137

WWOX Controls Cell Survival, Immune Response and Disease Progression by pY33 to pS14 Transition to Alternate Signaling Partners

Cells. 2022 Jul 7;11(14):2137. doi: 10.3390/cells11142137.

Authors

Tsung-Yun Liu¹, Ganesan Nagarajan^{1

2}, Ming-Fu Chiang³, Shenq-Shyang Huang¹, Tzu-Chia Lin^{1

4}, Yu-An Chen¹, Chun-I Sze⁵, Nan-Shan Chang^{1

6

7}

Affiliations

¹ Laboratory of Molecular Immunology, Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
² Department of Basic Sciences, PYD, King Faisal University, Al Hofuf 36362, Saudi Arabia.
³ Graduate Institute of Injury Prevention and Control, Taipei Medical University, Taipei 11031, Taiwan.
⁴ Anesthesiology Department, National Cheng Kung University, Tainan 70101, Taiwan.
⁵ Department of Cell Biology and Anatomy, National Cheng Kung University, Tainan 70101, Taiwan.
⁶ Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan.
⁷ Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, New York, NY 10314, USA.

Abstract

Tumor suppressor WWOX inhibits cancer growth and retards Alzheimer's disease (AD) progression. Supporting evidence shows that the more strongly WWOX binds intracellular protein partners, the weaker is cancer cell growth in vivo. Whether this correlates with retardation of AD progression is unknown. Two functional forms of WWOX exhibit opposite functions. pY33-WWOX is proapoptotic and anticancer, and is essential for maintaining normal physiology. In contrast, pS14-WWOX is accumulated in the lesions of cancers and AD brains, and suppression of WWOX phosphorylation at S14 by a short peptide Zfra abolishes cancer growth and retardation of AD progression. In parallel, synthetic Zfra4-10 or WWOX7-21 peptide strengthens the binding of endogenous WWOX with intracellular protein partners leading to cancer suppression. Indeed, Zfra4-10 is potent in restoring memory loss in triple transgenic mice for AD (3xTg) by blocking the aggregation of amyloid beta 42 (Aβ42), enhancing degradation of aggregated proteins, and inhibiting activation of inflammatory NF-κB. In light of the findings, Zfra4-10-mediated suppression of cancer and AD is due, in part, to an enhanced binding of endogenous WWOX and its binding partners. In this perspective review article, we detail the molecular action of WWOX in the HYAL-2/WWOX/SMAD4 signaling for biological effects, and discuss WWOX phosphorylation forms in interacting with binding partners, leading to suppression of cancer growth and retardation of AD progression.

Keywords: Alzheimer’s disease; TIAF1; WWOX; binding proteins; cancer; p53; therapeutic peptides; tumor suppressor.

Publication types

Review
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adaptor Proteins, Signal Transducing / pharmacology
Alzheimer Disease* / metabolism
Alzheimer Disease* / pathology
Amyloid beta-Peptides / metabolism
Animals
Cell Survival
Disease Progression
Humans
Immunity / genetics
Immunity / physiology
Mice
Neoplasms* / metabolism
Peptide Fragments / pharmacology
Protein Isoforms / metabolism
Tumor Suppressor Proteins / metabolism
WW Domain-Containing Oxidoreductase* / metabolism

Substances

APBB2 protein, human
Adaptor Proteins, Signal Transducing
Amyloid beta-Peptides
Peptide Fragments
Protein Isoforms
Tumor Suppressor Proteins
WW Domain-Containing Oxidoreductase

Grants and funding

This research was supported to NS Chang by the Ministry of Science and Technology, Taiwan (MOST 108-2320-B-006-020, 109-2320-B-006-058, and 110-2320-B-006-056), the National Health Research Institute (NHRI-EX107-10734NI) and the Department of Defense, USA (DAMD17-03-1-0736 and W81XWH-08-1-0682).