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Signaling from membrane receptors to tumor suppressor WW domain-containing oxidoreductase
Jean-Yun Chang1, Ruei-Yu He, Hsin-Ping Lin
1Institute of Molecular Medicine, National Cheng Kung University Medical College, Tainan, Taiwan.
Abstract:
The family of WW domain-containing proteins contains over 2000 members. The small WW domain module is responsible, in part, for protein/protein binding interactions and signaling. Many of these proteins are located at the membrane/cytoskeleton area, where they act as adaptors to receive signals from the cell surface. In this review, we provide molecular insights regarding recent novel findings on signaling from the cell surface toward WW domain-containing oxidoreductase, known as WWOX, FOR or WOX1. More specifically, transforming growth factor beta 1 utilizes cell surface hyaluronidase Hyal-2 (hyaluronoglucosaminidase 2) as a cognate receptor for signaling with WWOX and Smad4 to control gene transcription, growth and death. Complement C1q alone, bypassing the activation of classical pathway, signals a novel event of apoptosis by inducing microvillus formation and WWOX activation. Deficiency in these signaling events appears to favorably support cancer growth.
Insights
WW domain-containing oxidoreductase (WWOX) acts as a crucial signaling hub, receiving signals from the cell surface. Dysregulation of WWOX signaling pathways, involving transforming growth factor beta 1 and complement C1q, is linked to cancer progression.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- WW domain-containing proteins are a large family involved in protein interactions and cellular signaling.
- Many WW domain proteins function as adaptors at the membrane/cytoskeleton, relaying signals from the cell surface.
- WW domain-containing oxidoreductase (WWOX), also known as FOR or WOX1, is a key protein in this family.
Purpose of the Study:
- To review molecular insights into novel cell surface signaling pathways converging on WWOX.
- To highlight the role of WWOX in regulating gene transcription, cell growth, and apoptosis.
- To explore the implications of WWOX signaling in cancer development.
Main Methods:
- Literature review of recent findings on WWOX signaling pathways.
- Analysis of molecular mechanisms involving transforming growth factor beta 1 and hyaluronidase 2 (Hyal-2).
- Investigation of complement C1q-mediated apoptosis signaling and WWOX activation.
Main Results:
- Transforming growth factor beta 1 signals through cell surface Hyal-2 to WWOX and Smad4, regulating gene transcription, growth, and death.
- Complement C1q can independently trigger apoptosis via microvillus formation and WWOX activation, bypassing classical complement pathway activation.
- Impaired WWOX signaling pathways are associated with promoting cancer growth.
Conclusions:
- WWOX is a critical mediator of cell surface signaling pathways with significant roles in cell fate.
- Aberrant WWOX signaling contributes to the progression of various cancers.
- Understanding these pathways offers potential therapeutic targets for cancer treatment.
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