Targeting of lysosomal-bound protein mEAK-7 for cancer therapy
mEAK-7 (mammalian EAK-7 or MTOR-associated protein, eak-7 homolog), is an evolutionarily conserved lysosomal membrane protein that is highly expressed in several cancer cells. Multiple recent studies have identified mEAK-7 as a positive activator of mTOR (mammalian/mechanistic target of rapamycin) s...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-03-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2024.1375498/full |
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| author | Insoon Chang Yi-Ling Loo Jay Patel Joe Truong Nguyen Joe Truong Nguyen Jin Koo Kim Paul H. Krebsbach |
| author_facet | Insoon Chang Yi-Ling Loo Jay Patel Joe Truong Nguyen Joe Truong Nguyen Jin Koo Kim Paul H. Krebsbach |
| author_sort | Insoon Chang |
| collection | DOAJ |
| description | mEAK-7 (mammalian EAK-7 or MTOR-associated protein, eak-7 homolog), is an evolutionarily conserved lysosomal membrane protein that is highly expressed in several cancer cells. Multiple recent studies have identified mEAK-7 as a positive activator of mTOR (mammalian/mechanistic target of rapamycin) signaling via an alternative mTOR complex, implying that mEAK-7 plays an important role in the promotion of cancer proliferation and migration. In addition, structural analyses investigating interactions between mEAK-7 and V-ATPase, a protein complex responsible for regulating pH homeostasis in cellular compartments, have suggested that mEAK-7 may contribute to V-ATPase-mediated mTORC1 activation. The C-terminal α-helix of mEAK-7 binds to the D and B subunits of the V-ATPase, creating a pincer-like grip around its B subunit. This binding undergoes partial disruption during ATP hydrolysis, potentially enabling other proteins such as mTOR to bind to the α-helix of mEAK-7. mEAK-7 also promotes chemoresistance and radiation resistance by sustaining DNA damage-mediated mTOR signaling through interactions with DNA-PKcs (DNA-dependent protein kinase catalytic subunit). Taken together, these findings indicate that mEAK-7 may be a promising therapeutic target against tumors. However, the precise molecular mechanisms and signal transduction pathways of mEAK-7 in cancer remain largely unknown, motivating the need for further investigation. Here, we summarize the current known roles of mEAK-7 in normal physiology and cancer development by reviewing the latest studies and discuss potential future developments of mEAK-7 in targeted cancer therapy. |
| first_indexed | 2024-04-25T00:46:55Z |
| format | Article |
| id | doaj.art-e93b85020ed44f1eb44a34de24af0624 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-25T00:46:55Z |
| publishDate | 2024-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-e93b85020ed44f1eb44a34de24af06242024-03-12T04:50:18ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2024-03-011410.3389/fonc.2024.13754981375498Targeting of lysosomal-bound protein mEAK-7 for cancer therapyInsoon Chang0Yi-Ling Loo1Jay Patel2Joe Truong Nguyen3Joe Truong Nguyen4Jin Koo Kim5Paul H. Krebsbach6Section of Endodontics, Division of Regenerative and Reconstructive Sciences, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, United StatesSchool of Dentistry, University of California, Los Angeles, Los Angeles, CA, United StatesSchool of Dentistry, University of California, Los Angeles, Los Angeles, CA, United StatesLaboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, United StatesOral Immunobiology Unit, National Institutes of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, United StatesDivision of Oral and Systemic Health Sciences, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, United StatesDivision of Oral and Systemic Health Sciences, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, United StatesmEAK-7 (mammalian EAK-7 or MTOR-associated protein, eak-7 homolog), is an evolutionarily conserved lysosomal membrane protein that is highly expressed in several cancer cells. Multiple recent studies have identified mEAK-7 as a positive activator of mTOR (mammalian/mechanistic target of rapamycin) signaling via an alternative mTOR complex, implying that mEAK-7 plays an important role in the promotion of cancer proliferation and migration. In addition, structural analyses investigating interactions between mEAK-7 and V-ATPase, a protein complex responsible for regulating pH homeostasis in cellular compartments, have suggested that mEAK-7 may contribute to V-ATPase-mediated mTORC1 activation. The C-terminal α-helix of mEAK-7 binds to the D and B subunits of the V-ATPase, creating a pincer-like grip around its B subunit. This binding undergoes partial disruption during ATP hydrolysis, potentially enabling other proteins such as mTOR to bind to the α-helix of mEAK-7. mEAK-7 also promotes chemoresistance and radiation resistance by sustaining DNA damage-mediated mTOR signaling through interactions with DNA-PKcs (DNA-dependent protein kinase catalytic subunit). Taken together, these findings indicate that mEAK-7 may be a promising therapeutic target against tumors. However, the precise molecular mechanisms and signal transduction pathways of mEAK-7 in cancer remain largely unknown, motivating the need for further investigation. Here, we summarize the current known roles of mEAK-7 in normal physiology and cancer development by reviewing the latest studies and discuss potential future developments of mEAK-7 in targeted cancer therapy.https://www.frontiersin.org/articles/10.3389/fonc.2024.1375498/fullmEAK-7V-ATPaselysosomal membrane proteinmTOR signalingcancer |
| spellingShingle | Insoon Chang Yi-Ling Loo Jay Patel Joe Truong Nguyen Joe Truong Nguyen Jin Koo Kim Paul H. Krebsbach Targeting of lysosomal-bound protein mEAK-7 for cancer therapy Frontiers in Oncology mEAK-7 V-ATPase lysosomal membrane protein mTOR signaling cancer |
| title | Targeting of lysosomal-bound protein mEAK-7 for cancer therapy |
| title_full | Targeting of lysosomal-bound protein mEAK-7 for cancer therapy |
| title_fullStr | Targeting of lysosomal-bound protein mEAK-7 for cancer therapy |
| title_full_unstemmed | Targeting of lysosomal-bound protein mEAK-7 for cancer therapy |
| title_short | Targeting of lysosomal-bound protein mEAK-7 for cancer therapy |
| title_sort | targeting of lysosomal bound protein meak 7 for cancer therapy |
| topic | mEAK-7 V-ATPase lysosomal membrane protein mTOR signaling cancer |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2024.1375498/full |
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