GalNAc-T activation pathway
The GalNAc-T activation (GALA) pathway is a cellular process in which GalNAc-T enzymes, involved in O-linked glycosylation, are relocated from the Golgi to the ER. Activation of the pathway is thought to result in the alteration of the glycosylation status of a number of GalNAc-T substrates. This pathway was shown to be highly activated in cancer cells and was proposed as an explanation of the noticeable increased expression of Tn antigen seen in tumours.[1][2]
Mechanism
[edit]The retrograde transport of GalNAc-Ts from the Golgi to the ER is believed to result from the activation of the proto-oncogene tyrosine-protein kinase Src present on the Golgi membrane.[1] This was demonstrated through stimulation of HeLa cells with either EGF or PDGF. Activation of Src triggers the phosphorylation of the GTP exchange factor (GEF) GBF1 hence promoting an interaction between GBF1 and the small GTPase Arf1.[3] Ultimately those Src induced molecular events have been associated with the formation of COPI dependent transport carriers containing GalNAc-Ts and allowing their transport from the Golgi to the ER.[1][4]
Clinical significance
[edit]Activation of the GALA pathway has been tightly associated with ECM degradation. Study of the changes in glycosylation of the GalNAc-T substrate Calnexin-ERp57 has revealed a novel ECM degradative function for this oxidoreductase complex.[5] In fact, GALA activation results in changes in the glycosylation status of Calnexin leading to its relocalization to the cell surface and ultimately promoting this ECM degradation. GALA being highly activated in some cancer cells, Calnexin is logically a promising targetable tumour antigen. In addition, MMP14 is another GalNAc-T substrate for which GALA induced glycosylation changes impact the ECM degradation process.[6]
History
[edit]The retro-translocation of GalNAc-Ts from the Golgi to the endoplasmic reticulum was first observed in 2010 by Bard et al.[1] The term GALA was then first used in 2016 by Bard & Chia to designate this molecular pathway.[4] In 2017 the GALA pathway was subject to skepticism from the scientific community due to the inability of Tabak et al. to observe, as previously reported, the relocation of GalNAc-Ts and Tn antigens in HeLa cells upon EGF or PDGF stimulation.[7] However, results supporting the GALA pathway were subsequently re-obtained and critical review of the procedures that failed to support the pathway faded remaining reluctances for the model.[7]
References
[edit]- ^ a b c d Gill, David J.; Chia, Joanne; Senewiratne, Jamie; Bard, Frederic (2010-05-31). "Regulation of O-glycosylation through Golgi-to-ER relocation of initiation enzymes". The Journal of Cell Biology. 189 (5): 843–858. doi:10.1083/jcb.201003055. ISSN 1540-8140. PMC 2878949. PMID 20498016.
- ^ Chia, Joanne; Tay, Felicia; Bard, Frederic (2019). "The GalNAc-T Activation (GALA) Pathway: Drivers and markers". PLOS ONE. 14 (3): e0214118. Bibcode:2019PLoSO..1414118C. doi:10.1371/journal.pone.0214118. ISSN 1932-6203. PMC 6424425. PMID 30889231.
- ^ Chia, Joanne; Wang, Shyi-Chyi; Wee, Sheena; Gill, David James; Tay, Felicia; Kannan, Srinivasaraghavan; Verma, Chandra S; Gunaratne, Jayantha; Bard, Frederic A (2021). "Src activates retrograde membrane traffic through phosphorylation of GBF1". eLife. 10: e68678. doi:10.7554/eLife.68678. ISSN 2050-084X. PMC 8727025. PMID 34870592.
- ^ a b Chia, Joanne; Goh, Germaine; Bard, Frederic (August 2016). "Short O-GalNAc glycans: regulation and role in tumor development and clinical perspectives". Biochimica et Biophysica Acta (BBA) - General Subjects. 1860 (8): 1623–1639. doi:10.1016/j.bbagen.2016.03.008. ISSN 0304-4165. PMID 26968459.
- ^ André, Ros, Manon Nguyen, Anh Tuan Chia, Joanne Le Tran, Son Le Guezennec, Xavier McDowall, Ruth Vakhrushev, Sergey Clausen, Henrik Humphries, Martin James Saltel, Frederic Bard, Frederic (2020). ER-resident oxidoreductases are glycosylated and trafficked to the cell surface to promote matrix degradation by tumour cells. OCLC 1322750650.
{{cite book}}: CS1 maint: multiple names: authors list (link) - ^ Scita, Giorgio (2017-11-27). "Faculty Opinions recommendation of Organelle Specific O-Glycosylation Drives MMP14 Activation, Tumor Growth, and Metastasis". doi:10.3410/f.732114780.793539611.
- ^ a b Bard, Frederic; Chia, Joanne (2017-07-18). "Comment on "The GalNAc-T Activation Pathway (GALA) is not a general mechanism for regulating mucin-type O-glycosylation"". PLOS ONE. 12 (7): e0180005. Bibcode:2017PLoSO..1280005B. doi:10.1371/journal.pone.0180005. ISSN 1932-6203. PMC 5515448. PMID 28719645.