title: Tumor suppressor RARRES1 interacts with cytoplasmic carboxypeptidase AGBL2 to regulate the α-tubulin tyrosination cycle.
abstract: Even though it is among the most commonly methylated loci in multiple cancers, the retinoic acid-induced tumor suppressor retinoic acid receptor responder 1 (RARRES1) has no known function. We now show that RARRES1 is lost in many cancer cells, particularly those with a mesenchymal phenotype, and is a transmembrane carboxypeptidase inhibitor that interacts with ATP/GTP binding protein-like 2 (AGBL2), a cytoplasmic carboxypeptidase. Knockdown of AGBL2 results in a failure of the cell to detyrosinate the C-terminal EEY region of α-tubulin and indicates that it is a candidate for the long sought-after tubulin tyrosine carboxypeptidase important in the regulation of microtubule dynamics. In contrast, knockdown of RARRES1 increases the level of detyrosinated α-tubulin consistent with a role as the cognate inhibitor of AGBL2. We conclude that RARRES1, its interacting partners AGBL2, Eg5/KIF11, another EEY-bearing protein (EB1), and the microtubule tyrosination cycle are important in tumorigenesis and identify a novel area for therapeutic intervention.
authors.affiliation: Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: Ziad J
authors.initials: ZJ
authors.lastname: Sahab
authors.forename: Michael D
authors.initials: MD
authors.lastname: Hall
authors.forename: You
authors.initials: Y
authors.lastname: Me Sung
authors.forename: Sivanesan
authors.initials: S
authors.lastname: Dakshanamurthy
authors.forename: Yun
authors.initials: Y
authors.lastname: Ji
authors.forename: Deepak
authors.initials: D
authors.lastname: Kumar
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Byers
mesh_terms: D000595:Amino Acid Sequence; D002268:Carboxypeptidases / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010802:Phylogeny; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D014404:Tubulin / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; C452562:RARRES1 protein, human; D014404:Tubulin; D025521:Tumor Suppressor Proteins; D014443:Tyrosine; D002268:Carboxypeptidases; C557716:AGBL2 protein, human