AGBL2

AGBL2 (CCP2) is a cytosolic carboxypeptidase that catalyzes posttranslational modification of the carboxy-terminal tails of α-tubulin, acting both as a tubulin tyrosine carboxypeptidase that removes the C-terminal EEY tyrosine to generate detyrosinated tubulin (PMID:21303978) and as a deglutamylase that excises glutamic acid residues from tubulin and other substrate tails (PMID:25103237). Its enzymatic activity is restrained by binding partners: the transmembrane carboxypeptidase inhibitor RARRES1, whose depletion raises detyrosinated α-tubulin levels (PMID:21303978), and the carboxypeptidase inhibitor latexin (PMID:24884516). Through its detyrosination activity AGBL2 promotes cancer cell proliferation and migration and is associated with AKT phosphorylation, an effect partially blocked by the tubulin carboxypeptidase inhibitor parthenolide (PMID:39315218). In hepatocellular carcinoma it additionally suppresses apoptosis by enhancing IRGM-regulated autophagy and elevates TPX2 expression and Aurora A kinase activity to drive proliferation (PMID:29126912). Beyond these tubulin-centered and oncogenic roles, the broader substrate repertoire and the structural basis of substrate selection have not been characterized in the available corpus.

1. 2011 Medium

   Established AGBL2 as the candidate enzyme responsible for the long-sought tubulin tyrosine carboxypeptidase activity and identified its inhibitor, resolving how detyrosination of α-tubulin is controlled.

   Evidence siRNA knockdown of AGBL2 in cancer cells measuring detyrosinated α-tubulin, plus reciprocal RARRES1 knockdown, with Co-IP showing AGBL2–RARRES1 interaction

   PMID:21303978

   Open questions at the time

   • Activity inferred from cellular knockdown rather than reconstituted enzymology
   • Direct catalytic residues and mechanism of detyrosination not defined
   • RARRES1 inhibition shown functionally but not biochemically reconstituted
2. 2014 High

   Defined AGBL2/CCP2 biochemically as a deglutamylase acting on tubulin C-terminal tails, extending its function beyond tyrosine removal and placing it within the CCP enzyme family.

   Evidence In vitro carboxypeptidase activity assays on tubulin and other substrates plus tissue expression analysis

   PMID:25103237

   Open questions at the time

   • Full non-tubulin substrate range not enumerated
   • Confinement to ciliated tissues not connected to a defined ciliary phenotype
3. 2014 Low

   Identified latexin as an additional binding partner/inhibitor of AGBL2, implicating regulation of the tubulin tyrosination cycle in breast cancer stem cells.

   Evidence Co-immunoprecipitation of AGBL2 and latexin from breast cancer cell lysates

   PMID:24884516

   Open questions at the time

   • Single Co-IP without reciprocal validation or mutagenesis
   • Inhibition of catalytic activity not directly demonstrated
4. 2015 Low

   Extended the AGBL2–latexin interaction to gastric cancer and linked both proteins to proliferation and chemoresistance.

   Evidence Co-immunoprecipitation of AGBL2 and latexin plus immunohistochemistry on gastric cancer specimens

   PMID:25916089

   Open questions at the time

   • Single Co-IP, limited mechanistic follow-up
   • Causal link between interaction and chemoresistance not established
5. 2017 Medium

   Showed AGBL2 has oncogenic outputs beyond tubulin modification, suppressing apoptosis and promoting proliferation through autophagy and mitotic kinase pathways.

   Evidence Gain- and loss-of-function in HCC cell lines measuring IRGM-autophagy markers, TPX2, Aurora A activity, and in vivo tumor growth

   PMID:29126912

   Open questions at the time

   • Whether these effects depend on carboxypeptidase catalytic activity not tested
   • Mechanistic connection between tubulin modification and Aurora A/IRGM axes unresolved
6. 2024 Medium

   Connected AGBL2 detyrosination activity to RCC proliferation and migration and to AKT phosphorylation, with pharmacological inhibition confirming dependence on tubulin carboxypeptidase activity.

   Evidence Knockdown/overexpression in RCC cells, parthenolide inhibition, RNA-seq, AKT phosphorylation assay, and subcellular imaging showing nuclear localization

   PMID:39315218

   Open questions at the time

   • Nuclear localization reconciliation with cytosolic carboxypeptidase role unexplained
   • Direct mechanism linking detyrosination to AKT phosphorylation not defined
   • Parthenolide effect partial, implying additional activity-independent contributions

• The structural basis of substrate selection, the full non-tubulin substrate repertoire, and the physiological (e.g. ciliary) function of AGBL2 outside cancer contexts remain undefined.
• No structure of AGBL2 or its substrate complexes
• Catalytic mechanism inferred from family membership, not directly mapped
• Non-oncogenic physiological roles uncharacterized