AGBL2

AGBL2 (also designated cytosolic carboxypeptidase 2/CCP2) is a metallocarboxypeptidase that catalyzes detyrosination of the C-terminal EEY motif of α-tubulin and deglutamylation of tubulin C-terminal tails, thereby regulating the tubulin tyrosination cycle and microtubule dynamics (PMID:21303978, PMID:25103237). Its enzymatic activity is inhibited by the transmembrane carboxypeptidase inhibitor RARRES1 and by latexin, which form physical complexes with AGBL2 (PMID:21303978, PMID:24884516). In cancer cells, AGBL2 overexpression promotes proliferation, migration, and chemotherapy resistance through enhanced α-tubulin detyrosination, upregulation of Aurora A kinase activity via TPX2, stimulation of IRGM-regulated autophagy, and activation of AKT phosphorylation (PMID:29126912, PMID:39315218).

1. 2011 High

   Identification of AGBL2 as a tubulin carboxypeptidase that detyrosinates α-tubulin's C-terminal EEY sequence resolved a long-sought question about the identity of the enzyme (TCP) responsible for tubulin detyrosination, and simultaneously revealed RARRES1 as its cognate inhibitor.

   Evidence siRNA knockdown of AGBL2 with immunofluorescence/western blot readout of detyrosinated α-tubulin; co-immunoprecipitation of RARRES1 with AGBL2 in human cells

   PMID:21303978

   Open questions at the time

   • Whether AGBL2 is the sole or primary TCP in vivo versus other CCP family members
   • Structural basis of RARRES1 inhibition of AGBL2 is unknown
   • No in vitro reconstitution of AGBL2 enzymatic activity in this study
2. 2014 High

   Direct biochemical characterization established AGBL2/CCP2 as a deglutamylase that removes C-terminal glutamate residues from tubulin, defining its substrate specificity and distinguishing it from CCP3's dual deglutamylase/deaspartylase activity.

   Evidence In vitro enzymatic assays with tubulin and peptide substrates; mass spectrometry-based product analysis

   PMID:25103237

   Open questions at the time

   • Full range of non-tubulin substrates not established
   • Kinetic parameters and catalytic mechanism remain unresolved
   • Tissue restriction to ciliated tissues not mechanistically explained
3. 2014 Low

   Identification of latexin as a second carboxypeptidase inhibitor physically interacting with AGBL2 expanded the regulatory landscape and linked AGBL2 to cancer stem cell biology and chemotherapy resistance, though mechanistic depth was limited.

   Evidence Co-immunoprecipitation of AGBL2 and latexin in breast cancer stem cells; IHC in sorted CD44+/CD24− populations

   PMID:24884516

   Open questions at the time

   • Single Co-IP without reciprocal validation or domain mapping
   • Whether latexin directly inhibits AGBL2 catalytic activity or acts via indirect mechanisms is untested
   • Functional consequence of AGBL2–latexin interaction on tubulin modification not quantified
4. 2017 Medium

   Demonstrating that AGBL2 overexpression suppresses apoptosis via IRGM-regulated autophagy and activates Aurora A kinase through TPX2 upregulation revealed downstream oncogenic effector pathways beyond tubulin detyrosination.

   Evidence Ectopic overexpression and knockdown in HCC cell lines; apoptosis, autophagy flux, and Aurora A kinase activity assays; xenograft tumor models

   PMID:29126912

   Open questions at the time

   • Whether AGBL2 regulates IRGM and TPX2/Aurora A through its carboxypeptidase activity or via a separate function is unclear
   • Mechanism linking tubulin detyrosination to autophagy induction not established
   • Single lab study without independent replication
5. 2024 Medium

   Observation that AGBL2 enhances AKT phosphorylation and that its pro-tumorigenic effects are partially blocked by parthenolide broadened the signaling outputs of AGBL2 and provided pharmacological validation of its carboxypeptidase activity in cancer.

   Evidence AGBL2 knockdown/overexpression in RCC cell lines; parthenolide treatment; AKT phosphorylation by western blot; RNA sequencing

   PMID:39315218

   Open questions at the time

   • Direct versus indirect regulation of AKT by AGBL2 is unresolved
   • Parthenolide is not a specific AGBL2 inhibitor, limiting mechanistic interpretation
   • Nuclear localization of AGBL2 observed in RCC cells lacks functional characterization

• The structural basis of AGBL2 catalysis, its full non-tubulin substrate repertoire, the functional significance of its reported nuclear localization, and the precise mechanism by which AGBL2 carboxypeptidase activity connects to downstream signaling pathways (AKT, Aurora A, autophagy) remain unresolved.
• No crystal or cryo-EM structure of AGBL2 available
• Systematic identification of non-tubulin substrates not performed
• Nuclear function of AGBL2 unexplored