ANKRD35

ANKRD35 functions as a signaling intermediate in clear cell renal cell carcinoma (ccRCC) whose abundance is controlled by the E3 ubiquitin ligase RBCK1, which drives its ubiquitin-dependent proteasomal degradation (PMID:36732658). When stabilized, ANKRD35 binds SUMO2 and destabilizes MITD1 (PMID:36732658), operating within an RBCK1-ANKRD35-MITD1-ANXA1 axis that modulates AKT and ERK phosphorylation and thereby tunes sunitinib sensitivity in ccRCC (PMID:36732658). Beyond this axis defined in ccRCC, no further biochemical or structural characterization of ANKRD35 has been established in the available corpus.

1. 2023 Medium

   Establishing how ANKRD35 protein levels are controlled identified it as a degradation substrate of the E3 ligase RBCK1, linking it to the ubiquitin-proteasome system in ccRCC.

   Evidence Ubiquitin-proteasome pathway assays in ccRCC cell lines and patient specimens, in vitro and in vivo

   PMID:36732658

   Open questions at the time

   • Direct ubiquitination sites on ANKRD35 not mapped
   • Whether RBCK1 ubiquitinates ANKRD35 directly versus via an adaptor not resolved
   • Single-lab abstract-level detail without reciprocal validation
2. 2023 Medium

   Defining ANKRD35's downstream action showed it binds SUMO2 and destabilizes MITD1, placing it as an effector immediately downstream of RBCK1.

   Evidence Interaction and functional destabilization assays in ccRCC cells

   PMID:36732658

   Open questions at the time

   • No mutagenesis or reciprocal Co-IP reported to confirm the ANKRD35-SUMO2 interaction
   • Mechanism by which ANKRD35 destabilizes MITD1 unresolved
   • Whether SUMO2 binding is required for MITD1 destabilization untested
3. 2023 Medium

   Ordering the full RBCK1-ANKRD35-MITD1-ANXA1 axis connected ANKRD35 to AKT/ERK signaling and drug response, framing its role in sunitinib sensitivity.

   Evidence In vitro and in vivo epistasis studies with RBCK1 inhibition and AKT/MAPK and sunitinib-response readouts

   PMID:36732658

   Open questions at the time

   • Causal contribution of ANKRD35 versus other axis members to AKT/ERK changes not isolated
   • Generalizability beyond ccRCC unknown
   • How ANXA1 expression is mechanistically coupled to MITD1 not detailed

• The intrinsic molecular activity, domain function, and physiological role of ANKRD35 outside the ccRCC sunitinib-sensitivity context remain uncharacterized.
• No subcellular localization established
• No structural model of ANKRD35 or its interaction interfaces
• No evidence in non-renal tissues or normal physiology