ARL14

ARL14 (ARF7) is an Arf-family small GTPase that localizes to endosomes and the plasma membrane, where its targeting is dictated by an N-terminal amphipathic helix in a myristoylation-dependent but GTP-independent manner; swapping this helix with that of the Golgi-localized Arfrp1 redirects ARL14 to the Golgi, and the helix alone suffices to relocate cytosolic proteins, demonstrating that membrane association and GTP-dependent activation are uncoupled for this protein (PMID:32972971). In lung adenocarcinoma cells, ARL14 supports proliferation, migration, and invasion, and its silencing blocks ERK/p38 MAPK signaling, drives G0 cell cycle arrest, and de-represses CIDEC, with no effect on normal lung cells, indicating a tumor-specific dependency (PMID:31750299). Beyond these findings, no further mechanistic detail—including direct effectors, GEFs/GAPs, or the structural basis of its signaling output—has been characterized in the available corpus.

1. 2019 Medium

   Whether ARL14 contributes to tumor cell behavior was unknown; knockdown established it as a tumor-specific driver of proliferation, migration, and invasion acting upstream of ERK/p38 MAPK and CIDEC.

   Evidence siRNA knockdown in lung adenocarcinoma cells with proliferation, migration/invasion, flow-cytometry cell cycle, and western blot readouts

   PMID:31750299

   Open questions at the time

   • no pathway rescue to confirm ERK/p38 and CIDEC are direct downstream effectors
   • direct molecular link between ARL14 GTPase activity and MAPK activation not established
   • single-system result not extended beyond lung adenocarcinoma
2. 2020 High

   How ARL14 achieves its membrane targeting was unresolved; domain-swap and mutagenesis experiments showed the N-terminal amphipathic helix is necessary and sufficient for endosome/plasma membrane localization via myristoylation, and that this occurs independently of GTP binding.

   Evidence chimeric amphipathic-helix swaps between Arfrp1 and Arl14, localization imaging, myristoylation/acetylation and GTP-binding mutants

   PMID:32972971

   Open questions at the time

   • the GTP-bound effectors and GEF/GAP regulators of ARL14 remain unidentified
   • functional consequence of localization for downstream signaling not connected to the MAPK/CIDEC role
   • no structural model of the helix-membrane interaction

• It remains unknown what direct effectors couple membrane-anchored ARL14 to ERK/p38 MAPK activation and CIDEC suppression, and what regulates its GTPase cycle.
• no GEF, GAP, or direct effector identified
• mechanistic bridge between localization and signaling output unestablished