CASTOR2

CASTOR2 is a cytosolic arginine sensor that couples intracellular arginine availability to mTORC1 signaling through the GATOR2 complex (PMID:41506264). It heterodimerizes with the related sensor CASTOR1 (PMID:26972053) and, like CASTOR1, binds arginine directly, but it is tuned to respond at higher arginine concentrations whereas CASTOR1 reports low arginine (PMID:41506264). Both sensors interact with the GATOR2 component Mios and restrain Mios binding to GATOR1; arginine binding drives a conformational change at the ACT2–ACT4 domain interface that releases CASTOR2 from Mios, relieving GATOR2-mediated inhibition and thereby permitting mTORC1 activation (PMID:41506264). In C2C12 muscle cells this sensing function tunes mTORC1 activity and myogenesis to high arginine availability (PMID:41506264). CASTOR2 expression also constrains mTORC1-driven proliferation: in KSHV-transformed cells, viral suppression of CASTOR1/CASTOR2 activates mTORC1, and restoring CASTOR2 attenuates this activation and blocks colony formation (PMID:31305263).

1. 2016 High

   Established that CASTOR proteins act as cytosolic arginine sensors upstream of mTORC1 and that CASTOR2 participates by heterodimerizing with the arginine-binding sensor CASTOR1.

   Evidence Co-IP, in vitro binding with ITC Kd measurement, mutagenesis, and genetic rescue in cells

   PMID:26972053

   Open questions at the time

   • Arginine binding and GATOR2 regulation were defined for CASTOR1, not directly for CASTOR2
   • Physiological role of the CASTOR1-CASTOR2 heterodimer not resolved
   • No distinct affinity or functional readout assigned to CASTOR2 itself
2. 2019 Medium

   Demonstrated a disease-relevant consequence of CASTOR2 function by showing that its loss permits mTORC1 activation and oncogenic proliferation, while its restoration suppresses transformation.

   Evidence miRNA target reporter assays, knockdown/overexpression, colony formation, and mTORC1 immunoblotting in KSHV-transformed cells

   PMID:31305263

   Open questions at the time

   • Single-lab functional study without structural or direct arginine-binding characterization of CASTOR2
   • Whether CASTOR2 acts independently or only via CASTOR1 heterodimers not dissected
   • Mechanism of mTORC1 suppression inferred from pathway readouts rather than reconstitution
3. 2026 High

   Defined CASTOR2 as a bona fide arginine sensor with a distinct concentration set-point and resolved the mechanistic basis by which arginine binding triggers GATOR2 release.

   Evidence Biochemical arginine-binding assays, ACT-domain conformational analysis, co-IP with Mios, and loss-of-function in C2C12 cells with mTORC1 and myogenesis readouts

   PMID:41506264

   Open questions at the time

   • No high-resolution structure of the arginine-bound CASTOR2–Mios complex
   • Quantitative arginine affinity (Kd) for CASTOR2 not specified
   • In vivo relevance beyond C2C12 muscle cells not established

• How CASTOR2 and CASTOR1 divide labor across the arginine concentration range in intact tissues, and what determines the relative roles of homodimers versus heterodimers, remains unresolved.
• No structural model of CASTOR2 with bound arginine
• Tissue-specific contribution of CASTOR2 versus CASTOR1 not mapped
• Regulation of CASTOR2 expression beyond viral miRNA targeting unknown