CALCR

CALCR (calcitonin receptor) is a G protein-coupled receptor that transduces calcitonin and surrogate ligand signals through cAMP/PKA and MAPK/ERK pathways to regulate cell quiescence, proliferation, and neural circuit function. In muscle satellite cells, CALCR activation by calcitonin or Collagen V (downstream of Notch signaling) engages PKA to phosphorylate LATS1/2, suppressing YAP1 nuclear accumulation via the Hippo pathway and thereby maintaining quiescence (PMID:29795344, PMID:31747590). CALCR functions as a tumor suppressor in glioblastoma, where patient-derived loss-of-function mutations abolish its ability to inhibit Ras-mediated transformation and pro-oncogenic signaling, while in renal and gastric cancers it instead promotes proliferation through stabilization of CD44 and interaction with ANTXR1/AKT signaling (PMID:29263181, PMID:38985127, PMID:40195530). CALCR also forms functional heterodimers with the prostaglandin EP2 receptor that selectively attenuate Ca²⁺ mobilization, exhibits tissue-specific maternal imprinting in the brain, and marks neuronal populations in the medial amygdala and brainstem that regulate social behavior and food intake (PMID:29095955, PMID:12730726, PMID:36658598).

1. 1995 High

   Establishing the chromosomal location of CALCR at 7q21.3 provided the foundational genomic context for subsequent functional and disease-association studies.

   Evidence PCR of somatic cell hybrids and two-color FISH on human metaphase chromosomes

   PMID:7789182

   Open questions at the time

   • No functional information derived from mapping alone
   • Regulatory elements and promoter architecture uncharacterized
2. 1996 Medium

   Demonstrating that calcitonin-induced receptor down-regulation and adenylate cyclase uncoupling occur independently of mRNA changes and PKA/PKC activation established that homologous desensitization is an intrinsic property of CALCR itself.

   Evidence Receptor binding assays, adenylate cyclase activity measurements, RT-PCR, and pharmacological inhibitor studies in UMR106-06 and transfected HEK293 cells

   PMID:8895320

   Open questions at the time

   • Molecular mechanism of receptor-intrinsic uncoupling (e.g., phosphorylation sites, arrestin involvement) not identified
   • Not tested in primary cells or in vivo
3. 2003 Medium

   Discovery of tissue-specific maternal imprinting of Calcr in the brain revealed an epigenetic regulatory layer, raising the question of whether monoallelic expression influences CALCR-dependent neural functions.

   Evidence Allelic expression analysis in F1 mice from reciprocal crosses between B6 and JF strains

   PMID:12730726

   Open questions at the time

   • Functional consequence of monoallelic brain expression unknown
   • Imprinting control region not mapped
   • Not confirmed in human tissues
4. 2017 Medium

   Two studies established CALCR's roles in heterodimer signaling and tumor suppression: CALCR forms heterodimers with EP2 that selectively attenuate Ca²⁺ signaling, and patient-derived loss-of-function CALCR mutations abolish its tumor-suppressive activity in glioblastoma by failing to inhibit Ras-mediated transformation.

   Evidence Reciprocal co-IP, FRET, and Ca²⁺/cAMP functional assays in HEK293 cells (heterodimerization); patient-derived mutations in glioma cell lines, xenografts, and calcitonin treatment (tumor suppression)

   PMID:29095955 PMID:29263181

   Open questions at the time

   • Structural basis of EP2-CALCR heterodimer selectivity unknown
   • Which downstream effectors mediate CALCR tumor suppression in glioma beyond Ras not fully defined
   • In vivo relevance of EP2-CALCR heterodimerization not established
5. 2018 High

   Identification of Collagen V as a surrogate local ligand for CALCR in satellite cells, downstream of Notch, resolved how quiescence is maintained cell-autonomously and placed CALCR within a Notch–COLV signaling cascade.

   Evidence Conditional Col5a1 knockout, ChIP-seq, systemic calcitonin rescue of COLV-null satellite cells, genetic epistasis in mice

   PMID:29795344

   Open questions at the time

   • Direct binding of Collagen V to CALCR not biochemically demonstrated
   • Whether other collagens can substitute as CALCR ligands not tested
6. 2019 High

   Elucidation of the PKA–LATS1/2–YAP1 axis downstream of CALCR provided the complete intracellular signaling cascade by which CALCR enforces satellite cell quiescence through Hippo pathway activation.

   Evidence Transgenic PKA catalytic domain expression in CalcR-mutant mice, Yap1 genetic inactivation in CalcR-mutant cells (double-mutant rescue), phosphorylation assays

   PMID:31747590

   Open questions at the time

   • Whether this PKA–LATS–YAP axis operates in non-satellite-cell contexts not established
   • Identity of YAP1 transcriptional targets driving quiescence exit not fully cataloged
7. 2023 Medium

   Identification of Calcr-expressing GABAergic neurons in the medial amygdala that suppress social contacts expanded CALCR's role beyond endocrine/stem cell biology into circuit-level behavioral regulation.

   Evidence AAV-shRNA knockdown of Calcr in MeApd, behavioral assays during resocialization in mice

   PMID:36658598

   Open questions at the time

   • Downstream signaling in MeApd Calcr neurons not characterized
   • Whether calcitonin itself is the relevant ligand in this circuit is unclear
   • Specificity of shRNA knockdown not independently confirmed
8. 2024 Medium

   Discovery that CALCR directly binds CD44 to prevent its degradation and that CALCR couples to MAPK/ERK in addition to cAMP/PKA broadened understanding of CALCR's context-dependent signaling repertoire and its dual tumor-suppressive versus pro-tumorigenic roles.

   Evidence Co-IP of CALCR-CD44 with epistasis experiments and in vivo tumor assays in renal carcinoma (CD44 interaction); luciferase reporter assays for cAMP/PKA and MAPK/ERK with RAMP co-expression in chicken CTR system (dual pathway activation)

   PMID:38612299 PMID:38985127

   Open questions at the time

   • Structural determinants of CALCR-CD44 binding unknown
   • How tissue context determines whether CALCR acts as tumor suppressor or promoter not resolved
   • RAMP-dependent pathway switching in mammalian systems not confirmed
9. 2025 Low

   Interaction of CALCR with ANTXR1 and subsequent AKT activation was reported as a mechanism for CALCR-driven gastric cancer progression, though this rests on limited validation.

   Evidence Co-IP of CALCR-ANTXR1, CALCR knockdown with AKT phosphorylation western blotting, nude mouse xenograft

   PMID:40195530

   Open questions at the time

   • Single Co-IP without reciprocal validation or domain-mapping
   • Causal link between ANTXR1 binding and AKT activation not mechanistically dissected
   • Not independently replicated

• Key unresolved questions include the structural basis of CALCR ligand promiscuity (calcitonin vs. Collagen V), how tissue context switches CALCR between tumor-suppressive and pro-tumorigenic signaling, and the physiological ligand(s) activating CALCR in brain circuits controlling behavior.
• No co-crystal or cryo-EM structure of CALCR with Collagen V
• Mechanism governing context-dependent oncogenic vs. tumor-suppressive output undefined
• Endogenous ligand for neuronal CALCR populations not identified