CALCR

CALCR encodes the calcitonin receptor, a G protein-coupled receptor that couples ligand binding to cAMP/PKA signaling to control cell-cycle quiescence and tumor-suppressive transcription (PMID:31747590, PMID:29263181). In muscle satellite cells, CALCR maintains quiescence cell-autonomously through a PKA–LATS1/2–YAP1 axis: PKA activation downstream of the receptor phosphorylates LATS1/2, which restrains nuclear YAP1 and suppresses Hippo-target cell-cycle genes, with both PKA catalytic-domain transgenes and Yap1 inactivation rescuing CALCR-mutant quiescence defects (PMID:31747590). The local ligand for this satellite-cell program is Collagen V, produced downstream of Notch/RBPJ, and systemic calcitonin derivatives rescue quiescence defects in Collagen V-null cells (PMID:29795344). The same cAMP/PKA/LATS-Hippo cascade underlies CALCR's tumor-suppressive activity in glioblastoma, where calcitonin inhibits proliferation and Ras-mediated transformation in a receptor-dependent manner and patient-derived loss-of-function mutations abolish these effects (PMID:29263181). CALCR signaling is subject to homologous desensitization through ligand-induced receptor down-regulation and adenylate cyclase uncoupling independent of PKA/PKC and of receptor mRNA levels (PMID:8895320), and is modulated by heterodimerization with the EP2 prostaglandin receptor, which selectively dampens CALCR-mediated Ca2+ mobilization (PMID:29095955). The mouse Calcr gene shows brain-specific maternal imprinting (PMID:12730726), and CALCR-expressing neurons function in defined circuits, including GABAergic neurons of the posterodorsal medial amygdala that suppress social contact (PMID:36658598).

1. 1995 Medium

   Before functional dissection, the human CALCR locus had to be physically placed in the genome, establishing it as a distinct gene near but outside the Williams syndrome region.

   Evidence PCR of somatic cell hybrids, single-strand conformation analysis, and two-color FISH to metaphase chromosomes

   PMID:7789182

   Open questions at the time

   • No functional or regulatory information from mapping alone
   • Does not address receptor activity or signaling
2. 1996 Medium

   It was unclear how CALCR responsiveness is regulated after agonist exposure; this work showed receptor desensitization occurs via surface down-regulation and adenylate cyclase uncoupling, not transcriptional control or kinase feedback.

   Evidence Radioligand binding, adenylate cyclase assays, RT-PCR for CTR mRNA, and PKA/PKC pharmacology in transfected HEK293 and endogenous cells

   PMID:8895320

   Open questions at the time

   • Molecular machinery of down-regulation (internalization, arrestins) not identified
   • Studied in rat C1a isoform; human relevance not directly tested
3. 2003 Medium

   The question of whether Calcr is monoallelically expressed was answered by showing tissue-specific maternal imprinting restricted to the brain.

   Evidence Allelic expression analysis in F1 mice from reciprocal B6 × JF crosses

   PMID:12730726

   Open questions at the time

   • Imprinting control elements not mapped
   • Functional consequence of brain-specific maternal expression unknown
4. 2017 Medium

   Whether CALCR has anti-proliferative function was tested in glioblastoma, where calcitonin inhibited transformation and tumor growth in a receptor-dependent manner and patient mutations abolished this, defining CALCR as a tumor suppressor.

   Evidence Loss-of-function mutation characterization, in vitro transformation assay, patient-derived neurosphere assay, and mouse xenograft

   PMID:29263181

   Open questions at the time

   • Downstream signaling effectors not resolved in this study
   • Endogenous tumor-relevant ligand source unclear
5. 2017 Medium

   To explain how CALCR's Ca2+ signaling is tuned, heterodimerization with the EP2 prostaglandin receptor was shown to selectively reduce CALCR-mediated Ca2+ mobilization without altering cAMP output.

   Evidence Reciprocal Co-IP with LC-MS/MS, FRET, and functional Ca2+/cAMP assays in granulosa and HEK293 cells

   PMID:29095955

   Open questions at the time

   • Physiological setting of heterodimer beyond granulosa cells not established
   • Structural basis of biased signaling not resolved
6. 2018 High

   The endogenous local ligand and upstream regulation of CALCR in satellite cells were unknown; Collagen V was identified as a Notch/RBPJ-driven surrogate ligand maintaining quiescence.

   Evidence ChIP-seq, conditional Col5a1 knockout, and in vivo pharmacological rescue with a calcitonin derivative

   PMID:29795344

   Open questions at the time

   • Mode of Collagen V engagement of the receptor not structurally defined
   • Whether Collagen V acts elsewhere as a CALCR ligand untested
7. 2019 High

   How CALCR enforces quiescence at the signaling level was resolved by placing it in a PKA–LATS1/2–YAP1 cascade that suppresses Hippo-target cell-cycle genes, via genetic epistasis.

   Evidence PKA catalytic-domain transgenic rescue, CalcR × Yap1 double-mutant epistasis, and LATS1/2 phosphorylation assays

   PMID:31747590

   Open questions at the time

   • G protein/cAMP coupling step linking receptor to PKA not detailed
   • Generalizability beyond satellite cells not tested here
8. 2023 Low

   The circuit-level role of CALCR neurons in behavior was probed by showing MeApd CALCR-expressing GABAergic neurons suppress social contact.

   Evidence Immunohistochemistry for cell-type markers, AAV-shRNA Calcr knockdown, and resocialization behavioral assay

   PMID:36658598

   Open questions at the time

   • Single knockdown experiment with limited molecular pathway characterization
   • Ligand and downstream signaling in these neurons unidentified
9. 2024 Low

   Additional protein partners in cancer were sought; CALCR was shown to bind CD44 and stabilize it against degradation, supporting pro-tumorigenic phenotypes in renal cell carcinoma.

   Evidence Co-IP, CALCR knockdown with CD44 rescue, and in vivo tumor formation assay

   PMID:38985127

   Open questions at the time

   • Single Co-IP for binding claim without reciprocal/structural validation
   • Mechanism of CD44 stabilization unresolved
   • Apparent pro-tumor role conflicts with tumor-suppressor data in other tissues
10. 2025 Medium

    The glioblastoma tumor-suppressor mechanism was unified with the satellite-cell cascade by showing CTR/cAMP/PKA/LATS1 activation of Hippo suppresses YAP/TAZ, with structural rationale for mutant inactivity.

    Evidence Patient-derived glioma stem cell assays, LATS1/YAP phosphorylation and epistasis, intracranial orthotopic model with intranasal calcitonin, and all-atom molecular dynamics (preprint)

    Open questions at the time

    • Preprint, not yet peer-reviewed
    • In vivo efficacy across diverse patient tumors not established
11. 2025 Low

    The role of brainstem CALCR neurons in energy balance was characterized, identifying NTS Calcr/Prlh cells as mediators of long-term amylin-analog responsiveness.

    Evidence Single-nucleus RNA-seq, spatial transcriptomics, cross-species comparison, and in vivo activation of AP Calcr cells (preprint)

    Open questions at the time

    • Preprint with limited direct manipulation of CALCR itself
    • Receptor-intrinsic signaling in these neurons not dissected
12. 2025 Low

    Another cancer interaction was reported, with CALCR binding ANTXR1 and decreasing AKT phosphorylation to promote gastric cancer growth.

    Evidence Co-IP, siRNA knockdown, proliferation/apoptosis/migration assays, and nude mouse xenograft

    PMID:40195530

    Open questions at the time

    • Single Co-IP for binding claim without reciprocal validation
    • Mechanistic link from ANTXR1 interaction to AKT not characterized

• How CALCR can act as a tumor suppressor via Hippo in some contexts yet appear pro-tumorigenic through CD44/ANTXR1 in others, and what determines its tissue-specific signaling outputs, remains unresolved.
• No unifying model reconciling tumor-suppressive and pro-tumor roles
• Receptor structure and G-protein coupling determinants not defined in the corpus
• Endogenous ligands outside muscle Collagen V not established