KREMEN2

KREMEN2 is a transmembrane co-receptor that functions as a molecular switch in Wnt signaling, converting the Dickkopf protein Dkk2 from an activator into an inhibitor of Wnt/LRP6 signaling and cooperating with Dkk4 to suppress Wnt output, an interaction mediated by the second cysteine-rich domain of the Dkk partners (PMID:12527209). Through this Dkk/Krm/LRP5-6 ternary mechanism, KREMEN2 acts as a cell-autonomous negative regulator of canonical Wnt/β-catenin signaling and bone formation: its overexpression in osteoblasts causes severe osteoporosis with impaired osteoblast maturation and reduced β-catenin activity, whereas its loss yields high bone mass (PMID:20436912, PMID:25061805). In cancer, KREMEN2 is repurposed as a pro-survival, signaling-sustaining factor. It binds SOCS3 to block SOCS3-mediated ubiquitination and proteasomal degradation of EGFR, thereby maintaining EGFR levels and driving downstream PI3K-AKT and JAK2-STAT3 signaling (PMID:37270563), and it activates a PI3K/AKT/mTOR axis that promotes proliferation, migration, invasion, and EMT (PMID:40638942, PMID:33489867). KREMEN2 also interacts with and stabilizes ATF2 to inhibit ferroptosis and promote tumor progression (PMID:40057259). KREMEN2 expression is itself controlled at two levels: transcriptionally, loss of SWI/SNF (SMARCB1/cBAF) complexes permits CBP/p300-mediated H3K27 acetylation and upregulation at the KREMEN2 locus, after which KREMEN2 heterodimerizes with KREMEN1 to suppress apoptosis (PMID:38839769, PMID:39625239); post-transcriptionally, FTO-mediated m6A demethylation and IGF2BP1-mediated m6A reading set KREMEN2 mRNA stability and protein levels (PMID:38615731).

1. 2003 High

   Established the founding molecular function of KREMEN2: it is the cofactor that switches Dkk2 between Wnt activation and inhibition, defining its place in the Wnt/LRP6 axis.

   Evidence Co-transfection signaling assays in human 293 fibroblasts, Xenopus embryo overexpression, and Dkk domain-mapping

   PMID:12527209

   Open questions at the time

   • No structural model of the Krm2-Dkk-LRP6 complex
   • Endogenous receptor function not tested, only overexpression
2. 2010 High

   Demonstrated the physiological consequence of KREMEN2 Wnt inhibition in vivo, identifying it as a cell-autonomous negative regulator of osteoblast differentiation and bone formation.

   Evidence Complementary gain- and loss-of-function mouse models (Col1a1-Krm2 transgenic, Krm2-knockout) with histomorphometry and Wnt readouts

   PMID:20436912

   Open questions at the time

   • Mechanism of OPG regulation not detailed
   • Did not resolve relative contributions of Krm1 vs Krm2
3. 2014 Medium

   Extended the bone phenotype to tissue repair, showing KREMEN2 suppresses Wnt/β-catenin-dependent osteogenesis during fracture healing more potently than LRP5 loss.

   Evidence Transgenic mouse fracture model with histomorphometry, microarray, and active β-catenin immunohistochemistry

   PMID:25061805

   Open questions at the time

   • Downstream targets (e.g., Smpd3) not functionally validated
   • Single lab
4. 2021 Medium

   Opened the oncogenic chapter by linking KREMEN2 to pro-survival PI3K/Akt signaling in gastric cancer, contrasting with its tumor-suppressive Wnt-inhibitory role in bone.

   Evidence siRNA knockdown in gastric cancer lines with xenografts and pathway Western blots

   PMID:33489867

   Open questions at the time

   • No molecular mechanism connecting KREMEN2 to PI3K/Akt
   • No rescue experiments
5. 2023 High

   Provided the first molecular mechanism for KREMEN2's oncogenic signaling: it protects EGFR from SOCS3-mediated degradation, sustaining PI3K-AKT and JAK2-STAT3 activity.

   Evidence Reciprocal co-IP, ubiquitination assay, KREMEN2 knockout/knockdown, and in vivo xenograft/metastasis models in NSCLC

   PMID:37270563

   Open questions at the time

   • Whether KREMEN2-SOCS3 binding is direct not resolved
   • Relationship to Dkk/Wnt co-receptor function unaddressed
6. 2024 High

   Revealed how KREMEN2 is transcriptionally controlled in SWI/SNF-deficient cancers and identified a KREMEN2-KREMEN1 heterodimer as an anti-apoptotic module exploitable by CBP/p300 inhibition.

   Evidence Dual siRNA synthetic lethality screen, ChIP for chromatin marks/EZH2/CBP/p300, CBP/p300 inhibitor, co-IP, and xenografts in SMARCB1-deficient cancers

   PMID:38839769

   Open questions at the time

   • Mechanism by which KREMEN1-KREMEN2 dimer suppresses apoptosis not defined
   • Membrane topology of the heterodimer unresolved
7. 2024 Medium

   Defined post-transcriptional control of KREMEN2 via m6A, showing FTO demethylation and IGF2BP1 reading set its mRNA stability and protein abundance.

   Evidence MeRIP-qPCR, RIP, FTO overexpression, IGF2BP1/2/3 knockdown, and growth assays in high-grade serous ovarian cancer

   PMID:38615731

   Open questions at the time

   • m6A site mapping at single-nucleotide resolution not shown
   • Single lab
8. 2025 Medium

   Identified ATF2 as a KREMEN2 interaction partner whose stabilization mediates ferroptosis inhibition and tumor progression, adding a cell-death-resistance arm to KREMEN2 function.

   Evidence Co-IP, cycloheximide pulse-chase, ATF2-knockdown epistasis, and xenograft/ferroptosis assays in RCC

   PMID:40057259

   Open questions at the time

   • Whether KREMEN2-ATF2 interaction is direct not established
   • Mechanism of ATF2 stabilization not defined
9. 2025 Medium

   Consolidated the PI3K/AKT/mTOR effector axis of KREMEN2 with genetic epistasis and broadened the KREMEN2-KREMEN1 apoptotic dependency to the wider cBAF-deficient cancer class.

   Evidence siRNA/overexpression with PI3K activator rescue in NSCLC, and CBP/p300 inhibition with apoptosis assays/xenografts in SMARCA4/SMARCA2-deficient and SS18-SSX cancers

   PMID:39625239 PMID:40638942

   Open questions at the time

   • How KREMEN2 couples to PI3K upstream not mechanistically resolved
   • Single lab for each context
10. 2026 Low

    Recapitulated EGFR/JAK2/STAT3 dependence in colorectal cancer, supporting generality of the KREMEN2-EGFR signaling link across tumor types.

    Evidence siRNA knockdown in HCT116 with viability/migration assays and pathway Western blots

    PMID:41472941

    Open questions at the time

    • Single method without mechanistic linkage to EGFR/JAK2/STAT3
    • No rescue or in vivo validation

• It remains unresolved how KREMEN2's canonical role as a Dkk/Wnt co-receptor mechanistically connects to its tumor context-specific functions in EGFR stabilization, PI3K signaling, and ferroptosis suppression.
• No structural data integrating Wnt co-receptor and oncogenic interaction modes
• Whether SOCS3, ATF2, and KREMEN1 binding occur through shared or distinct domains is unknown
• Direct vs indirect nature of several reported interactions undetermined