KREMEN2

KREMEN2 is a transmembrane co-receptor that modulates Wnt/β-catenin signaling, bone homeostasis, and oncogenic survival pathways. It forms ternary complexes with Dickkopf (Dkk) family ligands and LRP5/6, converting Dkk2 from a Wnt activator to a Wnt inhibitor and cooperating with Dkk1/Dkk4 to suppress canonical Wnt signaling; genetic gain- and loss-of-function in mice establish KREMEN2 as a physiological negative regulator of osteoblast-mediated bone formation (PMID:12527209, PMID:20436912). Beyond Wnt modulation, KREMEN2 sustains EGFR protein stability by binding SOCS3 and blocking SOCS3-mediated EGFR ubiquitination, thereby activating PI3K-AKT and JAK2-STAT3 signaling in NSCLC, and independently stabilizes ATF2 to suppress ferroptosis in renal cell carcinoma (PMID:37270563, PMID:40057259). KREMEN2 expression is epigenetically controlled by the SWI/SNF–EZH2 axis: in cBAF/SMARCB1-deficient cancers, loss of H3K27me3 repression and gain of CBP/p300-dependent H3K27ac upregulate KREMEN2, whose heterodimerization with KREMEN1 provides a pro-survival signal that is abolished by CBP/p300 inhibition (PMID:38839769, PMID:39625239).

1. 2003 High

   Establishing that KREMEN2 functions as a co-receptor that switches Dkk2 from a Wnt activator to a Wnt inhibitor resolved how Dkk ligand context determines signaling outcome at the LRP5/6 receptor.

   Evidence Co-transfection luciferase reporter assays in HEK293 cells plus Xenopus embryo epistasis experiments with domain mapping

   PMID:12527209

   Open questions at the time

   • Structural basis of the Krm2–Dkk–LRP6 ternary complex not determined
   • Relative contribution of Krm2 versus Krm1 to Dkk-mediated Wnt inhibition unclear
   • Endogenous stoichiometry and tissue-level relevance not addressed
2. 2010 High

   Complementary transgenic overexpression and knockout mouse models demonstrated that KREMEN2 is a physiological negative regulator of bone formation acting through Dkk1/Krm/Lrp5/6-dependent Wnt inhibition in osteoblasts.

   Evidence Col1a1-Krm2 transgenic mice (severe osteoporosis) and Krm2-knockout mice (high bone mass), with histomorphometry and primary osteoblast assays

   PMID:20436912

   Open questions at the time

   • Whether KREMEN2 has bone-cell-extrinsic effects (e.g., on osteoclasts) not tested
   • Functional redundancy with KREMEN1 in bone not delineated
3. 2014 Medium

   Showing that Krm2 overexpression impaired fracture healing more severely than Lrp5 loss positioned KREMEN2-mediated Wnt inhibition as a rate-limiting step in bone repair upstream of β-catenin activation.

   Evidence Transgenic mouse fracture model with semi-rigid/flexible fixation, immunohistochemistry for active β-catenin, microarray

   PMID:25061805

   Open questions at the time

   • Direct comparison between Krm2 and Lrp5 mutants is confounded by different genetic backgrounds
   • Downstream effector Smpd3 linkage is correlative
4. 2021 Medium

   Demonstrating that KREMEN2 knockdown suppresses gastric cancer cell survival and PI3K/Akt signaling revealed a Wnt-independent oncogenic function, raising the question of how a Wnt inhibitory co-receptor promotes tumor growth.

   Evidence shRNA knockdown in gastric cancer cell lines, xenograft models, Western blot for PI3K/Akt pathway components

   PMID:33489867

   Open questions at the time

   • No direct binding partner linking KREMEN2 to PI3K/Akt was identified
   • Whether the gastric cancer role requires Wnt pathway engagement untested
5. 2023 High

   Identifying SOCS3 as a direct KREMEN2-binding partner that bridges KREMEN2 to EGFR stability provided the first mechanistic explanation for KREMEN2's Wnt-independent oncogenic activity via PI3K-AKT and JAK2-STAT3 signaling.

   Evidence Reciprocal Co-IP, ubiquitination assay, EGFR protein-level rescue, xenograft and metastatic mouse models in NSCLC cells

   PMID:37270563

   Open questions at the time

   • Whether KREMEN2–SOCS3 interaction occurs outside NSCLC contexts unknown
   • Domain on KREMEN2 responsible for SOCS3 binding not mapped
   • Relationship between KREMEN2's Wnt co-receptor and EGFR-stabilizing functions not addressed
6. 2024 High

   Revealing that SWI/SNF (SMARCB1/cBAF) complexes recruit EZH2-mediated H3K27me3 to repress KREMEN2, and that KREMEN2 upregulation in SWI/SNF-deficient cancers creates a CBP/p300-dependent vulnerability, established a chromatin-level mechanism controlling KREMEN2 expression and linked KREMEN1–KREMEN2 heterodimerization to anti-apoptotic signaling.

   Evidence ChIP for H3K27me3/H3K27ac, CBP/p300 dual inhibitor, Co-IP for KREMEN1–KREMEN2, dual siRNA screen, xenografts in SMARCB1-deficient and cBAF-deficient cancers

   PMID:38839769 PMID:39625239

   Open questions at the time

   • How KREMEN1–KREMEN2 heterodimer delivers an anti-apoptotic signal mechanistically unknown
   • Whether KREMEN2 upregulation is sufficient or merely necessary for the CBP/p300 vulnerability not fully resolved
   • Applicability beyond SWI/SNF-deficient cancer subtypes untested
7. 2024 Medium

   Demonstrating that m6A modifications on KREMEN2 mRNA are stabilized by the reader IGF2BP1 (countered by FTO demethylation) revealed a post-transcriptional regulatory layer controlling KREMEN2 abundance in high-grade serous ovarian cancer.

   Evidence MeRIP-qPCR, RNA immunoprecipitation with IGF2BP1/2/3, FTO overexpression, tumor growth assays

   PMID:38615731

   Open questions at the time

   • Specific m6A site(s) and their individual contributions not resolved at nucleotide resolution
   • Whether IGF2BP1-dependent stabilization operates in non-ovarian contexts unknown
8. 2025 Medium

   Identification of ATF2 as a direct KREMEN2-binding partner whose protein stability is maintained by KREMEN2 uncovered a ferroptosis-suppressive axis in renal cell carcinoma, adding a third Wnt-independent effector mechanism.

   Evidence Co-IP, cycloheximide pulse-chase, ATF2 epistasis knockdown, ferroptosis indicator assays, xenograft model

   PMID:40057259

   Open questions at the time

   • Mechanism by which KREMEN2 stabilizes ATF2 (e.g., blocking specific E3 ligase) not identified
   • Whether ATF2 stabilization is specific to renal cell carcinoma not tested
   • Relationship between ATF2 stabilization and KREMEN2's other signaling outputs unexplored

• A unified structural and signaling model explaining how KREMEN2 coordinates its Wnt co-receptor function with its Wnt-independent oncogenic activities (EGFR/SOCS3, ATF2, KREMEN1 heterodimerization) remains unresolved.
• No high-resolution structure of KREMEN2 alone or in complex exists
• Whether distinct KREMEN2 domains separately mediate Wnt-dependent and Wnt-independent functions is untested
• In vivo genetic evidence connecting KREMEN2's oncogenic roles to patient outcomes is lacking