CMTM4 is a novel interactor of CXCR4 and regulator of CXCL12/CXCR4 signaling

Abstract: CXCR4 is a chemokine receptor that belongs to the superfamily of G protein-coupled receptors. The natural ligand of CXCR4 is the chemokine CXCL12. The interaction between the receptor and its ligand activates numerous signaling pathways, controlling cell migration, survival, proliferation and chemotaxis. The CXCL12/CXCR4 axis is essential in embryogenesis, hematopoiesis, in the regulation of the immune system and in tissue repair after wounding. Several pathological conditions are linked to deregulated CXCR4 signaling, such as WHIM syndrome, autoimmune diseases and cancer, where CXCR4 upregulation promotes tumor growth and metastasis. Although the central role of CXCR4 in physiology and disease has been extensively investigated during the last twenty-five years, efforts to develop pharmaceutical compounds targeting CXCR4 have up to date limited success. Thus, there is a great interest in the exploration of alternative ways to regulate the expression and signaling of CXCR4.
In this study, we identified CMTM4, a member of the CKLF-like MARVEL Transmembrane domain containing protein family with relatively unknown function, as a novel interactor of CXCR4. CMTM4 has been mainly described as a tumor suppressor, and its expression is downregulated in many types of cancer by promoter methylation. We found that CMTM4, but not the closely related family member CMTM6, regulates the trafficking and protein stability of CXCR4 in transfected HEK 293T cells. To investigate how CMTM4 regulates CXCR4 signaling, we created a tetracycline-inducible CMTM4.F overexpression model in HeLa cells, a cervical cancer cell line that expresses endogenous CXCR4. We showed that CMTM4 co-immunoprecipitates and co-localizes with CXCR4 intracellularly and on the cell surface. Although CMTM4 does not affect the cell surface expression of CXCR4 or the ligand-independent endocytosis of the receptor, we found that it reduces the CXCL12-induced internalization of CXCR4. Additionally, we could show that CMTM4 expression reduces the activation of AKT in steady-state conditions and after ligand stimulation without affecting the activation of ERK1/2. The CXCL12-mediated chemotaxis and proliferation of CMTM4-expressing HeLa cells was also significantly attenuated while cell viability was not affected.
Overall, our findings identified CMTM4 as a novel interactor of CXCR4 and regulator of CXCL12/CXCR4 signaling that could potentially serve as a novel pharmacological approach to control CXCR4-mediated tumor growth and metastasis

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: Universität Freiburg, Dissertation, 2021

Classification and Topics

• Keyword: Signaltransduktion

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2021
• Creator: Bona, Alexandra
• Contributor: Walz, Gerd ; Albert-Ludwigs-Universität Freiburg. Fakultät für Biologie

Further information

• DOI: 10.6094/UNIFR/219107
• URN: urn:nbn:de:bsz:25-freidok-2191072
• Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 15.08.2025, 7:20 AM CEST