**5. Conclusions**

IGFBP-3 is a multifunctional protein and is involved in the pathophysiology of a variety of human diseases such as cancer, diabetes, fatty liver disease, ischemia, and Alzheimer's disease. Apart from the IGF/IGF-IR-dependent actions, IGFBP-3 exerts multiple biological activities through the IGF/IGF-IR-independent actions by interacting with distinct interacting proteins on the cell surface or within the cell. Much attention was given to identify a putative receptor for IGFBP-3 since early studies have demonstrated the anti-tumor function of IGFBP-3 in cancer. As described in this review, a few membrane proteins have been identified as "a putative IGFBP-3 receptor" and further characterized their functions with potential underlying mechanisms in cancer cells. Among them, TMEM219 appears to be the most critical IGFBP-3 receptor mediating anti-tumor and anti-metastatic activities of IGFBP-3. Given the fact that IGFBP-3/IGFBP-3R (TMEM219) axis is impaired and shown to have grea<sup>t</sup> impact on the survival outcome in specific cancers, IGFBP-3 and TMEM219 may serve as new diagnostic and prognostic biomarkers in specific cancers. Importantly, IGFBP-3R (TMEM219) agonists, in particular TMEM219 agonistic mAbs, are very attractive cancer therapeutics since these agonists would exhibit no other biological activities of IGFBP-3 induced by the interaction with other binding partners. Further characterization of specific gene regulation by TMEM219 activation and its crosstalk with other key signaling pathways will open a new avenue to treat many different types of cancer as a targeted monotherapy and a combination therapy with other chemotherapies.

**Author Contributions:** Writing, Q.C., M.D., and Y.O. Review and editing, M.D. and Y.O. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was supported, in part, by NIH-NCI Grant R21CA216685 (to Y.O).

**Conflicts of Interest:** The authors declare no conflicts of interest.
