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Among the IGFBPs family, which major function is modulating the biological functions of IGFs, IGFBP-2 has been received attention from researchers in biological area by the reason that it is involved in many signaling pathways which is implicated with various disease.
Accumulating studies have shown that IGFBP-2 interacts with not only IGFs in the circulation, but also components of the extracellular matrix (ECM), cell surface proteoglycans and integrin receptors. Understanding the complexes signaling pathways of IGFBP-2 will contribute to further studies about its function as a therapeutic target.
A number of studies have found that IGFBP-2 regulate access of IGFs to their receptors with involvement of specific IGFBP-2 protease, which can be activated by factors like hormones, cytokines, drugs and protease inhibitors also. IGFBP/IGF complex is cleaved by proteolysis in most cases, though it might show an acquired resistance to proteolysis. Thus, IGFs work its biological function. This has been usually reported in cancer studies and IGFBP-2 proteolysis might be a reason that makes tumor aggressiveness increase.
In addition, researches also revealed that IGFBP-2 can interact with a number of components of the extracellular matrix and cell membrane such as cell surface proteoglycan receptor (CSPG; RPTPβ) and integrin receptors (aVb3; a5b1), resulting in the activation and modulation of intercellular signaling elements and pathways. Interestingly, those signaling pathways not only regulate several cellular functions, but also the expression and action of IGFBP-2 in turn.
Moreover, it has been reported that IGFBP-2 enters cell by nuclear transportation complexes (importin α and β) and interact with some intracellular specific binders such as cell cycle inhibitor p21 or Pim-1-associated protein-1 (PAP-1)-associated protein-1 (PAPA-1). All these interactions have been demonstrated that involve in IGFBP-2 growth-promoting actions. For example, studies about tumorigenesis have shown that nuclear IGFBP-2 directly or indirectly contributes to the development of a pro-metastatic milieu by enhancing the expression of the angiogenic growth factor VEGF-A, which consistent with the enhancement of an aggressive cancer phenotype.
All cellular signaling pathways are illustrated (Figure 1).
Figure 1. IGFBP-2 cellular activities. (Russo V C, et al.)
Roles of IGFBP-2 in cancer
Previous researches have shown that IGFBP-2 is overexpressed in various tumors such as glioma, prostate cancer, breast cancer, lung cancer, leukemia, colorectal cancer, ovarian cancer, gastric cancer and so on. Furthermore, it has been shown that abnormal overexpression of IGFBP2 is implicated with tumor metastasis. Thus, IGFBP-2 is an important regulator of cell invasion and migration in the context of tumor development. It has been shown that IGFBP-2 works its function by involving in several steps of metastatic process, degrading almost all of the ECM components and activation the expression of VEGF-A during tumorigenesis and tumor progression. Thus, it might have potential clinical applications as a therapeutic target.
In addition to the roles in cancer, IGFBP-2 also plays important roles in metabolism process and other diseases including obesity and diabetes which has been report by a number of researches recently.