IGFBP-2 represents a multifunctional protein with effects on growth, reproductive development, aging, and metabolism. For the expression of these diverse effects in vivo, IGFBP-2 has a number of binding sites for IGFs, integrins, and proteoglycans. In order to assess the relative contributions of these binding sites to the multiple effects of IGFBP-2, we have developed transgenic mouse models overexpressing intact or mutant IGFBP-2. Here we discuss functions of the RGD-sequence present in the IGFBP-2 molecule and that has been demonstrated to mediate integrin binding in vitro and in vivo. Overexpression of intact IGFBP-2 in transgenic mice (D-mice) significantly (P<0.05) slowed down glucose clearance in the oral glucose tolerance test (GGT). By contrast, overexpression of mutant IGFBP-2 lacking the RGD sequence in transgenic mice (E-mice) did not affect glucose tolerance if compared to non-transgenic littermates (C-mice). We therefore may assume that the effects of IGFBP-2 on glucose clearance after GTT are dependent on the RGD-sequence. While the effects of the RGD-motif for glucose clearance were present both in male and female mice, the RGD-sequence mediates higher life expectancy or long term survival only in female but not in male mice. For somatic growth presence or absence of the RGD-sequence has no effect in both genders. Now we performed a comprehensive analysis of signal transduction (integrin signaling, MAPK and PI3K signaling pathways) in different tissues of our experimental system. Interestingly, intact and mutated IGFBP-2 disrupted intracellular cell signaling in a number of tissues. Depending on age, sex and tissue specific effects of the presence or absence of the RGD domain have been observed. We may thus assume that the RGD-sequence has both permissive and regulatory functions for intracellular signaling. By using transgenic mice overexpressing normal or mutated IGFBP-2 we provide evidence that the pleiotropic network can be assessed on a mechanistic level.