**9. Conclusions**

Although until recently the conventional view was that phosphorylation of tyrosine residues played a major role in the activation of the IGF-IR and initiated all downstream signaling, there is increasing evidence showing that this view was too simplistic and grossly underestimated the downstream complexity of the IGF-IR pathways. The IGF-IR has not only extensive cross-talk with many other receptors, but that the IGF-IR can be also considered as a functional RTK/GPCR hybrid, which integrates the kinase signaling with some IGF-IR mediated canonical GPCR characteristics. Like classical GPCRs the IGF-IR show homologous and heterologous desensitization. In addition, after activation by a ligand, the IGF-IR signaling can be translocated to the nucleus and function as a transcriptional cofactor. For example nuclear IGF-IR is able to autoregulate expression of its own gene.

Thus, it has become clear in recent years that the IGF-IR signaling pathway is far more complex than previously thought. It contains many points of regulation and shows signal divergence and cross-talk with many other signaling pathways at the receptor and post-receptor level. However, a big challenge for the (near) future will be how all this new knowledge about the IGF-IR signaling pathways can be translated into clinical practice and improve diagnosis and treatment of diseases.

**Funding:** This research received no external funding.

**Acknowledgments:** I thank Haim Werner for inviting me to agree to contribute a research article Special Issue on "Insulin-like Growth Factors in Development, Cancers and Aging" in the journal Cells. The author is grateful to Michael P. Brugts for comments and proofreading the manuscript.

**Conflicts of Interest:** The author declares no conflict of interest.
