Grb10 exceeding the boundaries of a common signaling adapter.

Growth factor receptor binding protein 10 (Grb10) has been identified as a cellular partner of a number of receptor tyrosine kinases and other signaling mediators, compatible with multiple roles in mitogenic, metabolic, and embryogenic signaling that are also supported by the tissue distribution of Grb10. In particular, a role has been implicated in the regulation of PI 3-kinase signaling downstream of the insulin receptor. At least seven alternative splice variants have been identified within the Grb10 gene, a proposed candidate for some types of human Silver-Russell syndrome. Located on chromosome 7 (human) or 11 (mouse) the gene is oppositely imprinted in both species. Grb10 isoforms are members of a super family of signaling mediators that includes Grb7, Grb14, and Caenorhabditis elegans MIG-10. All mammalian members of this family share a domain structure which is represented by N-terminal (proline) Pro-rich sequences, a homology domain with MIG-10 (GM) which includes a Ras-associating (RA)-like domain, a pleckstrin homology region (PH), a C-terminal Src homology 2 (SH2) domain, and a receptor binding domain located between the PH and the SH2 domains termed BPS. Various Grb10 isoforms have been identified as cellular partners of the insulin receptor (IR) and insulin-like growth factor-I (IGF-I) receptor that provide the best-established regulators of Grb10 signaling. A regulatory role of Grb10 has been established in the respective metabolic and mitogenic responses by numerous lines of experimental evidence. However, the specific contribution of Grb10 was found to be highly dependent on the cellular context including the balance of other signaling mediators that define whether increased Grb10 levels will enhance or restrain a given response. This is supported by observations with super family members Grb7 and Grb14 that may engage in competitive and redundant mechanisms when compared to Grb10. Grb10 gene disruption in the mouse results in embryonal and placental overgrowth. The underlying molecular mechanisms and their interpretation remain open until a more comprehensive analysis will be available which includes the contribution of the Grb7 and Grb14 super family members. From a physiologic perspective at the cellular level increased levels of Grb10 have been shown to stimulate insulin metabolic action or mitogenic growth factor responses whereas peptide mimetics representing individual Grb10 domains were found to act oppositely by inhibiting the respective cellular response. In an alternative experimental context increased cellular levels of Grb10 have repeatedly been shown to inhibit cellular responses and signaling mechanisms. This has been most specifically observed at the level of molecular interactions in vitro. How the various observations relate to the physiologic role of cellular Grb10 remains to be established, also in the context of possible cross-talk to Grb14 and Grb7 signaling. Based on its interactions with a number of signaling mediators including protein kinases, adapters, and enzymes such as a ubiquitin ligase, Grb10 may act as a signaling hub to integrate multiple incoming signals and as a molecular scaffold to help assemble signaling complexes. The specific contribution of Grb10 in a signaling complex may depend on the local stochiometric balance of associating mediators, including the ratio of competing signaling proteins. In this context a constant cellular level of Grb10 may enhance or restrain a specific signaling mechanism depending on the local distribution and balance of specific Grb10 signaling partners. This concept is compatible with the diverse experimental observations on Grb10 function and emphasizes the importance of the specific cellular context to define the consequences of local changes in Grb10 distribution. Thus, to think of Grb10 as either a positive or negative signaling mediator will be inadequate in reflecting the complexity that underlies the final output of the Grb10 signal.