Adaptor proteins that bind to tyrosine kinases and receptor tyrosine kinases have been postulated to modulate signal transduction. SH2B1 (1) is the prototype of a small family of adaptor proteins that also includes SH2B2 (2) (adaptor protein containing pleckstrin homology and SRC homology domains) and SH2B3 (3) (leukocyte adaptor protein). Given the large number of kinases that bind to SH2B1 [Janus kinase (JAK)-2 and JAK1; fibroblast growth factor receptor-1 (4); insulin receptor (5); insulin receptor substrate-1 (6)] or stimulate phosphorylation of SH2B1 [nerve growth factor (7) and platelet derived growth factor (8)], a vexing problem was the specificity of such a promiscuous binding protein and its potential regulatory functions. All three of the SH2B family members were identified after a yeast two-hybrid screening with various bait proteins. The three proteins share a common structure (9) with a pleckstrin homology domain (PH), an SRC homology (SH)-2 domain, various phosphorylation target motifs, and a C-terminal, proline-rich SH3 domain. The next step in defining SH2B1’s regulatory functions was to develop a whole-animal model wherein SH2B1 expression was lost: the Sh2b1 knockout mouse. The initial phenotypes of decreased growth, insulin resistance, and infertility (10) became overshadowed by subsequent studies that showed obesity and hyperphagia in the Sh2b1 knockout mouse (11). The constellation of the phenotypes is strikingly similar to the syndrome caused by loss of leptin signaling of hyperphagic obesity, insulin resistance, and infertility (12). This similarity of phenotypes led Rui and colleagues (13) to pursue the idea that the major functions of SH2B1 reside within the brain for modulating signaling by leptin receptor. Because the bait used in the initial yeast two-hybrid screening that fished out SH2B1 was JAK2, the modulation of leptin signaling was a perfect fit because JAK2 is the initiator of the signaling cascade for leptin binding to the leptin receptor (14). The group led by Dr. Rui (13) generated mice wherein SH2B1 was expressed in neurons of the brains of Sh2B1 knockout mice to test the idea that central SH2B1 function was the necessary component to correct the obesity of the mutant mice. Indeed, neuronal expression of SH2B1 was sufficient to correct the obese phenotype of Sh2b1 knockout mice (15) in a satisfyingly parallel fashion to the neuronal replacement of leptin receptor expression in Lepr db/db mice (16,17). These results led even greater impetus to the studies of interactions between SH2B1 and JAK2. Biochemical studies indicated that monomeric SH2B1 could bind nonphosphorylated dimers of JAK2, but activation of JAK2 caused a shift of the interacting region to the SH2 domain of SH2B1 with dimerization and phosphorylation of SH2B1 (18,19). Interestingly, leptin receptor exists as homodimers with prebound JAK2 dimers (20,21). Thus, SH2B1 could be bound to LEPR-JAK2 oligomers in either inactive or active states. The domains of SH2B1 have been structurally determined although their functions remain to be determined conclusively. A dimerization domain (residues 26-84 in human SH2B1) (18) near the N terminus has been described, although it is not required for JAK2 activation when tested in mammalian cells. The pleckstrin homology domain (residues 249-378) is thought to mediate binding to inactive JAK2, whereas the SH2 domain (residues 521-625) near the C terminus is critical to binding to active, phosphorylated JAK2 (22). Rui and his group (13) have now critically tested the role of the SH2 domain of SH2B1 with regard to the central nervous system and the obesity/insulin resistance phenotypes. They have generated transgenic mice that express mutant versions of SH2B1 in neurons only, either the R555E SH2 domain-incompetent version or the δ-N503 version that contains only the SH2 domain and does not contain the DD and PH domains and tested whether these mutant SH2B1 versions could correct the obesity and insulin resistance phenotypes. The most recent paper of Rui and colleagues (13) indicated that an intact SH2B1 is necessary to correct the obesity and insulin resistance phenotypes of Sh2b1 knockout mice. In fact, the SH2B1 R555E variant acted as a dominant negative and caused transgenic mice to become more susceptible to diet-induced obesity and insulin resistance. The published reports are interesting results because prior studies had indicated that the SH2 domain was sufficient to enhance JAK2 phosphorylation in a mammalian cell culture model (18). Thus, the DD region might be necessary to increase the fractional content of SH2B1 dimers or the PH domain might be necessary to bring SH2B1 to cognate receptors. In any case, the enhancement of JAK2 phosphorylation by the SH2 domain is insufficient to correct the obesity and insulin resistance phenotypes. These results indicated that the prior model of enhancement of leptin signaling enhancement solely by the SH2 domain of SH2B1 is incomplete (22). Unfortunately, the gonadal phenotypes were not reported for any of the groups because it would be interesting to ascertain the fertility of this specific stock. Another point would have been to directly test the idea that the DD and PH domains interact and bind the inactive JAK2, predicting that a C-terminal truncation of SH2B1 with only the DD and PH domains would act as a dominant negative, in a way analogous to the R555E variant. Another unexplored avenue is the means by which overexpression of SH2B1 protects against diet-induced obesity. Presumably, leptin resistance does not occur in SH2B1-overexpressing mice. Because eliminating the suppressor of cytokine signaling-3 within the central nervous system also prevents leptin resistance and diet-induced obesity, it would be interesting to determine whether SH2B1 interferes with the action of suppressor of cytokine signaling-3 on leptin receptor. All of the studies discussed underscore the complexity of issues involved with interpreting biochemical and functional studies of protein complexes. By their nature, adaptor proteins bind to a multitude of partners and exist in active/inactive forms. As the number of proteins and potential states increase, the activity of the protein complex becomes increasingly unpredictable, especially in the face of incomplete knowledge. The results from genetic manipulations of intact mice provide a means of testing the completeness and accuracy of our models, often pointing to unexpected areas that require explication. The example of SH2B1 holds great promise for explaining mechanisms of modulating the strength of signal transduction and for providing specificity of signal enhancement from various receptors.