Adaptor proteins that bind to tyrosine kinases and re-ceptor 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/dbmice (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 …