SH2B1 (previously named SH2-B), a cytoplasmic adaptor protein, binds via its Src homology 2 (SH2) domain to a variety of protein tyrosine kinases, including JAK2 and the insulin receptor. SH2B1-deficient mice are obese and diabetic. Here we demonstrated that multiple isoforms of SH2B1 (α, β, γ, and/or δ) were expressed in numerous tissues, including the brain, hypothalamus, liver, muscle, adipose tissue, heart, and pancreas. Rat SH2B1β was specifically expressed in neural tissue in SH2B1-transgenic (SH2B1 Tg ) mice. SH2B1 Tg mice were crossed with SH2B1-knockout (SH2B1 KO ) mice to generate SH2B1 TgKO mice expressing SH2B1 only in neural tissue but not in other tissues. Systemic deletion of the SH2B1 gene resulted in metabolic disorders in SH2B1 KO mice, including hyperlipidemia, leptin resistance, hyperphagia, obesity, hyperglycemia, insulin resistance, and glucose intolerance. Neuron-specific restoration of SH2B1β not only corrected the metabolic disorders in SH2B1 TgKO mice, but also improved JAK2-mediated leptin signaling and leptin regulation of orexigenic neuropeptide expression in the hypothalamus. Moreover, neuron-specific overexpression of SH2B1 dose-dependently protected against high-fat diet-induced leptin resistance and obesity. These observations suggest that neuronal SH2B1 regulates energy balance, body weight, peripheral insulin sensitivity, and glucose homeostasis at least in part by enhancing hypothalamic leptin sensitivity. IntroductionBody weight is controlled by a balance between energy intake and expenditure. Excess energy derived from a positive energy imbalance is stored as triglyceride (TG) in adipose tissue, resulting in obesity. Body weight is maintained within a narrow range by a homeostatic control system in which the brain, particularly the hypothalamus, senses and integrates various neuronal, hormonal, and nutrientrelated signals, thereby coordinating food intake and energy expenditure. Recent findings provide a framework for understanding this homeostatic regulation of body weight. Leptin, which serves as an essential adiposity signal, is produced primarily by white adipose tissue to convey information about peripheral energy storage and availability to the hypothalamus (1-3). Genetic deficiency of either leptin or its receptor disrupts the communication between the peripheral energy stores and the central sensors/integrators, resulting in severe energy imbalance and morbid obesity (4-8). Leptin resistance plays a key role in the development of obesity, which is a primary risk factor for type 2 diabetes and various cardiovascular disorders.Leptin binds to and activates its long form receptor (LEPRb) in the hypothalamus, initiating the activation of a variety of intracellular signaling pathways, including the STAT3 and PI3K pathways (8-12). Inhibition of either the STAT3 or PI3K pathways in the hypothalamus results in leptin resistance and obesity, demonstrating an essential role for these 2 pathways in mediating leptin regulation of energy metabolism and body weight (11-17). JAK2, ...

Projection micro stereolithography (PμSL) is a high-resolution (up to 0.6 μm) 3D printing technology based on area projection triggered photopolymerization, and capable of fabricating complex 3D architectures covering multiple scales and with multiple materials. This paper reviews the recent development of the PμSL based 3D printing technologies, together with the related applications. It introduces the working principle, the commercialized products, and the recent multiscale, multimaterial printing capability of PμSL as well as some functional photopolymers that are suitable to PμSL. This review paper also summarizes a few typical applications of PμSL including mechanical metamaterials, optical components, 4D printing, bioinspired materials and biomedical applications, and offers perspectives on the directions of the further development of PμSL based 3D printing technology.

Pleckstrin homology (PH) domains are phosphoinositide (PI)-binding modules that target proteins to membrane surfaces. Here we define a family of PH domain proteins, including Tiam1 and ArhGAP9, that demonstrates specificity for PI(4,5)P 2 , as well as for PI(3,4,5)P 3 and PI(3,4)P 2 , the products of PI 3-kinase. These PH domain family members utilize a noncanonical phosphoinositide binding pocket related to that employed by ␤-spectrin. Crystal structures of the PH domain of ArhGAP9 in complex with the headgroups of Ins(1,3,4)P 3 , Ins(1,4,5)P 3 , and Ins(1,3,5)P 3 reveal how two adjacent phosphate positions in PI(3,4)P 2 , PI(4,5)P 2 , and PI(3,4,5)P 3 are accommodated through flipped conformations of the bound phospholipid. We validate the non-canonical site of phosphoinositide interaction by showing that binding pocket mutations, which disrupt phosphoinositide binding in vitro, also disrupt membrane localization of Tiam1 in cells. We posit that the diversity in PI interaction modes displayed by PH domains contributes to their versatility of use in biological systems.The spatial and temporal regulation of protein localization plays an important role in the transduction of signals between sub-cellular compartments. Targeting of proteins to membrane surfaces through interactions with phosphoinositides (PIs) 4 promotes the formation of functional complexes and concomitantly restricts their site of biochemical activity (1).Phosphoinositides are lipid components of cellular membranes that function as signaling molecules. The inositol headgroups of phosphoinositides are differentially phosphorylated, and selectively bound by a variety of protein modules, including PH, FERM, ENTH, FYVE, and PX domains (2-4). PH domains were the first phosphoinositide binding domain identified (5) and serve important roles in kinase signaling and cytoskeletal organization (6, 7). PH domains consist of 100 -120 amino acids that form a seven-stranded ␤-sandwich with a C-terminal ␣-helix. The PI binding properties of PH domains are diverse, ranging from family members that display no detectable interaction to domains that bind one or more headgroups with nanomolar binding affinity (8 -10). Generally, PH domains that possess weak affinity for phosphoinositides are inefficient at PIdependent membrane localization. These PH domains may require multimerization or cooperation with other factors for their targeting function (11,12). In contrast, PH domains that bind with high affinity and selectivity to either PI(4,5)P 2 or the PI 3-kinase products PI(3,4,5)P 3 and PI(3,4)P 2 are efficiently targeted to membrane surfaces. The PH domain of PLC␦ is a specific sensor of PI(4,5)P 2 , whereas those of Akt, Btk, and Grp1 exemplify domains that selectively bind with high affinity to PI(3,4)P 2 and/or PI(3,4,5)P 3 (10).A basic consensus motif within the ␤1-␤2 loop region is characteristic of PH domains that bind phosphoinositides with high affinity and specificity (13). This motif defines the core of the canonical PI binding pocket, and mutations th...

The Na,K-ATPase classically serves as an ion pump creating an electrochemical gradient across the plasma membrane that is essential for transepithelial transport, nutrient uptake and membrane potential. In addition, Na,K-ATPase also functions as a receptor, a signal transducer and a cell adhesion molecule. With such diverse roles, it is understandable that the Na,K-ATPase subunits, the catalytic α-subunit, the β-subunit and the FXYD proteins, are controlled extensively during development and to accommodate physiological needs. The spatial and temporal expression of Na,K-ATPase is partially regulated at the transcriptional level. Numerous transcription factors, hormones, growth factors, lipids, and extracellular stimuli modulate the transcription of the Na,K-ATPase subunits. Moreover, epigenetic mechanisms also contribute to the regulation of Na,K-ATPase expression. With the ever growing knowledge about diseases associated with the malfunction of Na,K-ATPase, this review aims at summarizing the best-characterized transcription regulators that modulate Na,K-ATPase subunit levels. As abnormal expression of Na,K-ATPase subunits has been observed in many carcinoma, we will also discuss transcription factors that are associated with epithelial-mesenchymal transition, a crucial step in the progression of many tumors to malignant disease.

Leptin controls body weight by activating its long form receptor (LEPRb). LEPRb binds to Janus kinase 2 (JAK2), a cytoplasmic tyrosine kinase that mediates leptin signaling. We previously reported that genetic deletion of SH2B1 (previously known as SH2-B), a JAK2-binding protein, results in severe leptin-resistant and obese phenotypes, indicating that SH2B1 is a key endogenous positive regulator of leptin sensitivity. Here we show that SH2B1 regulates leptin signaling by multiple mechanisms. In the absence of leptin, SH2B1 constitutively bound, via its non-SH2 domain region(s), to non-tyrosyl-phosphorylated JAK2, and inhibited JAK2. Leptin stimulated JAK2 phosphorylation on Tyr(813), which subsequently bound to the SH2 domain of SH2B1. Binding of the SH2 domain of SH2B1 to phospho-Tyr(813) in JAK2 enhanced leptin induction of JAK2 activity. JAK2 was required for leptin-stimulated phosphorylation of insulin receptor substrate 1 (IRS1), an upstream activator of the phosphatidylinositol 3-kinase pathway. Overexpression of SH2B1 enhanced both JAK2- and JAK2(Y813F)-mediated tyrosine phosphorylation of IRS1 in response to leptin, even though SH2B1 did not enhance JAK2(Y813F) activation. Leptin promoted the interaction of SH2B1 with IRS1. These data suggest that constitutive SH2B1-JAK2 interaction, mediated by the non-SH2 domain region(s) of SH2B1 and the non-Tyr(813) region(s) in JAK2, increases the local concentration of SH2B1 close to JAK2 and inhibits JAK2 activity. Leptin-stimulated SH2B1-JAK2 interaction, mediated by the SH2 domain of SH2B1 and phospho-Tyr(813) in JAK2, promotes JAK2 activation, thus globally enhancing leptin signaling. SH2B1-IRS1 interaction facilitates IRS1 phosphorylation by recruiting IRS1 to JAK2 and/or by protecting IRS1 from dephosphorylation, thus specifically enhancing leptin stimulation of the phosphatidylinositol 3-kinase pathway.