Protein tyrosine phosphatase epsilon affects body weight by downregulating leptin signaling in a phosphorylation-dependent manner.

Molecular-level understanding of body weight control is essential for combating obesity. We show that female mice lacking tyrosine phosphatase epsilon (RPTPe) are protected from weight gain induced by high-fat food, ovariectomy, or old age and exhibit increased whole-body energy expenditure and decreased adiposity. RPTPe-deficient mice, in particular males, exhibit improved glucose homeostasis. Female nonobese RPTPe-deficient mice are leptin hypersensitive and exhibit reduced circulating leptin concentrations, suggesting that RPTPe inhibits hypothalamic leptin signaling in vivo. Leptin hypersensitivity persists in aged, ovariectomized, and high-fat-fed RPTPe-deficient mice, indicating that RPTPe helps establish obesity-associated leptin resistance. RPTPe associates with and dephosphorylates JAK2, thereby downregulating leptin receptor signaling. Leptin stimulation induces phosphorylation of hypothalamic RPTPe at its C-terminal Y695, which drives RPTPe to downregulate JAK2. RPTPe is therefore an inhibitor of hypothalamic leptin signaling in vivo, and provides controlled negative-feedback regulation of this pathway following its activation.

The MAP kinase signaling cascades: a system of hundreds of components regulates a diverse array of physiological functions.

Sequential activation of kinases within the mitogen-activated protein (MAP) kinase (MAPK) cascades is a common, and evolutionary-conserved mechanism of signal transduction. Four MAPK cascades have been identified in the last 20 years and those are usually named according to the MAPK components that are the central building blocks of each of the cascades. These are the extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-Terminal kinase (JNK), p38, and ERK5 cascades. Each of these cascades consists of a core module of three tiers of protein kinases termed MAPK, MAPKK, and MAP3K, and often two additional tiers, the upstream MAP4K and the downstream MAPKAPK, which can complete five tiers of each cascade in certain cell lines or stimulations. The transmission of the signal via each cascade is mediated by sequential phosphorylation and activation of the components in the sequential tiers. These cascades cooperate in transmitting various extracellular signals and thus control a large number of distinct and even opposing cellular processes such as proliferation, differentiation, survival, development, stress response, and apoptosis. One way by which the specificity of each cascade is regulated is through the existence of several distinct components in each tier of the different cascades. About 70 genes, which are each translated to several alternatively spliced isoforms, encode the entire MAPK system, and allow the wide array of cascade's functions. These components, their regulation, as well as their involvement together with other mechanisms in the determination of signaling specificity by the MAPK cascade is described in this review. Mis-regulation of the MAPKs signals usually leads to diseases such as cancer and diabetes; therefore, studying the mechanisms of specificity-determination may lead to better understanding of these signaling-related diseases.