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.

Background: Protein-tyrosine phosphatase ⑀ (cyt-PTPe) dephosphorylates and activates Src to promote osteoclast adhesion. Results: The adaptor protein GRB2 binds phosphorylated cyt-PTPe and recruits Src, thus promoting its activation. Conclusion: GRB2 links cyt-PTPe to Src downstream of activated integrins in osteoclasts.Significance: GRB2-mediated recruitment may constitute a general mechanism by which cyt-PTPe activates Src and related kinases.

The closely related tyrosine phosphatases PTPa and PTPe fulfill distinct roles in osteoclasts. The various effects of each PTP on podosome organization in osteoclasts are caused by their distinct N-termini. The function of PTPe in these cells requires the presence of its 12 N-terminal residues, in particular serine 2.

Osteoclasts, specialized cells that degrade bone, are key components of the cellular system that regulates and maintains bone homeostasis. Aberrant function of osteoclasts can lead to pathological loss or gain of bone mass, such as in osteopetrosis, osteoporosis, and several types of cancer that metastasize to bone. Phosphorylation of osteoclast proteins on tyrosine residues is critical for formation of osteoclasts and for their proper function and responses to physiological signals. Here we describe preparation and growth of osteoclasts from bone marrow of mice, use of viral vectors to downregulate expression of endogenous proteins and to express exogenous proteins in osteoclasts, and analysis of signaling processes triggered by M-CSF, estrogen, and physical contact with matrix in these cells.