Central regulation of metabolism by protein tyrosine phosphatases

Abstract

Protein tyrosine phosphatases (PTPs) are important regulators of intracellular signaling pathways via the dephosphorylation of phosphotyrosyl residues on various receptor and non-receptor substrates. The phosphorylation state of central nervous system (CNS) signaling components underlies the molecular mechanisms of a variety of physiological functions including the control of energy balance and glucose homeostasis. In this review, we summarize the current evidence implicating PTPs as central regulators of metabolism, specifically highlighting their interactions with the neuronal leptin and insulin signaling pathways. We discuss the role of a number of PTPs (PTP1B, SHP2, TCPTP, RPTPe, and PTEN), reviewing the findings from genetic mouse models and in vitro studies which highlight these phosphatases as key central regulators of energy homeostasis.

Keywords: PTEN; PTP1B; RPTPe; SHP2; TCPTP; insulin signaling; leptin signaling; protein tyrosine phosphatase.

Figure 1

Model of PTP regulation of central leptin and insulin signaling. When circulating leptin binds to its receptor LepRb, the associated tyrosine kinase JAK2 autophosphorylates and phosphorylates specific tyrosine residues along the intracellular tail of the LepRb. Phosphorylation of Y985 allows for recruitment of the PTP SHP2 which mediates downstream ERK1/2 signaling, while phosphorylation of Y1138 allows for activation of STAT3 which regulates transcription of key neuropeptides involved in energy homeostasis. Unlike leptin signaling, insulin binding to its receptor results in receptor autophosphorylation at tyrosine residues 1158, 1162, and 1163. This allows for recruitment of the effector IRS, which upon phosphorylation can recruit adaptor molecules and mediate downstream PI3K and ERK1/2 signaling. In contrast to SHP2 which positively regulates leptin signaling, several PTPs can negatively regulate central leptin and insulin signaling. PTP1B inhibits leptin and insulin signaling by dephosphorylating JAK2 and the IR, respectively. Additionally, PTP1B has been implicated in dephosphorylating the downstream leptin/insulin signaling protein Tub. Like PTP1B, RPTPe has been shown to inhibit leptin signaling at the level of JAK2, while TCPTP negatively regulates leptin signaling via dephosphorylation of STAT3. PTEN antagonizes neuronal insulin-induced PI3K signaling via dephosphorylation of the phospholipid PIP₃ into PIP₂, resulting in decreased K_ATP channel conductance.