Abstract
Several protein-tyrosine phosphatases (PTPs) have been implicated in the control of growth hormone receptor (GHR) signaling, but none have been shown to affect growth in vivo. We have applied a battery of molecular and cellular approaches to test a family-wide panel of PTPs for interference with GHR signaling. Among the subset of PTPs that showed activity in multiple readouts, we selected PTP-H1/PTPN3 for further in vivo studies and found that mice lacking the PTP-H1 catalytic domain show significantly enhanced growth over their wild type littermates. In addition, PTP-H1 mutant animals had enhanced plasma and liver mRNA expression of insulin-like growth factor 1, as well as increased bone density and mineral content. These observations point to a controlling role for PTP-H1 in modulating GHR signaling and systemic growth through insulin-like growth factor 1 secretion.
Highlights
The protein-tyrosine phosphatases (PTPs), enzymes that, if validated, constitute drugable targets that may be exploited to treat growth-related disorders [2]
PTP-H1 Control of growth hormone receptor (GHR) and Growth demonstrate that mice that lack the PTP-H1 catalytic domain are significantly heavier than their wild type littermates and present with increased plasma levels of insulin-like growth factor 1 (IGF-1), consistent with a greater sensitivity to Growth hormone (GH) and suggesting that PTP-H1 plays a controlling role in vivo in GHR signaling and adult body size
GHR expression limits the HEK response; only upon overexpression of full-length GHR could GH-induced Janus kinase 2 (JAK2) autophosphorylation and tyrosine-phosphorylated STAT-5 be detected in total cell lysate (Fig. 1B)
Summary
The PTPs, enzymes that, if validated, constitute drugable targets that may be exploited to treat growth-related disorders [2]. 4 The abbreviations used are: GH, growth hormone; GHR, GH receptor; JAK, Janus kinase; STAT, signal transducers and activators of transcription; PTP, protein-tyrosine phosphatase; SHP, Src homology domain 2-containing tyrosine phosphatase; IGF, insulin-like growth factor; GST, glutathione S-transferase; siRNA, small interfering RNA; KO, knock-out; HET, heterozygous; WT, wild type; DEXA, dual energy x-ray absorptiometry; X-gal, 5-bromo-4-chloro-3-indolyl--D-galactopyranoside.
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