TULA-2, a novel histidine phosphatase, regulates bone remodeling by modulating osteoclast function
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Cellular and Molecular Life Sciences
RESEARCH ARTICLE
TULA-2, a novel histidine phosphatase, regulates bone remodeling by modulating osteoclast function Steven H. Back • Naga Suresh Adapala • Mary F. Barbe Nick C. Carpino • Alexander Y. Tsygankov • Archana Sanjay
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Received: 18 September 2012 / Revised: 16 October 2012 / Accepted: 18 October 2012 / Published online: 13 November 2012 Ó Springer Basel 2012
Abstract Bone is a dynamic tissue that depends on the intricate relationship between protein tyrosine kinases (PTK) and protein tyrosine phosphatases (PTP) for maintaining homeostasis. PTKs and PTPs act like molecular on and off switches and help modulate differentiation and the attachment of osteoclasts to bone matrix regulating bone resorption. The protein T cell ubiquitin ligand-2 (TULA-2), which is abundantly expressed in osteoclasts, is a novel histidine phosphatase. Our results show that of the two family members, only TULA-2 is expressed in osteoclasts and that its expression is sustained throughout the course of osteoclast differentiation, suggesting that TULA-2 may play a role during early as well late stages of osteoclast differentiation. Skeletal analysis of mice that do not express TULA or TULA-2 proteins (DKO mice) revealed
that there was a decrease in bone volume due to increased osteoclast numbers and function. Furthermore, in vitro experiments indicated that bone marrow precursor cells from DKO mice have an increased potential to form osteoclasts. At the molecular level, the absence of TULA-2 in osteoclasts results in increased Syk phosphorylation at the Y352 and Y525/526 residues and activation of phospholipase C gamma 2 (PLCc2) upon engagement of immune-receptor-tyrosine-based-activation-motif (ITAM)— mediated signaling. Furthermore, expression of a phosphatase-dead TULA-2 leads to increased osteoclast function. Taken together, these results suggest that TULA-2 negatively regulates osteoclast differentiation and function.
Electronic supplementary material The online version of this article (doi:10.1007/s00018-012-1203-2) contains supplementary material, which is available to authorized users.
Introduction
S. H. Back M. F. Barbe A. Sanjay Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA, USA A. Y. Tsygankov Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA, USA N. C. Carpino Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY, USA N. S. Adapala A. Sanjay (&) Department of Orthopaedic Surgery, New England Musculoskeletal Institute, University of Connecticut Health Center, Farmington, CT, USA e-mail: [email protected]
Keywords Syk ITAM Fc receptor PLCc Tyrosine kinase
Osteoclasts are large multinucleated cells whose major function in the body is to resorb bone under physiological and pathological conditions. These cells are of monocytemacrophage lineage, and require macrophage colony stimulating factor (M-CSF) and receptor activator of NFjB ligand
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