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1. Back, Steven. TULA-2: A Novel Protein Tyrosine Phosphatase That Regulates Osteoclast Differentiation and Function.
Degree: PhD, 2014, Temple University
The human skeleton is a dynamic organ that serves multiple functions to maintain normal physiology and health. It protects vital organs, provides support for movement, houses marrow and maintains calcium homeostasis. The skeleton is maintained by the work of two cells with opposing functions: osteoblasts, cells that synthesize organic bone matrix and osteoclasts that degrade and resorb it. These cells interact with one another in a tightly regulated process known as the bone remodeling cycle. This cycle maintains the health of bone by removing and replacing weak or damaged bone and responding to stress loads by remodeling portions of the skeleton that require reinforcement. Osteoblasts differentiate from mesenchymal stem cells and respond to hormonal stimuli by synthesizing and secreting cytokines necessary for osteoclast differentiation. Osteoblasts may become embedded within mineralized matrix, becoming osteocytes, cells that can sense changes in mechanical loading and facilitate localization of the remodeling cycle. Osteoclasts differentiate from hematopoietic stem cells (HSC) when the cell surface receptors, c-FMS and RANK, are activated by ligands produced by osteoblasts, M-CSF and RANKL respectively. In addition to c-FMS and RANK stimulation, another calcium-mediated, co-stimulatory pathway must be activated to ensure proper osteoclast differentiation. This pathway is activated by two immunoreceptors, OSCAR and TREM-2 that interact with adaptor proteins termed FcRγ and DAP12 respectively. These adaptor proteins harbor immunoreceptor tyrosine-based activation motifs (ITAM), which exist on their cytoplasmic tail. Once the immunoreceptors are triggered, specific tyrosines within the ITAM motifs become phosphorylated and act as docking points for the tyrosine kinase, Syk. Once bound, Syk autophosphorylates and acts on its downstream targets. Syk dephosphorylation is, therefore, necessary to attenuate this signal to prevent over activation of osteoclasts. Recently, a novel tyrosine phosphatase, T-cell Ubiquitin ligand -2 (TULA-2) has been shown to dephosphorylate specific phosphotyrosine residues on Syk in various systems and has shown an increased specificity to dephosphorylate tyrosine 352. The goal of this project is to determine how TULA-2 mediated dephosphorylation of Syk regulates osteoclast differentiation and function. TULA-2 is a member of the TULA family of proteins, TULA and TULA-2. In spite of a significant homology and similar domain organization between TULA and TULA-2, only TULA-2 has significant phosphatase activity. Furthermore, whereas TULA is expressed only in lymphocytes, TULA-2 is expressed in most tissues albeit a higher level of expression is seen in cells of hematopoietic origin. In vivo analysis including Micro-computed tomography (Micro CT) and histomorphometry indicated that mice that lack both TULA and TULA-2 (DKO) have decreased bone mass compared to wild-type (WT) counterparts. An in vitro cell differentiation assay revealed that a larger population of osteoclast-like…Advisors/Committee Members: Sanjay, Archana, Tsygankov, Alexander;, Barbe, Mary F., Popoff, Steven N., Soprano, Dianne R., Rizzo, Victor, Hankenson, Kurt D.;.
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APA (6th Edition):
Back, S. (2014). TULA-2: A Novel Protein Tyrosine Phosphatase That Regulates Osteoclast Differentiation and Function. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,254886
Chicago Manual of Style (16th Edition):
Back, Steven. “TULA-2: A Novel Protein Tyrosine Phosphatase That Regulates Osteoclast Differentiation and Function.” 2014. Doctoral Dissertation, Temple University. Accessed September 20, 2020. http://digital.library.temple.edu/u?/p245801coll10,254886.
MLA Handbook (7th Edition):
Back, Steven. “TULA-2: A Novel Protein Tyrosine Phosphatase That Regulates Osteoclast Differentiation and Function.” 2014. Web. 20 Sep 2020.
Back S. TULA-2: A Novel Protein Tyrosine Phosphatase That Regulates Osteoclast Differentiation and Function. [Internet] [Doctoral dissertation]. Temple University; 2014. [cited 2020 Sep 20]. Available from: http://digital.library.temple.edu/u?/p245801coll10,254886.
Council of Science Editors:
Back S. TULA-2: A Novel Protein Tyrosine Phosphatase That Regulates Osteoclast Differentiation and Function. [Doctoral Dissertation]. Temple University; 2014. Available from: http://digital.library.temple.edu/u?/p245801coll10,254886