Protein tyrosine phosphatases in skeletal development and diseases

Abstract

Skeletal development and homeostasis in mammals are modulated by finely coordinated processes of migration, proliferation, differentiation, and death of skeletogenic cells originating from the mesoderm and neural crest. Numerous molecular mechanisms are involved in these regulatory processes, one of which is protein posttranslational modifications, particularly protein tyrosine phosphorylation (PYP). PYP occurs mainly through the action of protein tyrosine kinases (PTKs), modifying protein enzymatic activity, changing its cellular localization, and aiding in the assembly or disassembly of protein signaling complexes. Under physiological conditions, PYP is balanced by the coordinated action of PTKs and protein tyrosine phosphatases (PTPs). Dysregulation of PYP can cause genetic, metabolic, developmental, and oncogenic skeletal diseases. Although PYP is a reversible biochemical process, in contrast to PTKs, little is known about how this equilibrium is modulated by PTPs in the skeletal system. Whole-genome sequencing has revealed a large and diverse superfamily of PTP genes (over 100 members) in humans, which can be further divided into cysteine (Cys)-, aspartic acid (Asp)-, and histidine (His)-based PTPs. Here, we review current knowledge about the functions and regulatory mechanisms of 28 PTPs involved in skeletal development and diseases; 27 of them belong to class I and II Cys-based PTPs, and the other is an Asp-based PTP. Recent progress in analyzing animal models that harbor various mutations in these PTPs and future research directions are also discussed. Our literature review indicates that PTPs are as crucial as PTKs in supporting skeletal development and homeostasis.

A Multifunctional Therapeutic Strategy Using P7C3 as A Countermeasure Against Bone Loss and Fragility in An Ovariectomized Rat Model of Postmenopausal Osteoporosis

“…[ 68 ] Protein tyrosine phosphorylation tightly modulates the lineage commitment of BMSCs, [ 69 ] as well as influences the proliferation, osteogenic differentiation, [ 70 ] and maturation of osteoblast precursors, as well as the function of osteocytes, and osteoclasts. [ 71 , 72 , 73 ] Their deletion results in severe osteopenia, limb deformity, and impaired mineralization. [ 74 , 75 ] To further investigate the mode of action, we investigated the response of these cell surface proteins to P7C3 in vitro ( Figure 3 ).…”

Loss of coactosin-like F-actin binding protein 1 (Cotl1) decreases platelet-mediated osteoclastogenesis and causes osteopetrosis phenotypes in mouse

“…Therefore, tyrosine phosphatases (PTPs), which regulate tyrosine phosphorylation, are primary regulators of osteoclast function and production 40 . The protein tyrosine phosphatases SHP-1 (encoded by Ptpn-6 ) and SHP-2 (encoded by Ptpn-11 ) are members of the Src homology 2 domain-containing cytoplasmic PTP family and are involved in osteoclast development 41 . SHP-2 is a well-known regulator of M-CSF- and RANK-evoked signaling, and Shp2 mutant mice develop osteopetrosis with abnormal osteoclastic bone resorptive dynamics 42 , suggesting an important role of SHP-2 in bone homeostasis and osteoclastogenesis.…”

Importance of Tyrosine Phosphorylation in Hormone-Regulated Plant Growth and Development

“…The protein tyrosine phosphatases (PTPs) are enzymes functioning in a coordinated manner with PTKs to control the Tyr phosphorylation status of many protein substrates, thus regulating many signaling pathways involved in diverse physiological processes. Altered expression and/or activity of PTPs can lead to dysregulation of Tyr phosphorylation in cells and cause a wide range of human diseases such as tumorigenesis, autoimmune disorders, and abnormal skeletal development [ 30 , 31 ]. So far, at least 126 putative PTPs have been found in the human genome.…”

“…In addition to the Tyr residue, some members of this large family exhibit other substrate specificities, such as Ser/Thr residues, inositides, glycogens, mRNAs, or even inorganic moieties [ 20 , 32 , 33 , 34 ]. Based on the nucleophilic catalytic residues in their catalytic motifs and topology, these PTPs can be broadly grouped into three families: cysteine (Cys)-, aspartic acid (Asp)-, and histidine (His)-based PTPs [ 30 , 34 , 35 , 36 ]. The Cys-based PTPs family, which is characterized by conserved signature motif (H/V)CX 5 R(S/T) (H, histidine; V, valine; R, arginine; and X for any amino acid residue) in the catalytic domain, is the largest group that can be divided further into three subgroups: classes I, II, and III PTPs based on their evolutionary lineages [ 30 , 34 ].…”

“…Based on the nucleophilic catalytic residues in their catalytic motifs and topology, these PTPs can be broadly grouped into three families: cysteine (Cys)-, aspartic acid (Asp)-, and histidine (His)-based PTPs [ 30 , 34 , 35 , 36 ]. The Cys-based PTPs family, which is characterized by conserved signature motif (H/V)CX 5 R(S/T) (H, histidine; V, valine; R, arginine; and X for any amino acid residue) in the catalytic domain, is the largest group that can be divided further into three subgroups: classes I, II, and III PTPs based on their evolutionary lineages [ 30 , 34 ]. Class I consists of up to 117 PTPs, accounting for more than 95% of the Cys-based PTP family, which can be further divided into six subclasses: the classical phosphotyrosine (pTyr)-specific phosphatases, Vaccinia virus H1(VH1)-like/dual-specificity phosphatases (DUSP), SAC (suppressor of yeast actin mutations) phosphoinositide phosphatases, phosphatase domain-containing paladin 1 (PALD1), INPP4 (inositol polyphosphate 4-phosphatase) phosphatases, and TMEM55 (transmembrane protein 55A) phosphatases.…”