Functional Characterization of Density Enhanced Protein - Literature review Example

TABLE OF CONTENT ABBREVIATIONS 2 LITERATURE REVIEW 3 ABSTRACT 3 1.2. CD 148 7 1.2.1 Expression of CD148 on haematopoietic and non-haematopoietic cells 8 1.2.2. Expression of CD 148 in Megakaryocytes cells 10 1.2.3 CD148 as a marker for memory B cells 11 1.2.4 CD148 negatively regulates T-cell signaling 11 1.2.5. CD148 function in granulocytes 13 1.2.6. Role of CD148 in cells of the mononuclear phagocyte system 13 1.2.7. Physiological Functions of CD148 in non-haematopoietic cells 15 1.2.8. CD148 and diseases 16 1.2.8.1. CD148 and inflammation 18 REFERENCES 21 ABBREVIATIONS CD 45- cluster of differentiation no.45 CD148- Cluster of differentiation no. 148 CSF-I – colony stimulating factor 1 DEP-1- Density-enhanced phosphatase-1 GPCR- G –protein coupled receptor HPTP- human protein tyrosine phosphatase ITAM- immunoreceptor tyrosine-based activation motif ITIMs- immunoreceptor tyrosine-based inhibitory motifs LAT- linker for activation of T cells PERK- phospho-extracellular regulated kinase PTKs-protein tyrosine kinases PTP- protein tyrosine phosphatase RPTP- receptor protein tyrosine phosphatase Scc1- susceptibility to colon cancer locus SFKs- Src family kinases SH2- src homology-2 SHIPS- src homology-domain-containing inositide phosphatases TCR- T-cell receptor VCAM-1 vascular cell adhesion molecule 1 ZAP 70 - zeta chain associated protein kinase 70 LITERATURE REVIEW ABSTRACT Density-enhanced phosphatase-1 (DEP-1) is receptor-like protein tyrosine phosphatases (PTPs), which is also termed as HPTP-eta/CD148. It exists as a glycoprotein of 180 kDa in rat and mouse and 220-250 kDa in human and consists of an extracellular segment which comprises of 8 fibronectin type-3 repeats, a single transmembrane segment and an intracellular protein tyrosine phosphatase (PTP) domain. DEP-1 plays important functions in signal transduction in leukocytes and is involved in the mechanisms of cellular differentiation. The DEP-1 is widely expressed on the surfaces of B and T cells, granulocytes, macrophages, some dendritic cells, mature thymocytes and neutrophils in the lymphoid organs. It is expressed in fibrocytes, Schwann and melanocytes cells, and many epithelial cell types with endocrine and/or glandular differentiation in non-lymphoid tissues. DEP-1 has been found to inhibit TCR mediated activation in Jurkat cells, which results in the reduction of expression of the early activation of Ag CD 69, inhibition of tyrosine phosphorylation of many intracellular proteins such as; tyrosine kinase ZAP-70 and impairment of mitogen-activated protein kinase activation process. Although DEP-1 has inherent enzymatic activity, it is also involved in the induction of protein tyrosine phosphorylation in human lymphocytes and serine/threonine and /or tyrosine phosphorylation in cancerous cell lines. 1.1. PROTEIN TYROSINE PHOSPHATASE (PTP) The protein tyrosine phosphatase (PTP) represents a superfamily of enzymes that functions in a properly coordinated manner in conjunction with protein tyrosine kinases to control signal transduction pathways in many fundamental physiological processes. The PTPs are encoded by the largest family of phosphatases genes and they are well-defined by the active-site motif HCX5R, in which the cysteine residue works as a nucleophile and is vital for catalysis (Tonks, 2006). The protein phosphatases have evolved in distinct families that are structurally and functionally different. Among these families, the serine/threonine phosphatases exist in vivo as a group of holoenzyme complexes, which comprise of multiple combinations of both catalytic and regulatory sub-units that control a broad spectrum of signaling processes (Heinrich, Neel, & Rapoport, 2002). On the basis of the signature motif C(x) 5 R, PTPs can be categorized into two major classes: the tyrosine-specific or classical PTPS, characterized by the prototypic member PTP1B in which the signature motif is “(I/V) HCSxGxGR(S/T)G”; and the dual specificity phosphatases (DSPs), which can accommodate the dephosphorylation of tyrosine, serine, and threonine residues, in addition to inositol phospholipids, in their active site (Venter, et al., 2001). Analysis of Human Genome from Celera has reported the presence of 56 tyrosine-specific human PTPs (Venter, et al., 2001). These enzymes catalyze the direct hydrolysis of phosphor-substrate in a process facilitated by two metal ions at the active site of the enzyme. The importance of the serine/threonine is phosphatases are exhibited by being sensitive to many inhibitors. For example, the tumour promoter okadaic acid, which is an important tool in the classification of phosphorylation-dependent signal transduction (Andersen, et al., 2001). Recent research interest has focused on the haloacid dehalogenases, which comprise of phosphatases like the Eyes absent (Eya), which works as a transcription factor, and chronophin, a regulator of cofilin phosphorylation which affects the dynamics of the actin cytoskeleton (Wiggan, Bernstein, & Bamburg, 2005). These enzymes catalyze dephosphorylation in an unusual process that involves aspartic acid residues at the active site. In addition, many other phosphatases have been found to regulate signal transduction by directly acting on non-protein substrates, such as src homology-2 (SH2)-domain-containing inositide phosphatases (SHIPS) and synaptojanins, which catalyze the dephosphorylation of inositol phospholipids (Andersen, et al., 2001). Furthermore, in conjunction with the protein tyrosine kinases (PTKs), the PTPs regulate the reversible phosphorylation of tyrosine residues in proteins, thereby controlling such fundamental physiological processes as cell growth and differentiation, cell cycle, metabolism, and cytoskeletal function. The interference with the subtle stability between counter-acting PTKs and PTPs has been shown to be in the development of human diseases such as autoimmunity, diabetes and cancer (Mak & Simard, 1998). Structurally, members of the PTP protein family are classified broad into two categories which consist of non-transmembrane or transmembrane receptor-like molecules (Moller, Jansen, Iversen, & Andersen, 2002), which can further be divided into 17 major subtypes according to the amino acid sequence homology of their conserved PTP domains (Andersen, et al., 2001). PTP genes have characteristic very short introns between the 6 – 9 exons that encode the PTP domain. This domain is approximately 280 amino acids compared with the size of introns found in the non-catalytic portion. The PTP domain coding sequences spans approximately 30,000 base pairs; a significantly smaller sequence than the typical large introns found in the 5’ regions of the genes (Mak & Simard, 1998). While many cytoplasmic PTPs appear to be involved in lymphocyte signaling, just one membrane PTP, CD 45, is the only membrane PTP demonstrated to affect the signaling process after antigen receptor engagement. Density enhanced protein-1 (DEP-1) is the first tyrosine-specific PTP to be assigned a convincing role as a tumour suppressor in relations to the development of several human cancers (Ruivenkamp, Wezel, Zanon, & Stassen, 2002). Positional cloning demonstrated that DEP-1 is the underlying mouse gene responsible for the susceptibility to colon cancer locus Scc1 (Ruivenkamp, Wezel, Zanon, & Stassen, 2002), and loss of heterozygosity at the human DEP-1 locus at 11p11-p12 was observed in 19 of the 39 human colorectal adenocarcinomas. The receptor PTK Met, which was abnormally upregulated in several human tumors(Maulik, Shrikhande, Kijima, Ma, & Morrison, 2002), is a substrate of the DEP-1.Mutations in DEP-1 have been detected in tumour types associated with abnormal Met signaling, raising the possibility of a functional interaction between DEP-1 and Met in the progression of certain human cancers. Additionally, PTP was located to a small 140 kb deletion observed in 18 of 29 primary central nervous system cancers; the lack of this protein in 22 of these surgically removed lymphomas supports the argument for a likely tumor suppressor role for this gene in this neoplasm (Nakamura, Kishi, Sakaki, Hashimoto, & Nakase, 2003). 1.2. CD 148 CD 148 was characterized in 1994 as a new membrane tyrosine phosphatase by two groups which worked independently on the membrane of HeLa cell line (Ostman, Yang, & Tonks, 1994) or F-36P human leukemic cell line (Honda, Inazawa, Nishida, Yazaki, & Hirai, 1994), and was named DEP-1/HPTP-η. They isolated a cDNA encoding a molecule of 1344 amino acids. This molecule contains an extracellular portion compromised of fibronectin III domains, a transmembrane segment and an intracytoplasmic tail which contains a single PTP domain, which is in contrast with most receptor PTPs which contain a tandem repeat of two cytoplasmic phosphatase domains. The presence of fibronectin III motifs in the extracellular domain suggests its possible involvement in cell adhesion processes. The gene coding for this phosphatase was determined to be on the chromosome 11p11.2 (Honda, Inazawa, Nishida, Yazaki, & Hirai, 1994). This molecule was characterized as CD 148 by use of two different monoclonal antibodies by the VI WLDAD (Schraven, Hegen, Autschbach, Gaya, Schwartz, & Meuer, 1997). Immunoprecipitation and western blot experiments of CD 148 from unseparated PBMC demonstrated an apparent molecular weight of 240kD, although minor differences has been observed depending on the type of cells that have been studied (Ostman, Yang, & Tonks, 1994). These differences could be related with a differential glycosylation state of the molecule. The immunochemical characterization of CD 148 confirmed that this molecule contains both O- and N-linked carbohydrates. Analysis with glycosidases indicated that the major part of the carbohydrates is N-linked. This is in agreement with 34 potential sites for N-linked glycosylation as determined from cDNA sequence (Ostman, Yang, & Tonks, 1994; Honda, Inazawa, Nishida, Yazaki, & Hirai, 1994). CD 148 is a transmembrane protein tyrosine phosphatase with type III fibronectin repeats motifs in the extracellular domain and a PTPase domain in its cytoplasmic tail. Its function is obscure at this time, although the CD 148 gene has been found often deleted in malignant cells, an indication that it could be playing a tumour suppressor function (Mak & Simard, 1998). The receptor-tyrosine phosphatase DEP-1 (CD 148/PTP-η) is involved in the processes of cell growth and differentiation as well as in regulating phosphorylation of junctional proteins. However, the role of DEP-1in regulating tight junction phosphorylation and the integrity of cell-cell junctions remains elusive. In epithelial cells, the trapping mutant of DEP-1 interacts with the tight junction proteins occluding and ZO-1 in tyrosine phosphorylation dependent manner (Sallee & Burridge, 2009). In contrast, PTP-PEST, Shp2 and PTP-µ do not interact with these proteins, an implication that the interaction of DEP-1 with occluding and ZO-1 is specific. Additionally, occluding and ZO-1 were dephosphorylated by DEP-1 but not these other phosphatases in vitro. Overexpression of DEP-1 increased barrier function as measured by transepithelial electrical resistance and also reduced paracellular flux of fluorescein isothiocyanayte-dextran following a calcium switch (Sallee & Burridge, 2009). 1.2.1 Expression of CD148 on haematopoietic and non-haematopoietic cells CD 148 is widely expressed in many cell types, including epithelial and endothelial cells, fibroblasts, and most hematopoietic cell. Outside the immune system, CD 148 expression has been shown to be upregulated in cells that are cultured at high cell density as well as upon cellular differentiations. By use of monoclonal antibodies to CD 148, the expression pattern of CD 148 in murine and human immune system has been examined. The expression patterns of CD 148 are different between mice and humans. In mice, CD 148 is expressed primarily in platelets, B cells and myeloid lineage cells however, in the T cell lineage is more restricted (Heddy, 2007). Transient expression has been noted in DN thymocytes. In peripheral T cells, CD 148 expression is induced only after TCR activation. By contrast, in humans, CD 148 is widely expressed in mature thymocytes, peripheral T cells (with CD 8+ T cells having higher levels than CD4+T cells), B cells, NK cells, granulocytes, macrophages, and certain DC populations. The expression of CD 148 on human peripheral T cells is further induced upon TCR stimulation (Acton, 2012). The Src family kinases (SFKs) play a critical role in ensuring communication between a cell and its extra-cellular environment in the hematopoietic cells. These non-receptors PTKs are located on the proximal position in numerous signaling transduction cascades including those emanating from the T and B cell antigen receptors, Fc receptors, growth factor receptors, cytokine receptors, and integrins. Additionally, SFKs function as negative regulators of cellular signaling by phosphorylating immunoreceptor tyrosine-based inhibitory motifs (ITIMs) on inhibitory receptors, leading to the recruitment and activation of inhibitory molecules, which includes Src homology 2 (SH2) domain-containing phosphatase 1 (SHP-1) and SH2 containing 5’- inositol phosphatase 1 (SHIP-1) (Holsinger, Ward, Duffield, & Zachwieja, 2002). The extra cellular domain consists of eight to nine fibronectin domains and 34 potential N-linked glycosylation sites. Contrasting the tandem PTP domains of CD 45, CD 148 has only a single PTP homology domain in the cytoplasm. The PTP domain of CD 148 contains a cysteine residue that is critical for its catalytic activity. When the cysteine residue is mutated to serine, the catalytic activity of CD 148 is abolished (Sallee & Burridge, 2009). 1.2.2. Expression of CD 148 in Megakaryocytes cells Megakaryocyte can be defined as a cell positioned in bone marrow that produces blood thrombocytes which are essential for normal blood clotting. CD148 is barely the RPTP articulated on human platelet surface. To investigate whether CD148 plays a role in regulating platelet function, a study was carried out using CD148 loss-of-function mutant mice through a global membrane proteomics approach. The study demonstrated that CD148 is responsible for platelet activation through a major platelet surface receptors such as; ITAM, G protein–coupled receptors and integrin. In addition, CD148 is crucial in positive regulation of arterial thrombosis in vivo and homeostasis (Acton, 2012). Immunochemical analysis revealed that CD 148 is expressed by non-lymphoid cell types, especially by epithelial cells with glandular differentiation, as well as by some endocrine cells, among others. In mouse and rat CD 148 has been found to be expressed on non-lymphoid tissues. Thus, mCD 148 is found expressed at higher level in other tissues with the highest level in epithelial cells as detected by in situ hybridization (11). Evaluation of rCD 148 expression by Northern blot revealed that rat CD 148 transcripts are particularly high in the cerebellum, brain cortex, megakaryocytes and kidney cortex and somewhat less abundant in spleen, liver, placenta and lung, but are not present in all of the muscle tissues. Expression of rCD 148 in endothelial cells is only detectable in vessels composed of both smooth muscular cells (SMC) and endothelium (Borges, et al., 1996). 1.2.3 CD148 as a marker for memory B cells CD 148 is expressed on lymphocytosis of cell B which represent expansion on memory B cells; CD 148 membrane acts as a transducing molecule in addition to module signaling e.g. via the receptor T-cell. These regulatory mechanisms contrive to ensure a homeostatic cellular environment allowing the cell to respond appropriately to several types of natural stimuli implicating the balance of tyrosine phosphorylation (Heddy, 2007). CD148 is revealed to share surplus function by positive control of SFKs in signaling path of immunoreceptor in B cells and macrophages. This is critical in the neutrophil response to S. aureus infection and in chemoattractant-mediated chemotaxis. Deficiency in CD 148 exclusively influences neutrophil G- coupled protein receptor reactions. CD148 regulate the functions of GPCR and proximal signals including Ca2+, phosphatidylinositol 3′OH kinase (PI3K), and phospho-extracellular regulated kinase (pERK) activity (Desmond & Marion, 2001). 1.2.4 CD148 negatively regulates T-cell signaling In the hematopoietic lineage, CD148 inhibits the downstream of transduction signaling in T cell receptor. Similar to CD45, CD148 activates and inhibits the SFKs engaged in signaling of TCR. However, in the absence of CD45, stimulating effects exist, leading to functional complementation of CD45 deficiency in human T cell lines (Shirish, 2012). This is significantly independent of CD148 C-terminal tail tyrosines; conflicting the newly suggested phosphotyrosine displacement model as a mechanism of SFK activation by CD148. Collectively, differential effects of CD148 in T cells and other leukocyte subsets are explained by its dual inhibitory/activatory function and specific expression pattern (Mak & Simard, 1998). Analysis of CD148 expression on lymphoid cells demonstrates that CD148 is lowly expressed in T cells and positively regulated in response to activation. Several groups have observed that CD148 negatively controls T cell stimulation in response to cross reactivity of its antigen receptor, a factor signifying its role in feedback inhibition of the T cell immune response (Tonks, 2006). In the B cell compartment, expression of CD148 is limited to the memory sub-population, increasing its likelihood to provide exclusive roles mainly in these cells. Latest studies portrays that CD148 interrelate with PDZ domain-containing protein syntenin, increasing the chances that either its task or localization among substrates in T and B cells might be managed by a connected interface with a different PDZ domain protein (Heddy, 2007). The progression of activities in T-cell antigen receptor (TCR) signaling resulting in T-cell stimulation encompasses regulation of numeral protein tyrosine kinases (PTKs) and phosphorylation condition of numerous substrates. Tyrosine phosphorylation is usually of extremely low stoichiometry in intact cells and is swiftly reversed because the enzymes protein tyrosine phosphatases that eliminate phosphate from tyrosine-phosphorylated substrates have higher capacity than the PTKs (Holsinger, Ward, Duffield, & Zachwieja, 2002). A moderate alteration in equilibrium between PTK/PTPase significantly impacts disposable tyrosine phosphorylation hence stimulating and propagating T-cells. This portrays the functions of PTKs and PTPases in up and down regulation of T-cell stimulation (Mak & Simard, 1998). 1.2.5. CD148 function in granulocytes The extracellular domain of CD148 has 10 fibronectin III motifs, and the cytoplasmic C-terminal region has a single protein tyrosine phosphatase domain. Amongst hematopoietic cells, CD148 is expressed strongly at inflammatory sites on monocytes, granulocytes, T cells, platelets and dendritic cells. CD148 also known as HPTP-eta/DEP-1 is involved in the following functions; in leucocytes it contributes to mechanisms of cellular differentiation and Signal transduction (Andersen, et al., 2001). In lymphoid organs, CD148 are broadly expressed on cell B in addition to T, granulocytes, macrophages, certain dendritic cells and mature thymocytes. Leucocytes expressing CD148 are significantly up regulated in inflamed tissues and a subset of the cells co-express activation marker CD25 (Heddy, 2007). It also plays a role in growth regulation of epithelial cells. Among non-hematopoietic cells, CD148 is expressed by characteristic types of epithelial and non-epithelial cells. Down regulation of CD148 might promote dedifferentiation and autonomous growth of such cells in malignant tumors (Desmond & Marion, 2001). CD148 inhibits cell development as well as negative control of cell T cell stimulation in response to cross linking of T cell antigen receptor. This suggests that it inhibits feedback in T cell immune system. CD148 is stimulated via LPS and CSF-I on macrophages required for vascular development. 1.2.6. Role of CD148 in cells of the mononuclear phagocyte system CD148 regulates functioning and inflammation in macrophage. CD148 is a well expressed PTP receptor in macrophages regulated via pro-inflammatory stimuli. Usually CD148 is restricted to plasma cover of macrophages (Nakamura, Kishi, Sakaki, Hashimoto, & Nakase, 2003). When stimulated by CSF-1 /LPS, there is accumulation and re-arrangement of CD148 in region of membrane ruffling. Management of macrophages using anti-CD148 monoclonal antibody repressed CSF-1-stimulated spreading of macrophage, chemotaxis and reorganization of cytoskeletal without disturbing cell existence (Lin & Weiss, 2003). CD148 plays a central role in normal immune cell functioning through joint regulation of tyrosine phosphorylation via protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). When the balance between activities of PTK and PTP is disturbed this leads to autoimmunity, deficiency in immune system and malignancy (Nobel & Ian, 2006). Src family kinases (SFKs) plays a fundamental task in functioning of the immune cell and disease because they are strategically located in several signal transduction cascade counting those derived from development factor, cytokine receptors and integrin (Mak & Simard, 1998). CD 148 aids in regulation of several signaling pathways resulting to development, phagocytosis, differentiation, activation and adhesion in macrophages. CD148 (PTPs) is involved in active phosphorylation of cell status and extensive control of physiological developments by biochemically offsetting the actions of protein tyrosine kinases. The function of CD 148 in leukocytes was initially analyzed using forced expression of CD 148 in a Jurkat T-cell line. These studies demonstrated that induced expression of CD 148 led to selective dephosphorylation of phospholipase Cc1 (PLCc1) and linker for activation of T cells (LAT), resulting in downregulation of TCR-dependent signaling (Holsinger, Ward, Duffield, & Zachwieja, 2002). However, it was not clear whether this was due to direct or indirect actions of the phosphatase, as it was also plausible that the phosphatase could activate a negative feedback loop resulting in activation of other phosphatases within the cell that then downregulate the TCR response. Consistent with a potential role in termination of the immune response, immunofluorescence microscopy revealed that the extracellular domain of CD 148 mediated its exclusion from the immunological synapse, sequestering it from potential substrates (Lin & Weiss, 2003). It was proposed that upon T cell-antigen-presenting cell disengagement, CD 148 could then access and dephosphorylate its relevant substrates, resulting in termination of prolonged TCR signaling (Lin & Weiss, 2003). 1.2.7. Physiological Functions of CD148 in non-haematopoietic cells CD148 (RPTP) plays inhibitory role in signaling and propagation in non-hematopoietic cells. Study of CD148 loss of function mice proposes that CD148 positively regulates the role of macrophages and B-cells. Analysis of CD148/CD45 doubly-deficient B cells and macrophages exposed hyper-phosphorylation of the tyrosine c-terminal that inhibits SFKs along with significant changes in B in addition to myeloid heredity growth and malfunctioning immunoreceptor signaling. The results imply the C-terminal tyrosine of SFKs has a universal substrate for both CD148 and CD45 phosphatases (William & Judah, 2008). CD148 is known to regulate inhibition of cell growth that depends on density in addition to cellular separation in non-hematopoietic cells. In addition, it facilitates signal transduction processes in numerous non-lymphoid hematopoietic cell forms. CD148 is lowly articulated on T cells and up synchronized in reaction to activation has confirmed on lymphoid cells. Observations reveal that CD148 negatively controls activation of T cell in response to cross relating of T cell antigen receptor, signifying a task in feedback reserve in immune response of T cell. In B cell zone, expression of CD148 is limited to memory subpopulation, increasing the chances of serving exclusive role in these cells. latest studies show that CD148 interrelate with a domain( PDZ) that hold protein syntenin increasing chances that either its role or localization with substrates in T and B cells can be managed through this or an associated interaction with a different PDZ domain protein. CD148 reduces transduction of mitogenic indicator in non-hematopoietic cells. In the same way CD148 reduced the downstream in signal transduction of T cell receptor. CD148 triggers and inhibits SFKs concerned in TCR signaling. Conversely, stimulation effects exist without CD45, leading to functional harmonized shortage of CD45 in human T cell lines. In general, disparity in effects of CD148 in T cells and leukocyte subsets is not clarified by CD148 failure in activating T cell but slightly its double inhibitory/activatory function and specific expression pattern (Yehuda, Richard, & Gershwin, 2008). 1.2.8. CD148 and diseases CD 148 plays a significant regulatory role in phosphorylation condition of cells. CD 148 is displayed on an individual eosinophils and eosinophilic cell line EoL-3 and acts as a transduction molecule on these cells. Cross relating of CD148 is capable of stimulating degranulation and orientation of superoxide anion production. Through use of particular inhibitor and western blotting, tyrosine kinase activation is involved in this transduction lane. The activation capacity of CD148 on eosinophils proposes a possible accountability of this molecule on inflammatory diseases, for instance allergic and parasitic diseases, associated with eosinophilia (Nobel & Ian, 2006). CD 148 is capable of stimulating superoxide anion production triggered by vascular cell adhesion molecule 1 (VCAM-1) [34]. prospective signaling capabilities of CD148 on human eosinophils clearly shows that cross relating CD148 is satisfactory to stimulate the respiratory rupture and discharge particular lethal proteins from eosinophil granules for example ECP and EPX. The significance of discharging these substances is supported by reality that these intermediaries are poisonous to tissues thus contributing to pathogenesis of asthma (Shirish, 2012). Many molecular studies have implicated CD 148 as a tumor suppressor. The loss of heterozygosity for CD 148 has been associated with colon, lung, and breast carcinomas. Furthermore, positional cloning of a gene responsible for susceptibility to colon cancer (Scc1) in mice revealed CD148 as a major candidate. Whether or not CD 148 may play a similar role in hematologic malignancies is not clear. CD 148 has been associated with an autoimmune disease, Cogan’s syndrome which is a chronic inflammatory disease characterized by sensorineural hearing loss, keratitis and vasculitis (Lunardi & al, 2002). This was demonstrated by the presence of autoantibodies to CD 148 in the patients, which inhibited proliferation of CD 148 expressing cells and replicated the features of Cogan’s disease when infused into mice (Lunardi & al, 2002; Ruivenkamp et al., 2003). To date, many proteins have identified as potential CD 148 substrates. These include PDGFR, HGFR (c-Met), p120ctn, c-Src (C-terminal inhibitory tyrosine), and P13K (Lunardi & al, 2002; Holsinger, Ward, Duffield, & Zachwieja, 2002). Unfortunately, the majorities of these putative substrates were found using substrate trapping methodologies in vitro or overexpression approaches in cell lines and have not been validated in vivo (Lunardi & al, 2002). 1.2.8.1. CD148 and inflammation The activation capacity of CD148 on eosinophils implies its potential role on inflammatory diseases, for instance allergic and parasitic diseases, related to eosinophilia. The molecule is expressed on human eosinophils and eosinophilic cell line EoL-3 and acts as a transduction molecule on these cells. Thus, the cross relating of CD148 is able to induce the degranulation and the induction of superoxide anion generation. When a particular inhibitor and western blotting are employed, tyrosine kinase stimulation is involved in transduction pathway. Additionally, presence of a serine/threonine kinase activity is related with CD148.This portrays its potential role on inflammatory diseases (Heddy, 2007). CD148 is copiously expressed in vascular endothelial cells. When the role of CD148 in endothelial vessel formation is explored by a generated monoclonal antibody, Ab1, versus the ectodomain series of CD148, it was observed that a bivalent form of Ab1 antibody reduces the development of endothelial-cell and obstruct angiogenesis in mouse cornea in vivo. Further observations revealed that bivalent Ab1 seized the progression in cell-cycle of CD148-transfected CHO cells at G(0)/G(1) stage, the co-expression of dormant CD148 mutants inhibits Ab1 cell growth and bivalent Ab1 represses phosphorylation of ERK1/2 kinases with increased activities of tyrosine phosphatase associated with CD148. These findings reveal that Ab1-stimulates ectodomain oligomerization arresting the growth of endothelial-cells by means of a catalytic action of CD148 cytoplasm domain. Thus CD148 is considered a significant target for ant angiogenesis treatment (Bernadette & Thomas, 2008). Increasing evidence reveals an outstanding role of CD148 in depressing growth regulation factor, repressing cell propagation and alteration. Nevertheless, its extracellular ligand(s) are strange. To identify the ligand(s) of CD148, HA-tagged CD148 were introduced into refined endothelial cells and its association with extracellular protein(s) was isolated using biotin surface tagging and successive similar purifications. It was examined that soluble thrombospondin-1 (TSP1) connects to the extracellular element of CD148 with high attraction and specificity, and its binding enhances CD148 catalytic activity, leading to dephosphorylation of the substrate proteins. The study portrays the receptor role of CD148 for TSP1 and reconciles reduction in cell growth. 1.2.8.2. Role of CD148 in malignancy Disturbance of balance involving activities of PTK and PTP could lead to malignancy, immunodeficiency or autoimmunity. Joint regulation of tyrosine phosphorylation by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) is essential to normal immune cell function. Src family kinases (SFKs) significantly participates in functioning of the immune cell and disease because they are strategically located on several signal transduction cascade counting those coming from cytokine receptors, integrin, antigen receptors of T and B-cell and development factor (Talk & John, 1998). Tyrosine phosphorylation is significant in eukaryotic cells signaling. Monogenic stimulation of tyrosine kinases in cancer and introduction of new drugs for fighting cancer aiming these enzymes is common. Tyrosine phosphorylation is as well managed by protein-tyrosine phosphatases (PTPs). Latest evidence reveals that PTPs could suppress tumors. Additionally, a number of PTPs, counting SHP2, absolutely regulate growth indicators are monogenic. A better understanding of enzyme control and functioning may support development of fresh anticancer drugs. CD148 is articulated and synchronized in cell lines of breast cancer during separation. Stimulation of CD148 appearance double reduces growth of breast cancer cell. Re-expression of vigorous CD148 in cell line of colon cancer that suppress CD148 highly inhibits cell propagation and relocation. Repression of CD148 in cell membrane of colon epithelial with endogenous levels of CD148 improves proliferation. Chemo protective nutrients with respect to growth of colon cancer (butyrate, green tea, apple polyphenols) may increase expression of endogenous CD148, thus inhibiting cell development and relocation (Acton, 2012). REFERENCES Acton, Q. A. 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