Expression of PTP35, the Murine Homolog of the Protein Tyrosine Phosphatase-Related Sequence IA-2, Is Regulated during Cell Growth and Stimulated by Mitogens in 3T3 Fibroblasts

Magistrelli, Giovanni; Covini, Nevie; Mosca, Monica; Lippoli, Guido; Isacchi, Antonella

doi:10.1006/bbrc.1995.2758

Cited by 20 publications

(10 citation statements)

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“…27 In this context, it is noteworthy that RTP IA2 is expressed in barely detectable amounts Leukemia in quiescent cells but it is highly expressed in proliferating cells and its expression is induced by mitogenic stimulation of quiescent cells. 28 It is likely therefore that RTP IA2 may also play a role in LMO2-induced leukemias.…”

Section: Figurementioning

confidence: 99%

Identification of genes potentially involved in LMO2-induced leukemogenesis

2000

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The most common translocations in childhood T cell acute lymphoblastic leukemias involve the LMO2 locus on chromosome 11p13 and cause ectopic expression of the LMO2 gene in thymocytes. Transgenic mice with enforced expression of LMO2 in their thymocytes develop T cell leukemias thus demonstrating the role of LMO2 in leukemogenesis. The physiologic and leukemogenic functions of LMO2 are mediated through its transcriptional regulatory activities, but the identity of the target genes is completely unknown. In this report, we have used cDNA representational difference analysis (cDNA-RDA) to identify genes that are over-expressed and are likely to play a role in the LMO2 induced leukemias. cDNA-RDA was performed using very small amounts of mRNA pool (from 1 g of total RNA) to reverse transcribe the cDNAs from leukemic cells or normal thymocytes. The cDNA-RDA led to the isolation of nine distinct clones that were specifically overexpressed in the leukemic cells. Sequence analysis revealed that five of the nine clones had identity or homology to known genes that are known to play a role in the pathogenesis of leukemias or other cancers. Three clones had no significant homology to any known genes and thus represent novel candidate genes. Our study demonstrates that cDNA-RDA using very small amounts of total RNA is a highly efficient method to identify novel genes that may play a role in leukemogenesis.

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Section: Figurementioning

confidence: 99%

Identification of genes potentially involved in LMO2-induced leukemogenesis

2000

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“…The crude peptide was purified by reverse-phase HPLC and the sequence was confirmed by amino acid analysis and fast atom bombardment mass spectrometry. A BamHI-EcoRI fragment encoding the protein tyrosine phosphatase 35 intracellular domain (aa 601-979) was amplified by PCR on the protein tyrosine phosphatase 35 cDNA (23) and subcloned into the expression vector pGEX-2T (Pharmacia, Uppsala, Sweden). Mouse rIA-2 was expressed in Escherichia coli as a GST-fusion protein and purified by affinity chromatography on glutathione-Sepharose, followed by thrombin cleavage to recover Ͼ98% pure mouse rIA-2 (rmIA-2), as described (24).…”

Section: Antigensmentioning

confidence: 99%

Early Th1 Response in Unprimed Nonobese Diabetic Mice to the Tyrosine Phosphatase-Like Insulinoma-Associated Protein 2, an Autoantigen in Type 1 Diabetes

Trembleau

Penna

Gregori

et al. 2000

The Journal of Immunology

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The insulinoma-associated protein 2 (IA-2) is a phosphatase-like autoantigen inducing T and B cell responses associated with human insulin-dependent diabetes mellitus (IDDM). We now report that T cell responses to IA-2 can also be detected in the nonobese diabetic (NOD) mouse, a model of human IDDM. Cytokine secretion in response to purified mouse rIA-2, characterized by high IFN-γ and relatively low IL-10 and IL-6 secretion, was elicited in spleen cells from unprimed NOD mice. Conversely, no response to IA-2 was induced in spleen cells from BALB/c, C57BL/6, or Biozzi AB/H mice that express, like NOD, the I-Ag7 class II molecule, but are not susceptible to spontaneous IDDM. The IA-2-induced IFN-γ response in NOD spleen cells could already be detected at 3 wk and peaked at 8 wk of age, whereas the IL-10 secretion was maximal at 4 wk of age and then waned. IA-2-dependent IFN-γ secretion was induced in CD4+ cells from spleen as well as pancreatic and mesenteric lymph nodes. It required Ag presentation by I-Ag7 molecules and engagement of the CD4 coreceptor. Interestingly, cytokines were produced in the absence of cell proliferation and IL-2 secretion. The biological relevance of the response to IA-2 is indicated by the enhanced IDDM following a single injection of the recombinant protein emulsified in IFA into 18-day-old NOD mice. In addition, IFN-γ production in response to IA-2 and IDDM acceleration could be induced by IL-12 administration to 12-day-old NOD mice. These results identify IA-2 as an early T cell-inducing autoantigen in the NOD mouse and indicate a role for the IA-2-induced Th1 cell response in IDDM pathogenesis.

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“…Two such proteins, IA-2 and IA-2␤, have drawn quite some attention because they were identified as the precursors of 40-and 37-kDa insulin-dependent diabetes mellitus-specific major auto-antigens, respectively (19). IA-2 (20) (also termed PTP35 (21) or ICA512 (22)) and IA-2␤ (23) (also known as Phogrin (24), PTP-NP (25), ICAAR (26), or IAR (27)) are membrane-spanning RPTP-like proteins, with a cysteine-rich region at their Nterminal extracellular part, a single-pass transmembrane region, and a single inactive intracellular PTP domain. The lack of phosphotyrosine-specific activity is due to some major substitutions of conserved amino acids within the PTP domain that are critical for the specific activity of PTPs against substrates.…”

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confidence: 99%

Multimerization of the Protein-tyrosine Phosphatase (PTP)-like Insulin-dependent Diabetes Mellitus Autoantigens IA-2 and IA-2β with Receptor PTPs (RPTPs)

Gross¹,

Blanchetot

Schepens³

et al. 2002

Journal of Biological Chemistry

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Most receptor-type protein-tyrosine phosphatases (RPTPs) contain two tandem PTP domains. For some RPTPs the enzymatically inactive membrane-distal phosphatase domains (D2) were found to bind enzymatically active membrane proximal PTP (D1) domains, and oligomerization has been proposed as a general regulatory mechanism. The RPTP-like proteins IA-2 and IA-2␤, major autoantigens in insulin-dependent diabetes mellitus, contain just a single enzymatically inactive PTPlike domain. Their physiological role is as yet enigmatic. To investigate whether the catalytically inactive cytoplasmic domains of IA-2 and IA-2␤ are involved in oligomerization, we exploited interaction trap assay in yeast and glutathione S-transferase pull-down and coimmunoprecipitation strategies on lysates of transfected COS-1 cells. The results show that IA-2 and IA-2␤ are capable of homo-and heterodimerization to which both the juxtamembrane region and the phosphataselike segment can contribute. Furthermore, they can form heterodimers with some other RPTP members, most notably RPTP␣ and RPTP⑀, and down-regulate RPTP␣ enzymatic activity. Thus, in addition to homodimerization, the enzymatic activity of receptor-type PTPs can be regulated through heterodimerization with other RPTPs, including the catalytically inactive IA-2 and IA-2␤.

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Expression of PTP35, the Murine Homolog of the Protein Tyrosine Phosphatase-Related Sequence IA-2, Is Regulated during Cell Growth and Stimulated by Mitogens in 3T3 Fibroblasts

Cited by 20 publications

References 0 publications

Identification of genes potentially involved in LMO2-induced leukemogenesis

Identification of genes potentially involved in LMO2-induced leukemogenesis

Early Th1 Response in Unprimed Nonobese Diabetic Mice to the Tyrosine Phosphatase-Like Insulinoma-Associated Protein 2, an Autoantigen in Type 1 Diabetes

Multimerization of the Protein-tyrosine Phosphatase (PTP)-like Insulin-dependent Diabetes Mellitus Autoantigens IA-2 and IA-2β with Receptor PTPs (RPTPs)

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