Ligand-mediated negative regulation of a chimeric transmembrane receptor tyrosine phosphatase

Desai, Dev M.; Sap, Jan; Schlessinger, Joseph; Weiss, Arthur

doi:10.1016/0092-8674(93)90141-c

Cited by 269 publications

(188 citation statements)

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“…Forced dimerization of chimeric CD45 phosphatase molecules inhibits CD45 function, resulting in blunted TCR signaling (Desai et al, 1993). This appears to be mediated by a juxtamembrane wedge-like structure that can interact with and block the catalytic site of the partner phosphatase during dimerization (Majeti et al, 1998;Majeti et al, 2000).…”

Section: Model Of Regulation and Activationmentioning

confidence: 99%

Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation

2004

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The function of the Src-family kinases (SFKs) Lck and Fyn in T cells has been intensively studied over the past 15 years. Animal models and cell line studies both indicate a critical role for Lck and Fyn in proximal T-cell antigen receptor (TCR) signal transduction. Recruited SFKs phosphorylate TCR ITAMs (immunoreceptor tyrosinebased activation motifs) in the CD3 and f chains, which then serve as docking sites for Syk-family kinases. SFKs then phosphorylate and activate the recruited Syk-family kinase. Lck and Fyn are spatially segregated in cell membranes due to differential lipid raft localization, and may undergo sequential activation. In addition to the CD4 and CD8 coreceptors, a recently described adaptor, Unc119, may link SFKs to the TCR. CD45 and Csk provide positive and negative regulatory control of SFK functions, respectively, and Csk is constitutively bound to the transmembrane adapter protein, PAG/Cbp. TCRbased signaling is required at several stages of T-cell development, including at least pre-TCR signaling, positive selection, peripheral maintenance of naive T cells, and lymphopenia-induced proliferation. SFKs are required for each of these TCR-based signals, and Lck seems to be the major contributor.

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Section: Model Of Regulation and Activationmentioning

confidence: 99%

Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation

2004

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“…Studies on the crystal structure of RPTP␣-D1 indicate that a helix-loophelix wedge-like structure to the N-terminal side of D1 occludes the catalytic site of the dyad-related monomer (16). The RPTP CD45 is also regulated by dimerization (17,18). Mutations in the wedge-like structure of CD45 and RPTP␣ abolished dimerization-induced inactivation (15,19) proving that the wedgelike structure is essential for the regulation of RPTP activity by rotational coupling of the monomers in the dimer.…”

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confidence: 99%

H2O2-induced Intermolecular Disulfide Bond Formation between Receptor Protein-tyrosine Phosphatases

Wijk

Overvoorde

Hertog

2004

Journal of Biological Chemistry

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Receptor protein-tyrosine phosphatase ␣ (RPTP␣) belongs to the subfamily of receptor-like protein-tyrosine phosphatases that are characterized by two catalytic domains of which only the membrane-proximal one (D1) exhibits appreciable catalytic activity. The C-terminal catalytic domain (D2) regulates RPTP␣ catalytic activity by controlling rotational coupling within RPTP␣ dimers. RPTP␣-D2 changes conformation and thereby rotational coupling within RPTP␣ dimers in response to changes in the cellular redox state. Here we report a decrease in motility of RPTP␣ from cells treated with H 2 O 2 on non-reducing SDS-polyacrylamide gels to a position that corresponds to RPTP␣ dimers, indicating intermolecular disulfide bond formation. Using mutants of all individual cysteines in RPTP␣ and constructs encoding the individual protein-tyrosine phosphatase domains, we located the intermolecular disulfide bond to the catalytic Cys-723 in D2. Disulfide bond formation and dimer stabilization showed similar levels of concentration and time dependence. However, treatment of lysates with dithiothreitol abolished intermolecular disulfide bonds but not stable dimer formation. Intermolecular disulfide bond formation and rotational coupling were also found using a chimera of the extracellular domain of RPTP␣ fused to the transmembrane and intracellular domain of the leukocyte common antigen-related protein (LAR). These results suggest that H 2 O 2 treatment leads to oxidation of the catalytic Cys in D2, which then rapidly forms a disulfide bond with the D2 catalytic Cys of the dyad-related monomer, rendering an inactive RPTP dimer. Recovery from oxidative stress first leads to the reduction of the disulfide bond followed by a slower refolding of the protein to the active conformation. Protein-tyrosine phosphatases (PTPs)1 form a family of enzymes that catalyze the dephosphorylation of tyrosine residues in proteins. They are characterized by one or two catalytic domains containing a signature sequence (I/V)HCXAGXXR(S/ T/G) including a catalytic cysteine (for review, see Refs. 1 and 2). This cysteine forms a thiol-phosphate intermediate in the dephosphorylation reaction and is therefore essential for enzyme activity (3). Because of the low pK a of the catalytic cysteine, PTPs are very susceptible to oxidation (for review, see Ref. 4). Reactive oxygen species induce oxidation of catalytic cysteines, thereby inactivating these PTPs (5-8). Extracellular stimuli like growth factors and UV irradiation result in an increase in intracellular reactive oxygen species and oxidation of PTPs (5, 9 -12). Inhibition of enzyme activity by oxidative stress is increasingly recognized as an important mechanism of regulation of the PTP family. Therefore, PTPs may serve as sensors of the cellular redox state.RPTP␣ belongs to the receptor-like PTPs that are characterized by a single transmembrane domain. RPTP␣ has two catalytic domains of which the N-terminal one (D1) contains almost all of the catalytic activity of the enzyme. RPTP␣ was found to constitutive...

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“…We initially hypothesized that CD45, similar to receptor protein tyrosine kinases, would be positively regulated by ligand-mediated dimerization (9). Surprisingly, forced dimerization of a chimeric molecule consisting of the extracellular and transmembrane domains of the epidermal growth factor receptor and the CD45 cytoplasmic domain inhibited CD45 functional activity (10). The crystal structures of the juxtamembrane and N-terminal phosphatase domain of a related RPTP, PTP␣, suggested a potential molecular mechanism for this inhibition (11).…”

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Differential impact of the CD45 juxtamembrane wedge on central and peripheral T cell receptor responses

Hermiston¹,

Zikherman²,

Tan

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The cooperative activity of protein tyrosine kinases and phosphatases plays a central role in regulation of T cell receptor (TCR) signal strength. Perturbing this balance, and thus the threshold for TCR signals, has profound impacts on T cell development and function. We previously generated mice containing a point mutation in the juxtamembrane wedge of the receptor-like protein tyrosine phosphatase CD45. Demonstrating the critical negative regulatory function of the wedge, the CD45 E613R (WEDGE) mutation led to a lymphoproliferative disorder (LPD) and a lupus-like autoimmune syndrome. Using genetic, cellular, and biochemical approaches, we now demonstrate that the CD45 wedge influences T cell development and function. Consistent with increased TCR signal strength, WEDGE mice have augmented positive selection and enhanced sensitivity to the CD4-mediated disease experimental autoimmune encephalitis (EAE). These correspond with hyperresponsive calcium and pERK responses to TCR stimulation in thymocytes, but surprisingly, not in peripheral T cells, where these responses are actually depressed. Together, the data support a role for the CD45 wedge in regulation of T cell responses in vivo and suggest that its effects depend on cellular context. autoimmunity ͉ tyrosine phosphatase ͉ tyrosine kinase ͉ thymocyte development T cell receptor (TCR) signal strength is influenced by the integration of multiple inputs including affinity for antigen, presence and activity of costimulatory molecules, and duration of the interaction with antigen-presenting cells (APCs) (1). Alterations in TCR signal strength impact many aspects of T cell biology including CD4 versus CD8 lineage commitment (1), effector and memory cell generation (2), and autoimmunity (3, 4). Currently, the factors defining signal strength and its functional outcome are incompletely understood.CD45, a receptor-like protein tyrosine phosphatase (RPTP) expressed on all nucleated hematopoietic cells, plays a critical positive regulatory role in antigen receptor signaling. Its absence in both mice and humans results in severe combined immunodeficiency (5, 6). CD45 mediates its effects, at least in part, by modulating the activation state of Src family protein tyrosine kinases (SFKs) (5, 7). Phosphorylation of the SFK C-terminal tyrosine by Csk inhibits the kinase while autophosphorylation of the catalytic domain tyrosine results in full activity. CD45 opposes Csk by dephosphorylating the negative regulatory tyrosine, generating a pool of primed SFKs capable of rapid activation upon receptor stimulation. In some cell types, CD45 can also dephosphorylate the catalytic tyrosine and negatively regulate SFKs.Regulation of CD45 itself is complex. Alternative splicing of the extracellular domain, regulated in a cell-and activation-specific manner, generates multiple isoforms differing in size and charge (5). Interestingly, CD45 polymorphisms influencing its alternative splicing, and thus isoform expression, are associated with several human autoimmune diseases (8). We initi...

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Ligand-mediated negative regulation of a chimeric transmembrane receptor tyrosine phosphatase

Cited by 269 publications

References 64 publications

Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation

Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation

H2O2-induced Intermolecular Disulfide Bond Formation between Receptor Protein-tyrosine Phosphatases

Differential impact of the CD45 juxtamembrane wedge on central and peripheral T cell receptor responses

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