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For Casein Kinase 2 Serves As a Binding and Phosphoacceptor Site 19-Amino Acid Insert in Domain II That CD45 Function Is Regulat

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For Casein Kinase 2 Serves As a Binding and Phosphoacceptor Site 19-Amino Acid Insert in Domain II That CD45 Function Is Regulat CD45 Function Is Regulated by an Acidic 19-Amino Acid Insert in Domain II That Serves as a Binding and Phosphoacceptor Site for Casein Kinase 2 This information is current as of September 24, 2021. Susanna F. Greer, Yan-ni Wang, Chander Raman and Louis B. Justement J Immunol 2001; 166:7208-7218; ; doi: 10.4049/jimmunol.166.12.7208 http://www.jimmunol.org/content/166/12/7208 Downloaded from References This article cites 46 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/166/12/7208.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 24, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2001 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. CD45 Function Is Regulated by an Acidic 19-Amino Acid Insert in Domain II That Serves as a Binding and Phosphoacceptor Site for Casein Kinase 21 Susanna F. Greer,2* Yan-ni Wang,2* Chander Raman,† and Louis B. Justement3* In this study experiments were conducted to elucidate the physical/functional relationship between CD45 and casein kinase 2 (CK2). Immunoprecipitation experiments demonstrated that CK2 associates with CD45 and that this interaction is inducible upon Ag receptor cross-linking in B and T cell lines as well as murine thymocytes and splenic B cells. However, yeast two-hybrid analysis failed to demonstrate a physical interaction between the individual CK2 ␣, ␣؅,or␤ subunits and CD45. In contrast, a yeast ,three-hybrid assay in which either CK2 ␣ and ␤ or ␣؅ and ␤ subunits were coexpressed with the cytoplasmic domain of CD45 demonstrated that both CK2 subunits are necessary for the interaction with CD45. Experiments using the yeast three-hybrid assay Downloaded from also revealed that a 19-aa acidic insert in domain II of CD45 mediates the physical interaction between CK2 and CD45. Structure/ function experiments in which wild-type or mutant CD45RA and CD45RO isoforms were expressed in CD45-deficient Jurkat cells revealed that the 19-aa insert is important for optimal CD45 function. The ability of both CD45RA and CD45RO to reconstitute CD3-mediated signaling based on measurement of calcium mobilization and mitogen-activated protein kinase activation was significantly decreased by deletion of the 19-aa insert. Mutation of four serine residues within the 19-aa insert to alanine affected CD45 function to a similar extent compared with that of the deletion mutants. These findings support the hypothesis that a physical http://www.jimmunol.org/ interaction between the CD45 cytoplasmic domain and CK2 is important for post-translational modification of CD45, which, in turn, regulates its catalytic function. The Journal of Immunology, 2001, 166: 7208–7218. olocalization of the Src family protein tyrosine kinases and therefore lymphocyte biology, through its ability to regulate (PTK)4 with the Ag receptor (AgR) complex on T and B Src PTK function. C cells plays an important role in the initiation and propa- Although significant progress has been made toward under- gation of signal transduction in response to Ag stimulation (1, 2). standing how CD45 regulates AgR signaling, there is still much to Numerous studies have demonstrated that CD45, a transmembrane be learned regarding the mechanism(s) by which CD45 substrate protein tyrosine phosphatase (PTP), also plays an important role in specificity and catalytic activity are controlled. The cytoplasmic by guest on September 24, 2021 regulating lymphocyte biology (3, 4). CD45 expression is essential tail of CD45 contains tandem repeat PTP domains, designated do- for normal T and B cell development and for optimal activation in main I (DI) and II (DII), that exhibit a significant degree of ho- response to AgR cross-linking (5–8). It has been shown that B cell mology to PTP IB (40 and 33%, respectively) (4). It is apparent, Ag receptor (BCR)-mediated signal transduction via Lyn, Fyn, and however, that DI, but not DII, is catalytically active based on mu- Blk is dependent on the expression of CD45 (9–12). Similarly, in tational analysis of conserved cysteine residues within the catalytic T cells, dephosphorylation of Lck and Fyn by CD45 leads to their site of each. Results from in vitro as well as in vivo studies have activation and participation in TCR signaling cascades (13–16). shown that mutation of the conserved cysteine residue in DI to Thus, CD45 regulates reversible protein tyrosine phosphorylation, serine completely abrogates CD45 catalytic function, whereas mu- tation of the analogous cysteine residue in DII has no effect (17– 19). Moreover, recent studies have shown that DI of CD45 exhibits phosphatase activity when expressed as a recombinant protein in *Department of Microbiology, Division of Developmental and Clinical Immunology, the absence of DII, whereas DII has no phosphatase activity when and †Department of Medicine, Division of Clinical Immunology and Rheumatology, isolated from DI (20). University of Alabama, Birmingham, AL 35294 Although DII does not directly play a role in dephosphorylation Received for publication November 10, 2000. Accepted for publication April 12, 2001. of substrates, there is substantial evidence to suggest that it may, in fact, influence both the catalytic activity and the substrate speci- The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance ficity of DI (18–20). Studies using recombinant CD45 have dem- with 18 U.S.C. Section 1734 solely to indicate this fact. onstrated that deletion of DII in its entirety can either decrease or 1 This work was supported in part by National Institutes of Health Grant GM46524. completely abrogate the ability of DI to dephosphorylate artificial 2 S.F.G. and Y.W. contributed equally to this work and should be considered as substrates in vitro. Smaller deletions within DII, including a trun- co-first authors. cation of the carboxyl-terminal 15 aa, affect the catalytic function 3 Address correspondence and reprint requests to Dr. Louis B. Justement, 378 Wallace of DI as well (18, 19). Finally, in vivo studies have demonstrated Tumor Institute, Division of Developmental and Clinical Immunology, University of Al- abama, Birmingham, AL 35294-3300. E-mail address: [email protected] that replacement of CD45 DII with DII from the PTP LAR abro- gates the ability of the chimeric CD45 molecule to reconstitute 4 Abbreviations used in this paper: PTK, protein tyrosine kinase; AgR, Ag receptor; PTP, protein tyrosine phosphatase; BCR, B cell Ag receptor; DI, CD45 protein ty- TCR-mediated IL-2 production due to an alteration in the ability to rosine phosphatase domain I; DII, CD45 protein tyrosine phosphatase domain II; recruit TCR-␨ (21). CK2, casein kinase 2; BD, GAL4 binding domain; AD, GAL4 activation domain; Erk1/2, extracellular signal-regulated kinase 1/2; Jnk, c-Jun N-terminal kinase; DII of CD45 contains a unique 19-aa acidic insert that is not MAPK, mitogen-activated protein kinase. found in other transmembrane PTPs. Deletion of this insert has Copyright © 2001 by The American Association of Immunologists 0022-1767/01/$02.00 The Journal of Immunology 7209 been shown to selectively alter the ability of CD45 to dephosphor- ␮g/ml) or CD3 (OKT3, 10 ␮g/ml) at 37°C for 10 min. Control samples ylate artificial substrates in vitro (18–20). The 19-aa insert con- received neither anti-BCR nor anti-CD3 mAbs, but were incubated at 37°C tains multiple casein kinase 2 (CK2) consensus sites, suggesting for 10 min. Reactions were stopped by the addition of ice-cold PBS. Next, cells were washed twice with ice-cold PBS and lysed in 0.5 ml lysis buffer that the catalytic function of CD45 may be regulated by serine (25 mM HEPES (pH 7.8), 150 mM NaCl, 10 mM EDTA, 1 mM EGTA, phosphorylation of DII. Indeed, studies have demonstrated that and 0.1 mM Na3VO4) containing 1% Nonidet P-40. Cell lysates were in- CD45 is phosphorylated by CK2 at a high stoichiometry (22) and cubated for1honiceandthen centrifuged at 13,000 ϫ g for 15 min at 4°C. that multiple residues within the 19-aa insert are phosphoacceptor Detergent-soluble lysates were precleared by incubation with protein G- Sepharose and protein A-agarose for1hat4°C. CD45 was immunopre- sites for this kinase (23, 24). Phosphorylation of CD45 within the cipitated from precleared K46 lysates by the addition of I3/2.5 mAb (10 acidic insert has been shown to regulate both its substrate speci- ␮g/ml) plus protein G-Sepharose for1hat4°Cwith rotation. CD45 was ficity as well as its activity in vitro (23, 24). Additionally, work has immunoprecipitated from precleared Jurkat lysates by incubation with pre- shown that decreased serine phosphorylation of CD45 is associ- coated protein G-Sepharose beads for1hat4°Cwith rotation. For these ated with a decrease in its catalytic function (24, 25). These find- experiments protein G-Sepharose beads were precoated initially with the anti-human CD45 mAb RPI-14 and then with saturating amounts of mAb ings demonstrate that the ability of DII to alter the substrate spec- I3/2.5 (anti-murine CD45).
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