• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of embojLink to Publisher's site
EMBO J. Sep 16, 1996; 15(18): 4909–4918.
PMCID: PMC452228

Association of inhibitory tyrosine protein kinase p50csk with protein tyrosine phosphatase PEP in T cells and other hemopoietic cells.


p50csk is a tyrosine protein kinase (TPK) that represses the activity of Src family TPKs. We previously showed that Csk is a potent negative regulator of antigen receptor signaling in T lymphocytes and that its Src homology (SH) 3 and SH2 domains are required to inhibit these signals. To test the idea that the Csk SH3 and SH2 domains mediate interactions with other cellular proteins, we attempted to identify Csk-associated polypeptides using the yeast two-hybrid system. The results of our experiments demonstrated that Csk physically associates with PEP, a protein tyrosine phosphatase (PTP) expressed in hemopoietic cells. Further analyses revealed that this interaction was mediated by the Csk SH3 domain and by a proline-rich region (PPPLPERTP) in the non-catalytic C-terminal portion of PEP. The association between Csk and PEP was documented in transiently transfected Cos-1 cells and in a variety of cells of hemopoietic lineages, including T cells. Additional analyses demonstrated that the association between Csk and PEP is highly specific. Together, these data indicated that PEP may be an effector and/or a regulator of p50csk in T cells and other hemopoietic cells. Moreover, they allowed the identification of PEP as the first known ligand for the Csk SH3 domain.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.2M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Bergman M, Mustelin T, Oetken C, Partanen J, Flint NA, Amrein KE, Autero M, Burn P, Alitalo K. The human p50csk tyrosine kinase phosphorylates p56lck at Tyr-505 and down regulates its catalytic activity. EMBO J. 1992 Aug;11(8):2919–2924. [PMC free article] [PubMed]
  • Bergman M, Joukov V, Virtanen I, Alitalo K. Overexpressed Csk tyrosine kinase is localized in focal adhesions, causes reorganization of alpha v beta 5 integrin, and interferes with HeLa cell spreading. Mol Cell Biol. 1995 Feb;15(2):711–722. [PMC free article] [PubMed]
  • Bowtell DD, Langdon WY. The protein product of the c-cbl oncogene rapidly complexes with the EGF receptor and is tyrosine phosphorylated following EGF stimulation. Oncogene. 1995 Oct 19;11(8):1561–1567. [PubMed]
  • Charest A, Wagner J, Shen SH, Tremblay ML. Murine protein tyrosine phosphatase-PEST, a stable cytosolic protein tyrosine phosphatase. Biochem J. 1995 Jun 1;308(Pt 2):425–432. [PMC free article] [PubMed]
  • Chow LM, Veillette A. The Src and Csk families of tyrosine protein kinases in hemopoietic cells. Semin Immunol. 1995 Aug;7(4):207–226. [PubMed]
  • Chow LM, Fournel M, Davidson D, Veillette A. Negative regulation of T-cell receptor signalling by tyrosine protein kinase p50csk. Nature. 1993 Sep 9;365(6442):156–160. [PubMed]
  • Chow LM, Jarvis C, Hu Q, Nye SH, Gervais FG, Veillette A, Matis LA. Ntk: a Csk-related protein-tyrosine kinase expressed in brain and T lymphocytes. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4975–4979. [PMC free article] [PubMed]
  • Chow LM, Davidson D, Fournel M, Gosselin P, Lemieux S, Lyu MS, Kozak CA, Matis LA, Veillette A. Two distinct protein isoforms are encoded by ntk, a csk-related tyrosine protein kinase gene. Oncogene. 1994 Dec;9(12):3437–3448. [PubMed]
  • Cloutier JF, Chow LM, Veillette A. Requirement of the SH3 and SH2 domains for the inhibitory function of tyrosine protein kinase p50csk in T lymphocytes. Mol Cell Biol. 1995 Nov;15(11):5937–5944. [PMC free article] [PubMed]
  • Cohen GB, Ren R, Baltimore D. Modular binding domains in signal transduction proteins. Cell. 1995 Jan 27;80(2):237–248. [PubMed]
  • Cooper JA, Howell B. The when and how of Src regulation. Cell. 1993 Jun 18;73(6):1051–1054. [PubMed]
  • Davidson D, Fournel M, Veillette A. Oncogenic activation of p59fyn tyrosine protein kinase by mutation of its carboxyl-terminal site of tyrosine phosphorylation, tyrosine 528. J Biol Chem. 1994 Apr 8;269(14):10956–10963. [PubMed]
  • Evan GI, Lewis GK, Ramsay G, Bishop JM. Isolation of monoclonal antibodies specific for human c-myc proto-oncogene product. Mol Cell Biol. 1985 Dec;5(12):3610–3616. [PMC free article] [PubMed]
  • Feng S, Kasahara C, Rickles RJ, Schreiber SL. Specific interactions outside the proline-rich core of two classes of Src homology 3 ligands. Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12408–12415. [PMC free article] [PubMed]
  • Fields S, Song O. A novel genetic system to detect protein-protein interactions. Nature. 1989 Jul 20;340(6230):245–246. [PubMed]
  • Flores E, Roy G, Patel D, Shaw A, Thomas ML. Nuclear localization of the PEP protein tyrosine phosphatase. Mol Cell Biol. 1994 Jul;14(7):4938–4946. [PMC free article] [PubMed]
  • Gout I, Dhand R, Hiles ID, Fry MJ, Panayotou G, Das P, Truong O, Totty NF, Hsuan J, Booker GW, et al. The GTPase dynamin binds to and is activated by a subset of SH3 domains. Cell. 1993 Oct 8;75(1):25–36. [PubMed]
  • Gross JA, Appleby MW, Chien S, Nada S, Bartelmez SH, Okada M, Aizawa S, Perlmutter RM. Control of lymphopoiesis by p50csk, a regulatory protein tyrosine kinase. J Exp Med. 1995 Feb 1;181(2):463–473. [PMC free article] [PubMed]
  • Howell BW, Cooper JA. Csk suppression of Src involves movement of Csk to sites of Src activity. Mol Cell Biol. 1994 Aug;14(8):5402–5411. [PMC free article] [PubMed]
  • Imamoto A, Soriano P. Disruption of the csk gene, encoding a negative regulator of Src family tyrosine kinases, leads to neural tube defects and embryonic lethality in mice. Cell. 1993 Jun 18;73(6):1117–1124. [PubMed]
  • Klages S, Adam D, Class K, Fargnoli J, Bolen JB, Penhallow RC. Ctk: a protein-tyrosine kinase related to Csk that defines an enzyme family. Proc Natl Acad Sci U S A. 1994 Mar 29;91(7):2597–2601. [PMC free article] [PubMed]
  • Koren HS, Handwerger BS, Wunderlich JR. Identification of macrophage-like characteristics in a cultured murine tumor line. J Immunol. 1975 Feb;114(2 Pt 2):894–897. [PubMed]
  • Matthews RJ, Bowne DB, Flores E, Thomas ML. Characterization of hematopoietic intracellular protein tyrosine phosphatases: description of a phosphatase containing an SH2 domain and another enriched in proline-, glutamic acid-, serine-, and threonine-rich sequences. Mol Cell Biol. 1992 May;12(5):2396–2405. [PMC free article] [PubMed]
  • Nada S, Okada M, MacAuley A, Cooper JA, Nakagawa H. Cloning of a complementary DNA for a protein-tyrosine kinase that specifically phosphorylates a negative regulatory site of p60c-src. Nature. 1991 May 2;351(6321):69–72. [PubMed]
  • Neet K, Hunter T. The nonreceptor protein-tyrosine kinase CSK complexes directly with the GTPase-activating protein-associated p62 protein in cells expressing v-Src or activated c-Src. Mol Cell Biol. 1995 Sep;15(9):4908–4920. [PMC free article] [PubMed]
  • Oetken C, Couture C, Bergman M, Bonnefoy-Bérard N, Williams S, Alitalo K, Burn P, Mustelin T. TCR/CD3-triggering causes increased activity of the p50csk tyrosine kinase and engagement of its SH2 domain. Oncogene. 1994 Jun;9(6):1625–1631. [PubMed]
  • Pawson T, Gish GD. SH2 and SH3 domains: from structure to function. Cell. 1992 Oct 30;71(3):359–362. [PubMed]
  • Peri KG, Gervais FG, Weil R, Davidson D, Gish GD, Veillette A. Interactions of the SH2 domain of lymphocyte-specific tyrosine protein kinase p56lck with phosphotyrosine-containing proteins. Oncogene. 1993 Oct;8(10):2765–2772. [PubMed]
  • Reske-Kunz AB, Rüde E. Insulin-specific T cell hybridomas derived from (H-2b x H-2k)F1 mice preferably employ F1-unique restriction elements for antigen recognition. Eur J Immunol. 1985 Oct;15(10):1048–1054. [PubMed]
  • Rodrigues GA, Park M. Dimerization mediated through a leucine zipper activates the oncogenic potential of the met receptor tyrosine kinase. Mol Cell Biol. 1993 Nov;13(11):6711–6722. [PMC free article] [PubMed]
  • Sabe H, Knudsen B, Okada M, Nada S, Nakagawa H, Hanafusa H. Molecular cloning and expression of chicken C-terminal Src kinase: lack of stable association with c-Src protein. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2190–2194. [PMC free article] [PubMed]
  • Sabe H, Hata A, Okada M, Nakagawa H, Hanafusa H. Analysis of the binding of the Src homology 2 domain of Csk to tyrosine-phosphorylated proteins in the suppression and mitotic activation of c-Src. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3984–3988. [PMC free article] [PubMed]
  • Simonson MS, Wang Y, Herman WH. Nuclear signaling by endothelin-1 requires Src protein-tyrosine kinases. J Biol Chem. 1996 Jan 5;271(1):77–82. [PubMed]
  • Veillette A, Bookman MA, Horak EM, Bolen JB. The CD4 and CD8 T cell surface antigens are associated with the internal membrane tyrosine-protein kinase p56lck. Cell. 1988 Oct 21;55(2):301–308. [PubMed]
  • Veillette A, Caron L, Fournel M, Pawson T. Regulation of the enzymatic function of the lymphocyte-specific tyrosine protein kinase p56lck by the non-catalytic SH2 and SH3 domains. Oncogene. 1992 May;7(5):971–980. [PubMed]
  • Yamaji Y, Amemiya M, Cano A, Preisig PA, Miller RT, Moe OW, Alpern RJ. Overexpression of csk inhibits acid-induced activation of NHE-3. Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6274–6278. [PMC free article] [PubMed]
  • Yang Q, Co D, Sommercorn J, Tonks NK. Cloning and expression of PTP-PEST. A novel, human, nontransmembrane protein tyrosine phosphatase. J Biol Chem. 1993 Mar 25;268(9):6622–6628. [PubMed]

Articles from The EMBO Journal are provided here courtesy of The European Molecular Biology Organization


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Compound
    PubChem Compound links
  • Gene
    Gene links
  • Gene (nucleotide)
    Gene (nucleotide)
    Records in Gene identified from shared sequence links
  • GEO Profiles
    GEO Profiles
    Related GEO records
  • HomoloGene
    HomoloGene links
  • MedGen
    Related information in MedGen
  • Nucleotide
    Published Nucleotide sequences
  • OMIM
    OMIM record citing PubMed
  • Pathways + GO
    Pathways + GO
    Pathways, annotations and biological systems (BioSystems) that cite the current article.
  • Protein
    Published protein sequences
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...