Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1995 Dec 19;92(26):12338–12342. doi: 10.1073/pnas.92.26.12338

Phosphotyrosine-independent binding of a 62-kDa protein to the src homology 2 (SH2) domain of p56lck and its regulation by phosphorylation of Ser-59 in the lck unique N-terminal region.

I Park 1, J Chung 1, C T Walsh 1, Y Yun 1, J L Strominger 1, J Shin 1
PMCID: PMC40352  PMID: 8618896

Abstract

A previously undescribed 62-kDa protein (p62) that does not contain phosphotyrosine but, nevertheless, binds specifically to the isolated src homology 2 (SH2) domain of p56lck has been identified. The additional presence of the unique N-terminal region of p56lck prevents p62 binding to the SH2 domain. However, phosphorylation at Ser-59 (or alternatively, its mutation to Glu) reverses the inhibition and allows interaction of the p56lck SH2 domain with p62. Moreover, p62 is associated with a serine/threonine kinase activity and also binds to ras GTPase-activating protein, a negative regulator of the ras signaling pathway. Thus, phosphotyrosine-independent binding of p62 to the p56lck SH2 domain appears to provide an alternative pathway for p56lck signaling that is regulated by Ser-59 phosphorylation.

Full text

PDF
12338

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Autero M., Saharinen J., Pessa-Morikawa T., Soula-Rothhut M., Oetken C., Gassmann M., Bergman M., Alitalo K., Burn P., Gahmberg C. G. Tyrosine phosphorylation of CD45 phosphotyrosine phosphatase by p50csk kinase creates a binding site for p56lck tyrosine kinase and activates the phosphatase. Mol Cell Biol. 1994 Feb;14(2):1308–1321. doi: 10.1128/mcb.14.2.1308. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Chan A. C., Desai D. M., Weiss A. The role of protein tyrosine kinases and protein tyrosine phosphatases in T cell antigen receptor signal transduction. Annu Rev Immunol. 1994;12:555–592. doi: 10.1146/annurev.iy.12.040194.003011. [DOI] [PubMed] [Google Scholar]
  3. Chen C., Okayama H. High-efficiency transformation of mammalian cells by plasmid DNA. Mol Cell Biol. 1987 Aug;7(8):2745–2752. doi: 10.1128/mcb.7.8.2745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cleghon V., Morrison D. K. Raf-1 interacts with Fyn and Src in a non-phosphotyrosine-dependent manner. J Biol Chem. 1994 Jul 1;269(26):17749–17755. [PubMed] [Google Scholar]
  5. Cooper J. A., Howell B. The when and how of Src regulation. Cell. 1993 Jun 18;73(6):1051–1054. doi: 10.1016/0092-8674(93)90634-3. [DOI] [PubMed] [Google Scholar]
  6. Duplay P., Thome M., Hervé F., Acuto O. p56lck interacts via its src homology 2 domain with the ZAP-70 kinase. J Exp Med. 1994 Apr 1;179(4):1163–1172. doi: 10.1084/jem.179.4.1163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Eck M. J., Shoelson S. E., Harrison S. C. Recognition of a high-affinity phosphotyrosyl peptide by the Src homology-2 domain of p56lck. Nature. 1993 Mar 4;362(6415):87–91. doi: 10.1038/362087a0. [DOI] [PubMed] [Google Scholar]
  8. Fantl W. J., Escobedo J. A., Martin G. A., Turck C. W., del Rosario M., McCormick F., Williams L. T. Distinct phosphotyrosines on a growth factor receptor bind to specific molecules that mediate different signaling pathways. Cell. 1992 May 1;69(3):413–423. doi: 10.1016/0092-8674(92)90444-h. [DOI] [PubMed] [Google Scholar]
  9. Gupta S., Weiss A., Kumar G., Wang S., Nel A. The T-cell antigen receptor utilizes Lck, Raf-1, and MEK-1 for activating mitogen-activated protein kinase. Evidence for the existence of a second protein kinase C-dependent pathway in an Lck-negative Jurkat cell mutant. J Biol Chem. 1994 Jun 24;269(25):17349–17357. [PubMed] [Google Scholar]
  10. Joung I., Kim T., Stolz L. A., Payne G., Winkler D. G., Walsh C. T., Strominger J. L., Shin J. Modification of Ser59 in the unique N-terminal region of tyrosine kinase p56lck regulates specificity of its Src homology 2 domain. Proc Natl Acad Sci U S A. 1995 Jun 20;92(13):5778–5782. doi: 10.1073/pnas.92.13.5778. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kunkel T. A. Rapid and efficient site-specific mutagenesis without phenotypic selection. Proc Natl Acad Sci U S A. 1985 Jan;82(2):488–492. doi: 10.1073/pnas.82.2.488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Malek S. N., Desiderio S. A cyclin-dependent kinase homologue, p130PITSLRE is a phosphotyrosine-independent SH2 ligand. J Biol Chem. 1994 Dec 30;269(52):33009–33020. [PubMed] [Google Scholar]
  13. Mayer B. J., Jackson P. K., Van Etten R. A., Baltimore D. Point mutations in the abl SH2 domain coordinately impair phosphotyrosine binding in vitro and transforming activity in vivo. Mol Cell Biol. 1992 Feb;12(2):609–618. doi: 10.1128/mcb.12.2.609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Muller A. J., Pendergast A. M., Havlik M. H., Puil L., Pawson T., Witte O. N. A limited set of SH2 domains binds BCR through a high-affinity phosphotyrosine-independent interaction. Mol Cell Biol. 1992 Nov;12(11):5087–5093. doi: 10.1128/mcb.12.11.5087. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Pawson T., Schlessingert J. SH2 and SH3 domains. Curr Biol. 1993 Jul 1;3(7):434–442. doi: 10.1016/0960-9822(93)90350-w. [DOI] [PubMed] [Google Scholar]
  16. Payne G., Shoelson S. E., Gish G. D., Pawson T., Walsh C. T. Kinetics of p56lck and p60src Src homology 2 domain binding to tyrosine-phosphorylated peptides determined by a competition assay or surface plasmon resonance. Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):4902–4906. doi: 10.1073/pnas.90.11.4902. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Shin J., Doyle C., Yang Z., Kappes D., Strominger J. L. Structural features of the cytoplasmic region of CD4 required for internalization. EMBO J. 1990 Feb;9(2):425–434. doi: 10.1002/j.1460-2075.1990.tb08127.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Sun X. J., Crimmins D. L., Myers M. G., Jr, Miralpeix M., White M. F. Pleiotropic insulin signals are engaged by multisite phosphorylation of IRS-1. Mol Cell Biol. 1993 Dec;13(12):7418–7428. doi: 10.1128/mcb.13.12.7418. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Tobe K., Kadowaki T., Hara K., Gotoh Y., Kosako H., Matsuda S., Tamemoto H., Ueki K., Akanuma Y., Nishida E. Sequential activation of MAP kinase activator, MAP kinases, and S6 peptide kinase in intact rat liver following insulin injection. J Biol Chem. 1992 Oct 15;267(29):21089–21097. [PubMed] [Google Scholar]
  20. Weber J. R., Bell G. M., Han M. Y., Pawson T., Imboden J. B. Association of the tyrosine kinase LCK with phospholipase C-gamma 1 after stimulation of the T cell antigen receptor. J Exp Med. 1992 Aug 1;176(2):373–379. doi: 10.1084/jem.176.2.373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Weiss A., Littman D. R. Signal transduction by lymphocyte antigen receptors. Cell. 1994 Jan 28;76(2):263–274. doi: 10.1016/0092-8674(94)90334-4. [DOI] [PubMed] [Google Scholar]
  22. Winkler D. G., Park I., Kim T., Payne N. S., Walsh C. T., Strominger J. L., Shin J. Phosphorylation of Ser-42 and Ser-59 in the N-terminal region of the tyrosine kinase p56lck. Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5176–5180. doi: 10.1073/pnas.90.11.5176. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Wong G., Müller O., Clark R., Conroy L., Moran M. F., Polakis P., McCormick F. Molecular cloning and nucleic acid binding properties of the GAP-associated tyrosine phosphoprotein p62. Cell. 1992 May 1;69(3):551–558. doi: 10.1016/0092-8674(92)90455-l. [DOI] [PubMed] [Google Scholar]
  24. Xu H., Littman D. R. A kinase-independent function of Lck in potentiating antigen-specific T cell activation. Cell. 1993 Aug 27;74(4):633–643. doi: 10.1016/0092-8674(93)90511-n. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES