Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Structure and regulation of Src family kinases

Oncogene volume 23, pages 7918–7927 (2004)Cite this article

Abstract

Src family kinases are prototypical modular signaling proteins. Their conserved domain organization includes a myristoylated N-terminal segment followed by SH3, SH2, and tyrosine kinase domains, and a short C-terminal tail. Structural dissection of Src kinases has elucidated the canonical mechanisms of phosphotyrosine recognition by the SH2 domain and proline-motif recognition by the SH3 domain. Crystallographic analysis of nearly intact Src kinases in the autoinhibited state has shown that these protein interaction motifs turn inward and lock the kinase in an inactive conformation via intramolecular interactions. The autoinhibited Src kinase structures reveal a mode of domain assembly used by other tyrosine kinases outside the Src family, including Abl and likely Tec family kinases. Furthermore, they illustrate the underlying regulatory principles that have proven to be general among diverse modular signaling proteins. Although there is considerable structural information available for the autoinhibited conformation of Src kinases, how they may assemble into active signaling complexes with substrates and regulators remains largely unexplored.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Alonso G, Koegl M, Mazurenko N and Courtneidge SA . (1995). J. Biol. Chem., 270, 9840–9848.

  • Arold ST, Ulmer TS, Mulhern TD, Werner JM, Ladbury JE, Campbell ID and Noble ME . (2001). J. Biol. Chem., 276, 17199–17205.

  • Azam M, Latek RR and Daley GQ . (2003). Cell, 112, 831–843.

  • Berry DM, Nash P, Liu SK, Pawson T and McGlade CJ . (2002). Curr. Biol., 12, 1336–1341.

  • Booker GW, Breeze AL, Downing AK, Panayotou G, Gout I, Waterfield MD and Campbell LD . (1992). Nature, 358, 684–687.

  • Bradshaw JM and Waksman G . (2002). Adv. Protein Chem., 61, 161–210.

  • Brown MT and Cooper JA . (1996). Biochim. Biophys. Acta, 1287, 121–149.

  • Chackalaparampil I and Shalloway D . (1988). Cell, 52, 801–810.

  • Chan B, Lanyi A, Song HK, Griesbach J, Simarro-Grande M, Poy F, Howie D, Sumegi J, Terhorst C and Eck MJ . (2003). Nat. Cell Biol., 5, 155–160.

  • Cooper JA, Gould KL, Cartwright CA and Hunter T . (1986). Science, 231, 1431–1434.

  • Davidson D, Chow LM and Veillette A . (1997). J. Biol. Chem., 272, 1355–1362.

  • Eck MJ, Atwell SK, Shoelson SE and Harrison SC . (1994). Nature, 368, 764–769.

  • Eck MJ, Shoelson SE and Harrison SC . (1993). Nature, 362, 87–91.

  • Engel P, Eck MJ and Terhorst C . (2003). Nat. Rev. Immunol., 3, 813–821.

  • Feng S, Chen JK, Yu H, Simon JA and Schreiber SL . (1994). Science, 266, 1241–1247.

  • Feng S, Kasahara C, Rickles RJ and Schreiber SL . (1995). Proc. Natl. Acad. Sci. USA, 92, 12408–12415.

  • Gonfloni S, Frischknecht F, Way M and Superti-Furga G . (1999). Nat. Struct. Biol., 6, 760–764.

  • Gonfloni S, Williams JC, Hattula K, Weijland A, Wierenga RK and Superti-Furga G . (1997). EMBO J, 16, 7261–7271.

  • Gould KL, Woodgett JR, Cooper JA, Buss JE, Shalloway D and Hunter T . (1985). Cell, 42, 849–857.

  • Hamaguchi I, Yamaguchi N, Suda J, Iwama A, Hirao A, Hashiyama M, Aizawa S and Suda T . (1996). Biochem. Biophys. Res. Commun., 224, 172–179.

  • Hantschel O, Nagar B, Guettler S, Kretzschmar J, Dorey K, Kuriyan J and Superti-Furga G . (2003). Cell, 112, 845–857.

  • Harrison SC . (2003). Cell, 112, 737–740.

  • Hof P, Pluskey S, Dhe-Paganon S, Eck MJ and Shoelson SE . (1998). Cell, 92, 441–450.

  • Hubbard SR . (1997). EMBO J, 16, 5572–5581.

  • Hubbard SR and Till JH . (2000). Annu. Rev. Biochem., 69, 373–398.

  • Hubbard SR, Wei L, Ellis L and Hendrickson WA . (1994). Nature, 372, 746–754.

  • Huse M, Eck MJ and Harrison SC . (1998). J. Biol. Chem., 273, 18729–18733.

  • Huse M and Kuriyan J . (2002). Cell, 109, 275–282.

  • Kang H, Freund C, Duke-Cohan JS, Musacchio A, Wagner G and Rudd CE . (2000). EMBO J, 19, 2889–2899.

  • Kato JY, Takeya T, Grandori C, Iba H, Levy JB and Hanafusa H . (1986). Mol. Cell Biol., 6, 4155–4160.

  • Kesavan KP, Isaacson CC, Ashendel CL, Geahlen RL and Harrison ML . (2002). J. Biol. Chem., 277, 14666–14673.

  • Kim PW, Sun ZY, Blacklow SC, Wagner G and Eck MJ . (2003). Science, 301, 1725–1728.

  • Knighton DR, Zheng JH, Ten EL, Ashford VA, Xuong NH, Taylor SS and Sowadski JM . (1991a). Science, 253, 407–414.

  • Knighton DR, Zheng JH, Ten EL, Xuong NH, Taylor SS and Sowadski JM . (1991b). Science, 253, 414–420.

  • Koegl M, Zlatkine P, Ley SC, Courtneidge SA and Magee AI . (1994). Biochem. J., 303, 749–753.

  • Kuriyan J and Cowburn D . (1997). Annu. Rev. Biophys. Biomol. Struct., 26, 259–288.

  • Kypta RM, Goldberg Y, Ulug ET and Courtneidge SA . (1990). Cell, 62, 481–492.

  • LaFevre-Bernt M, Sicheri F, Pico A, Porter M, Kuriyan J and Miller WT . (1998). J. Biol. Chem., 273, 32129–32134.

  • Latour S, Gish G, Helgason CD, Humphries RK, Pawson T and Veillette A . (2001). Nat. Immunol., 2, 681–690.

  • Latour S, Roncagalli R, Chen R, Bakinowski M, Shi X, Schwartzberg PL, Davidson D and Veillette A . (2003). Nat. Cell Biol., 5, 149–154.

  • Lee CH, Leung B, Lemmon MA, Zheng J, Cowburn D, Kuriyan J and Saksela K . (1995). EMBO J, 14, 5006–5015.

  • Lim WA, Richards FM and Fox RO . (1994). Nature, 372, 375–379.

  • Lin RS, Rodriguez C, Veillette A and Lodish HF . (1998). J. Biol. Chem., 273, 32878–32882.

  • Liu Q, Berry D, Nash P, Pawson T, McGlade CJ and Li SS . (2003). Mol. Cell, 11, 471–481.

  • Mayer BJ . (2001). J. Cell Sci., 114, 1253–1263.

  • Moarefi I, LaFevre-Bernt M, Sicheri F, Huse M, Lee CH, Kuriyan J and Miller WT . (1997). Nature, 385, 650–653.

  • Musacchio A, Noble M, Pauptit R, Wierenga R and Saraste M . (1992). Nature, 359, 851–855.

  • Nada S, Okada M, MacAuley A, Cooper JA and Nakagawa H . (1991). Nature, 351, 69–72.

  • Nagar B, Hantschel O, Young MA, Scheffzek K, Veach D, Bornmann W, Clarkson B, Superti-Furga G and Kuriyan J . (2003). Cell, 112, 859–871.

  • Neel BG, Gu H and Pao L . (2003). Trends Biochem. Sci., 28, 284–293.

  • Noble M, EM, Musacchio A, Saraster M, Courtneidge SA and Wierenga RK . (1993). EMBO J., 12, 2617–2624.

  • Overduin M, Rios CB, Mayer BJ, Baltimore D and Cowburn D . (1992). Cell, 70, 697–704.

  • Pawson T . (1995). Nature, 373, 573–580.

  • Pawson T . (2004). Cell, 116, 191–203.

  • Pawson T and Nash P . (2003). Science, 300, 445–452.

  • Pitcher C, Honing S, Fingerhut A, Bowers K and Marsh M . (1999). Mol. Biol. Cell, 10, 677–691.

  • Pluk H, Dorey K and Superti-Furga G . (2002). Cell, 108, 247–259.

  • Poy F, Yaffe MB, Sayos J, Saxena K, Morra M, Sumegi J, Cantley LC, Terhorst C and Eck MJ . (1999). Mol. Cell, 4, 555–561.

  • Resh MD . (1999). Biochim. Biophys. Acta, 1451, 1–16.

  • Rudd CE, Trevillyan JM, Dasgupta JD, Wong LL and Schlossman SF . (1988). Proc. Natl. Acad. Sci. USA, 85, 5190–5194.

  • Sadowski I, Stone JC and Pawson T . (1986). Mol. Cell Biol., 6, 4396–4408.

  • Sawyer TK . (1998). Biopolymers, 47, 243–261.

  • Schindler T, Sicheri F, Pico A, Gazit A, Levitzki A and Kuriyan J . (1999). Mol. Cell, 3, 639–648.

  • Schlessinger J and Lemmon MA . (2003). Sci. STKE, 2003, RE12.

  • Shalloway D, Bagrodia S, Chackalaparampil I, Shenoy S, Lin PH and Taylor SJ . (1992). Ciba Found. Symp., 170, 248–265; discussion 265–275.

  • Shaw AS, Amrein KE, Hammond C, Stern DF, Sefton BM and Rose JK . (1989). Cell, 59, 627–636.

  • Shaw AS, Chalupny J, Whitney JA, Hammond C, Amrein KE, Kavathas P, Sefton BM and Rose JK . (1990). Mol. Cell Biol., 10, 1853–1862.

  • Shin J, Doyle C, Yang Z, Kappes D and Strominger JL . (1990). EMBO J., 9, 425–434.

  • Shin J, Dunbrack RLJ, Songjae L and Strominger JL . (1991). J. Biol. Chem., 266, 10658–10665.

  • Sicheri F, Moarefi I and Kuriyan J . (1997). Nature, 385, 602–609.

  • Sieg DJ, Hauck CR and Schlaepfer DD . (1999). J. Cell Sci., 112, 2677–2691.

  • Smart JE, Oppermann H, Czernilofsky AP, Purchio AF, Erikson RL and Bishop JM . (1981). Proc. Natl. Acad. Sci. USA, 78, 6013–6017.

  • Songyang Z, Shoelson SE, Chaudhuri M, Gish G, Pawson T, King F, Roberts T, Ratnofsky S, Lechleider RJ, Neel BG, Birge RB, Fajardo JE, Chou MM, Hanafusa H, Schaffhausen B and Cantley LC . (1993). Cell, 72, 767–778.

  • Summy JM, Qian Y, Jiang BH, Guappone-Koay A, Gatesman A, Shi X and Flynn DC . (2003). J. Cell Sci., 116, 2585–2598.

  • Takeya T and Hanafusa H . (1983). Cell, 32, 881–890.

  • Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, van der Burgt I, Crosby AH, Ion A, Jeffery S, Kalidas K, Patton MA, Kucherlapati RS and Gelb BD . (2001). Nat. Genet., 29, 465–468.

  • Taylor SS, Knighton DR, Zheng J, Ten EL and Sowadski JM . (1992). Annu. Rev. Cell Biol., 8, 429–462.

  • Thomas JW, Ellis B, Boerner RJ, Knight WB, White 2nd GC and Schaller MD . (1998). J. Biol. Chem., 273, 577–583.

  • Thomas SM and Brugge JS . (1997). Annu. Rev. Cell Dev. Biol., 13, 513–609.

  • Timson Gauen LK, Kong AN, Samelson LE and Shaw AS . (1992). Mol. Cell Biol., 12, 5438–5446.

  • Turner JM, Brodsky MH, Irving BA, Levin SD, Perlmutter RM and Littman DR . (1990). Cell, 60, 755–765.

  • Veillette A, Bookman A, Horak EM and Bolen JB . (1988). Cell, 55, 301–308.

  • Waksman G, Kominos D, Robertson SC, Pant N, Baltimore D, Birge RB, Cowburn D, Hanafusa H, Mayer BJ, Overduin M, Resh MD, Rios CB, Silverman L and Kuriyan J . (1992). Nature, 358, 646–653.

  • Waksman G and Kuriyan J . (2004). Cell, 116, S45–S48, 3 pp following S48.

  • Waksman G, Shoelson SE, Pant N, Cowburn D and Kuriyan J . (1993). Cell, 72, 779–790.

  • Watts JD, Welham MJ, Kalt L, Schrader JW and Aebersold R . (1993). J. Immunol., 151, 6862–6871.

  • Williams JC, Weijland A, Gonfloni S, Thompson A, Courtneidge SA, Superti-Furga G and Wierenga RK . (1997). J. Mol. Biol., 274, 757–775.

  • Winkler DG, Park I, Kim T, Payne NS, Walsh CT, Strominger JL and Shin J . (1993). Proc. Natl. Acad. Sci. USA, 90, 5176–5180.

  • Xu W, Doshi A, Lei M, Eck MJ and Harrison SC . (1999). Mol. Cell, 3, 629–638.

  • Xu W, Harrison SC and Eck MJ . (1997). Nature, 385, 595–602.

  • Yamaguchi H and Hendrickson WA . (1996). Nature, 384, 484–489.

  • Young MA, Gonfloni S, Superti-Furga G, Roux B and Kuriyan J . (2001). Cell, 105, 115–126.

  • Yu H, Rosen MK, Shin TB, Seidel-Dugan C, Brugge JS and Schreiber SL . (1992). Science, 258, 1665–1668.

Download references

Author information

Authors and Affiliations

  1. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Dana-Farber Cancer Institute, 44 Binney St., Boston, 02115, MA, USA

    Titus J Boggon & Michael J Eck

  2. Department of Cancer Biology, Dana-Farber Cancer Institute, 44 Binney St., Boston, 02115, MA, USA

    Titus J Boggon & Michael J Eck

Authors
  1. Titus J Boggon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael J Eck
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael J Eck.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Boggon, T., Eck, M. Structure and regulation of Src family kinases. Oncogene 23, 7918–7927 (2004). https://doi.org/10.1038/sj.onc.1208081

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208081

Keywords

This article is cited by

Search

Advanced search

Quick links