PTK Receptors and Disease

Given the importance of PTK receptors in the control of cell proliferation and migration, it is not surprising that over-activity of PTK receptors occurs in cancer and other diseases that involve excess cell proliferation, such as inflammatory and fibrotic conditions and psoriasis. About half of the PTK receptors are implicated in various human malignancies (Fig. 1) [2]. Often, the receptors are constitutively activated by amplification or mutational events. Several mutations of PTK receptors cause constitutive dimerization (1) by mutations affecting disulfide bonding in the extracellular parts of the receptors, thus causing the formation of covalent dimers, mutations of other residues in the transmembrane, or jux-tamembrane domains that promote dimerization; or (2) by formation of fusion proteins between the kinase domains of the receptors and proteins that normally occur as dimers or oligomers. The end result is a constitutively active kinase that drives cell growth.

Another mechanism of activation of PTK receptors seen in disease is overproduction of the corresponding ligand. If a cell produces a growth factor for which it has the corresponding receptor, autocrine stimulation of growth may result. Alternatively, the growth factor may stimulate cells in the environment in a paracrine manner, which is relevant in tumor progression. Tumor-derived factors (e.g., VEGFs and FGFs) act on angiogenic PTK receptors and cause vascularization of the tumors, which is a prerequisite for tumor growth [9]. Likewise, other growth factors produced by tumor cells (e.g., PDGFs) may stimulate the formation of tumor stroma, which is important for the balanced growth of tumors [43].

Given the importance of PTK receptors for serious diseases, clinically useful PTK receptor antagonists are warranted. Several types of antagonists are currently used clinically or are in clinical trials for cancer, including a monoclonal-antibody-recognizing ErbB2 and low-molecular-weight selective inhibitors of various tyrosine kinases [12]. It is likely that PTK receptor antagonists will be important tools in the treatment of cancer and possibly other diseases characterized by an excessive cell growth.


Ingegard Schiller is thanked for her valuable help in the preparation of this manuscript. For space reasons, referencing has been kept to a minimum, and I apologize to authors who have not been properly referenced.


1. Bae, Y. S., Sung, J.-Y., Kim, O.-S., Kim, Y. J., Hur, K. C., Kazlauskas, A., and Rhee, S. G. (2000). Platelet-derived growth factor-induced H2O2 production requires the activation of phosphatidylinositol 3-kinase. J. Biol. Chem. 275, 10527-10531.

2. Blume-Jensen, P. and Hunter, T. (2001). Oncogenic kinase signalling. Nature 411, 355-365.

3. Blume-Jensen, P., Siegbahn, A., Stabel, S., Heldin, C.-H., and Ronnstrand, L. (1993). Increased Kit/SCF receptor induced mitogenicity but abolished cell motility after inhibition of protein kinase C. EMBO J. 12, 4199-4209.

4. Brennan, P. J., Kumogai, T., Berezov, A., Murali, R., and Greene, M. I.

(2000). HER2/Neu: mechanisms of dimerization/oligomerization. Oncogene 19, 6093-6101.

5. Clague, M. J. and Urbe, S. (2001). The interface of receptor trafficking and signalling. J. Cell Sci. 114, 3075-3081.

6. Ekman, S., Kallin, A., Engstrom, U., Heldin, C.-H., and Ronnstrand, L. (2002). SHP-2 is involved in heterodimer specific loss of phosphoryla-tion of Tyr771 in the PDGF P-receptor. Oncogene (in press).

7. Fambrough, D., McClure, K., Kazlauskas, A., and Lander, E. S. (1999). Diverse signaling pathways activated by growth factor receptors induce broadly overlapping, rather than independent, sets of genes. Cell 97, 727-741.

8. Fantl, W. J., Johnson, D. E., and Williams, L. T. (1993). Signaling by receptor tyrosine kinases. Annu. Rev. Biochem. 62, 453-481.

9. Ferrara, N. and Alitalo, K. (1999). Clinical applications of angiogenic growth factors and their inhibitors. Nat. Med. 5, 1359-1364.

9a. Garett, T. P. J., McKern, N. M., Lou, M., Elleman, T. C., Adams, T. E., Lorrecs, G. O., Zhu, H.-J., Walker, F., Frenkel, M. J., Hoyne, P. A., Jorrissen, R. N., Nice, E. C., Burgess, A. W., and Ward, C. W. (2002). Crystal structure of a trunkated epidermal growth factor receptor extracellular domain bound to transforming growth factor-a. Cell 110, 763-773.

10. Giancotti, F. G. and Ruoslahti, E. (1999). Integrin signaling. Science 285, 1028-1032.

11. Gschwind, A., Zwick, E., Prenzel, N., Leserer, M., and Ullrich, A.

(2001). Cell communication networks: epidermal growth factor receptor transactivation as the paradigm for interreceptor signal transmission. Oncogene 20, 1594-1600.

12. Heldin, C.-H. (2001). Signal transduction: multiple pathways, multiple options for therapy. Stem Cells 19, 295-303.

13. Heldin, C.-H. and Ostman, A. (1996). Ligand-induced dimerization of growth factor receptors: variations on the theme. Cytokine Growth Factor Rev. 7, 3-10.

14. Heldin, C.-H., Ostman, A., and Ronnstrand, L. (1998). Signal trans-duction via platelet-derived growth factor receptors. Biochim. Biophys. Acta 1378, F79-F113.

15. Himanen, J.-P., Rajashankar, K. R., Lackmann, M., Cowan, C. A., Henkemeyer, M., and Nikolov, D. B. (2001). Crystal structure of an Eph receptor-ephrin complex. Nature 414, 933-938.

16. Hu, Q., Klippel, A., Muslin, A. J., Fantl, W. J., and Williams, L. T. (1995). Ras-dependent induction of cellular responses by constitutively active phosphatidylinositol-3 kinase. Science 268, 100-102.

17. Hubbard, S. R. (1997). Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog. EMBO J. 16, 5572-5581.

18. Ihle, J. N. (2001). The STAT family in cytokine signaling. Curr. Opin. Cell. Biol. 13, 211-217.

19. Jiang, G. and Hunter, T. (1999). Receptor signaling: when dimerization is not enough. Curr. Biol. 9, R568-R571.

20. Joazeiro, C. A., Wing, S. S., Huang, H., Leverson, J. D., Hunter, T., and Liu, Y. C. (1999). The tyrosine kinase negative regulator c-Cbl as a RINGtype, E2-dependent ubiquitin-protein ligase. Science 286, 309-312.

21. Kretzschmar, M., Doody, J., and Massague, J. (1997). Opposing BMP and EGF signaling pathways converge on the TGF-P family mediator SMAD1. Nature 389, 618-622.

22. Levkowitz, G., Waterman, H., Zamir, E., Kam, Z., Oved, S., Langdon, W. Y., Beguinot, L., Geiger, B., and Yarden, Y. (1998). c-Cbl/Sli-1 regulates endocytic sorting and ubiquitination of the epidermal growth factor receptor. Genes Dev. 12, 3663-3674.

23. Lin, S.-Y., Makino, K., Xia, W., Matin, A., Wen, Y., Kwong, K. Y., Bourguignon, L., and Hung, M.-C. (2001). Nuclear localization of EGF receptor and its potential new role as a transcription factor. Nat. Cell Biol. 3, 802-808.

24. Ni, C.-Y., Murphy, M. P., Golde, T. E., and Carpenter, G. (2001). ■y-Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science 294, 2179-2181.

24a. Ogiso, H., Ishitaui, R., Nureki, O., Fukai, S., Yamanaka, M., Kim, J.-H., Saito, K., Sakamoto, A., Inoue, M., Shirouzu, M., and Yokoyama, S. (2002). Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Cell 110, 775-787.

25. Pawson, T. and Nash, P. (2000). Protein-protein interactions define specificity in signal transduction. Genes Dev. 14, 1027-1047.

26. Rodriguez-Viciana, P., Warne, P. H., Dhand, R., Vanhaesebroeck, B., Gout, I., Fry, M. J., Waterfield, M. D., and Downward, J. (1994). Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370, 527-532.

27. Saito, Y., Haendeler, J., Hojo, Y., Yamamoto, K., and Berk, B. C. (2001). Receptor heterodimerization: essential mechanism for platelet-derived growth factor-induced epidermal growth factor receptor transactivation. Mol. Cell. Biol. 21, 6387-6394.

28. Schindler, C. and Strehlow, I. (2000). Cytokines and STAT signaling. Adv. Pharmacol. 47, 113-174.

29. Schlessinger, J. (2000). Cell signaling by receptor tyrosine kinases. Cell 103, 211-225.

30. Schlessinger, J., Plotnikov, A. N., Ibrahimi, O. A., Eliseenkova, A. V., Yeh, B. K., Yayon, A., Linhardt, R. J., and Mohammadi, M. (2000). Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization. Mol. Cell 6, 743-750.

31. Schmucker, D. and Zipursky, S. L. (2001). Signaling downstream of Eph receptors and ephrin ligands. Cell 105, 701-704.

32. Shewchuk, L. M., Hassell, A. M., Ellis, B., Holmes, W. D., Davis, R., Horne, E. L., Kadwell, S. H., McKee, D. D., and Moore, J. T. (2000). Structure of the Tie2 RTK domain: self-inhibition by the nucleotide binding loop, activation loop, and C-terminal tail. Struct. Fold Des. 8, 1105-1113.

33. Shrivastava, A., Radziejewski, C., Campbell, E., Kovac, L., McGlynn, M., Ryan, T. E., Davis, S., Goldfarb, M. P., Glass, D. J., Lemke, G., and Yancopoulos, G. D. (1997). An orphan receptor tyrosine kinase family whose members serve as nonintegrin collagen receptors. Mol. Cell 1, 25-34.

34. Soker, S., Takashima, S., Miao, H. Q., Neufeld, G., and Klagsbrun, M. (1998). Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92, 735-745.

35. Sundaresan, M., Yu, Z. X., Ferrans, V. J., Irani, K., and Finkel, T. (1995). Requirement for generation of H2O2 for platelet-derived growth factor signal transduction. Science 270, 296-299.

36. Venter, J. C. et al. (2001). The sequence of the human genome. Science 291, 1304-1351.

37. Verveer, P. J., Wouters, F. S., Reynolds, A. R., and Bastiaens, P. I. H. (2000). Quantitative imaging of lateral ErbB1 receptor signal propagation in the plasma membrane. Science 290, 1567-1570.

38. Vogel, W., Gish, G., Alves, F., and Pawson, T. (1997). The discoidin domain receptor tyrosine kinases are activated by collagen. Mol. Cell 1, 13-23.

39. Wiesmann, C., Fuh, G., Christinger, H. W., Eigenbrot, C., Wells, J. A., and de Vos, A. M. (1997). Crystal structure at 1.7 Â resolution of VEGF in complex with domain 2 of the Flt-1 receptor. Cell 91, 695-704.

40. Wybenga-Groot, L. E., Baskin, B., Ong, S. H., Tong, J., Pawson, T., and Sicheri, F. (2001). Structural basis for autoinhibition of the EphB2 receptor tyrosine kinase by the unphosphorylated juxtamem-brane region. Cell 106, 745-757.

41. Yarden, Y. and Sliwkowski, M. X. (2001). Untangling the ErbB signalling network. Nat. Rev. Mol. Cell Biol. 2, 127-137.

42. Östman, A. and Böhmer, F.-D. (2001). Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatases. TICB 11, 258-266.

43. Östman, A. and Heldin, C.-H. (2001). Involvement of platelet-derived growth factor in disease: development of specific antagonists. Adv. Cancer Res. 80, 1-38.

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook

Post a comment