Skip to main content
SpringerLink
Log in

Molecular basis for HEF1/NEDD9/Cas-L action as a multifunctional co-ordinator of invasion, apoptosis and cell cycle

  • Published:
Cell Biochemistry and Biophysics Aims and scope Submit manuscript

Abstract

Upregulation of the scaffolding protein HEF1, also known as NEDD9 and Cas-L, has recently been identified as a pro-metastatic stimulus in a number of different solid tumors, and has also been strongly associated with pathogenesis of BCR-Abl-dependent tumors. As the evidence mounts for HEF1/NEDD9/Cas-L as a key player in metastatic cancer, it is timely to review the molecular regulation of HEF1/NEDD9/Cas-L. Most of the mortality associated with cancer arises from uncontrolled metastases, thus a better understanding of the properties of proteins specifically associated with promotion of this process may yield insights that improve cancer diagnosis and treatment. In this review, we summarize the extensive literature regarding HEF1/NEDD9/Cas-L expression and function in signaling relevant to cell attachment, migration, invasion, cell cycle, apoptosis, and oncogenic signal transduction. The complex function of HEF1/NEDD9/Cas-L revealed by this analysis leads us to propose a model in which alleviation of cell cycle checkpoints and acquired resistance to apoptosis is permissive for a HEF1/NEDD9/Cas-L-promoted pro-metastatic phenotype.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Minn, A. J., Gupta, G. P., Siegel, P. M., Bos, P. D., Shu, W., Giri, D. D., Viale, A., Olshen, A. B., Gerald, W. L., & Massague, J. (2005). Genes that mediate breast cancer metastasis to lung. Nature, 436, 518–524.

    Article  PubMed  CAS  Google Scholar 

  2. Natarajan, M., Stewart, J. E., Golemis, E. A., Pugacheva, E. N., Alexandropoulos, K., Cox, B. D., Wang, W., Grammer, J. R., & Gladson, C. L. (2006). HEF1/NEDD9/Cas-L is a necessary and specific downstream effector of FAK that promotes the migration of glioblastoma cells. Oncogene, 25, 1721–1732.

    Article  PubMed  CAS  Google Scholar 

  3. Kim, M., Gans, J. D., Nogueira, C., Wang, A., Paik, J. H., Feng, B., Brennan, C., Hahn, W. C., Cordon-Cardo, C., Wagner, S. N., Flotte, T. J., Duncan, L. M., Granter, S. R., & Chin, L. (2006). Comparative oncogenomics identifies NEDD9 as a melanoma metastasis gene. Cell, 125, 1269–1281.

    Article  PubMed  CAS  Google Scholar 

  4. Kumar, S., Tomooka, Y., & Noda, M. (1992). Identification of a set of genes with developmentally down-regulated expression in the mouse brain. Biochemical and Biophysical Research Communications, 185, 1155–1161.

    Article  PubMed  CAS  Google Scholar 

  5. Law, S. F., Estojak, J., Wang, B., Mysliwiec, T., Kruh, G. D., & Golemis, E. A. (1996). Human Enhancer of Filamentation 1 (HEF1/NEDD9/Cas-L), a novel p130Cas-Like docking protein, associates with FAK, and induces pseudohyphal growth in yeast. Molecular and Cellular Biology, 16, 3327–3337.

    PubMed  CAS  Google Scholar 

  6. Minegishi, M., Tachibana, K., Sato, T., Iwata, S., Nojima, Y., & Morimoto, C. (1996). Structure and function of Cas-L, a 105-kD Crk-associated substrate-related protein that is involved in beta-1 integrin-mediated signaling in lymphocytes. Journal of Experimental Medicine, 184, 1365–1375.

    Article  PubMed  CAS  Google Scholar 

  7. Sakai, R., Iwamatsu, A., Hirano, N., Ogawa, S., Tanaka, T., Mano, H., Yazaki, Y., & Hirai, H. (1994). A novel signaling molecule, p130, forms stable complexes in vivo with v-Crk and v-Src in a tyrosine phosphorylation-dependent manner. EMBO Journal, 13, 3748–3756.

    PubMed  CAS  Google Scholar 

  8. Alexandropoulos, K., & Baltimore, D. (1996). Coordinate activation of c-Src by SH3- and SH2-binding sites on a novel, p130Cas-related protein, Sin. Genes & Development, 10, 1341–1355.

    Article  CAS  Google Scholar 

  9. Alexandropoulos, K., Donlin, L. T., Xing, L., & Regelmann, A. G. (2003). Sin: good or bad? A T lymphocyte perspective. Immunological Reviews, 192, 181–195.

    Article  PubMed  CAS  Google Scholar 

  10. Ishino, M., Ohba, T., Sasaki, H., & Sasaki, T. (1995). Molecular cloning of a cDNA encoding a phosphoprotein, Efs, which contains a Src homology 3 domain and associates with Fyn. Oncogene, 11, 2331–2338.

    PubMed  CAS  Google Scholar 

  11. Donlin, L. T., Danzl, N. M., Wanjalla, C., & Alexandropoulos, K. (2005). Deficiency in expression of the signaling protein Sin/Efs leads to T-lymphocyte activation and mucosal inflammation. Molecular and Cellular Biology, 25, 11035–11046.

    Article  PubMed  CAS  Google Scholar 

  12. Xing, L., Donlin, L. T., Miller, R. H., & Alexandropoulos, K. (2004). The adapter molecule Sin regulates T-cell-receptor-mediated signal transduction by modulating signaling substrate availability. Molecular and Cellular Biology, 24, 4581–4592.

    Article  PubMed  CAS  Google Scholar 

  13. Bouton, A. H., Riggins, R. B., & Bruce-Staskal, P. J. (2001). Functions of the adapter protein Cas: Signal convergence and the determination of cellular responses. Oncogene, 20, 6448–6458.

    Article  PubMed  CAS  Google Scholar 

  14. Defilippi, P., Di Stefano, P., & Cabodi, S. (2006). p130Cas: a versatile scaffold in signaling networks. Trends in Cell Biology, 16, 257–263.

    Article  PubMed  CAS  Google Scholar 

  15. Li, S. S. (2005). Specificity and versatility of SH3 and other proline-recognition domains: Structural basis and implications for cellular signal transduction. Biochemical Journal, 390, 641–653.

    Article  PubMed  CAS  Google Scholar 

  16. Machida, K., & Mayer, B. J. (2005). The SH2 domain: Versatile signaling module and pharmaceutical target. Biochimica et Biophysica Acta, 1747, 1–25.

    PubMed  CAS  Google Scholar 

  17. Briknarova, K., Nasertorabi, F., Havert, M. L., Eggleston, E., Hoyt, D. W., Li, C., Olson, A. J., Vuori, K., & Ely, K. R. (2005). The serine-rich domain from Crk-associated substrate (p130Cas) is a four-helix bundle. Journal of Biological Chemistry, 280, 21908–21914.

    Article  PubMed  CAS  Google Scholar 

  18. Canutescu, A. A., & Dunbrack, R. L. Jr. (2005). MollDE: A homology modeling framework you can click with. Bioinformatics, 21, 2914–2916.

    Article  PubMed  CAS  Google Scholar 

  19. Law, S. F., Zhang Y.-Z., Fashena, S., Toby, G., Estojak, J., & Golemis, E. A. (1999). Dimerization of the docking/adaptor protein HEF1/NEDD9/Cas-L via a carboxy-terminal helix-loop-helix domain. Experimental Cell Research, 252, 224–235.

    Article  PubMed  CAS  Google Scholar 

  20. Law, S. F., O’Neill G. M., Fashena, S. J., Einarson, M. B., & Golemis, E. A. (2000). The docking protein HEF1/NEDD9/Cas-L is an apoptotic mediator at focal adhesion sites. Molecular and Cellular Biology, 20, 5184–5195.

    Article  PubMed  CAS  Google Scholar 

  21. Pugacheva, E. N., & Golemis, E. A. (2005). The focal adhesion scaffolding protein HEF1/NEDD9/Cas-L regulates activation of the Aurora-A and Nek2 kinases at the centrosome. Nature Cell Biology, 7, 937–946.

    Article  PubMed  CAS  Google Scholar 

  22. Arold, S. T., Hoellerer, M. K., & Noble, M. E. (2002). The structural basis of localization and signaling by the focal adhesion targeting domain. Structure (Camb), 10, 319–327.

    Article  CAS  Google Scholar 

  23. O’Neill G. M., & Golemis, E. A. (2001). Proteolysis of the docking protein HEF1/NEDD9/Cas-L and implications for focal adhesion dynamics. Molecular and Cellular Biology, 21, 5094–5108.

    Article  PubMed  CAS  Google Scholar 

  24. Tamada, M., Sheetz, M. P., & Sawada, Y. (2004). Activation of a signaling cascade by cytoskeleton stretch. Developmental Cell, 7, 709–718.

    Article  PubMed  CAS  Google Scholar 

  25. Kostic, A., & Sheetz, M. P. (2006). Fibronectin rigidity response through Fyn and p130Cas recruitment to the leading edge. Molecular Biology of the Cell, 17, 2684–2695.

    Article  PubMed  CAS  Google Scholar 

  26. Sawada, Y., Tamada, M., Dubin-Thaler, B. J., Cherniavskaya, O., Sakai, R., Tanaka, S., & Sheetz, M. P. (2006). Force sensing by mechanical extension of the Src family kinase substrate p130Cas. Cell, 127, 1015–1026.

    Article  PubMed  CAS  Google Scholar 

  27. Nourry, C., Maksumova, L., Pang, M., Liu, X., & Wang, T. (2004). Direct interaction between Smad3, APC10, CDH1 and HEF1/NEDD9/Cas-L in proteasomal degradation of HEF1/NEDD9/Cas-L. BMC Cell Biology, 5, 20.

    Article  PubMed  Google Scholar 

  28. Liu, X., Elia, A. E. H., Law, S. F., Golemis, E. A., Farley, J., & Wang, T. (2000). A novel ability of Smad3 to regulate proteasomal degradation of a Cas family member, HEF1/NEDD9/Cas-L. EMBO Journal, 19, 6759–6769.

    Article  PubMed  CAS  Google Scholar 

  29. Law, S. F., Zhang, Y.-Z., Klein-Szanto, A., & Golemis, E. A. (1998). Cell-cycle regulated processing of HEF1/NEDD9/Cas-L to multiple protein forms differentially targeted to multiple compartments. Molecular and Cellular Biology, 18, 3540–3551.

    PubMed  CAS  Google Scholar 

  30. Reynolds, A. B., Kanner, S. B., Wang, H.-C. R., & Parsons, J. T. (1989). Stable association of activated pp60src with two tyrosine-phosphorylated cellular proteins. Molecular and Cellular Biology, 9, 3951–3958.

    PubMed  CAS  Google Scholar 

  31. Zheng, M., & McKeown-Longo, P. J. (2002). Regulation of HEF1/NEDD9/Cas-L expression and phosphorylation by TGF-beta 1 and cell adhesion. Journal of Biological Chemistry, 277, 39599–39608.

    Article  PubMed  CAS  Google Scholar 

  32. Tachibana, K., Urano, T., Fujita, H., Ohashi, Y., Kamiguchi, K., Iwata, S., Hirai, H., & Morimoto, C. (1997). Tyrosine phosphorylation of crk-associated substrates by focal adhesion kinase. A putative mechanism for the integrin-mediated tyrosine phosphorylation of crk-associated substrates. Journal of Biological Chemistry, 272, 29083–29090.

    Article  PubMed  CAS  Google Scholar 

  33. Riggins, R. B., Quilliam, L. A., & Bouton, A. H. (2003). Synergistic promotion of c-Src activation and cell migration by Cas and AND-34/BCAR3. Journal of Biological Chemistry, 278, 28264–28273.

    Article  PubMed  CAS  Google Scholar 

  34. Brabek, J., Constancio, S. S., Shin, N. Y., Pozzi, A., Weaver, A. M., & Hanks, S. K. (2004). CAS promotes invasiveness of Src-transformed cells. Oncogene, 23, 7406–7415.

    Article  PubMed  CAS  Google Scholar 

  35. Ruest, P. J., Shin, N. Y., Polte, T. R., Zhang, X., & Hanks, S. K. (2001). Mechanisms of CAS substrate domain tyrosine phosphorylation by FAK and Src. Molecular and Cellular Biology, 21, 7641–7652.

    Article  PubMed  CAS  Google Scholar 

  36. Zheng, M., & McKeown-Longo, P. J. (2006). Cell adhesion regulates Ser/Thr phosphorylation and proteasomal degradation of HEF1/NEDD9/Cas-L. Journal of Cell Science, 119, 96–103.

    Article  PubMed  CAS  Google Scholar 

  37. Bargon, S. D., Gunning, P. W., & O’Neill G. M. (2005). The Cas family docking protein, HEF1/NEDD9/Cas-L, promotes the formation of neurite-like membrane extensions. Biochimica et Biophysica Acta, 1746, 143–154.

    PubMed  CAS  Google Scholar 

  38. Hu, K., Ji, L., Applegate, K. T., Danuser, G., & Waterman-Storer, C. M. (2007). Differential transmission of actin motion within focal adhesions. Science, 315, 111–115.

    Article  PubMed  CAS  Google Scholar 

  39. Paszek, M. J., Zahir, N., Johnson, K. R., Lakins, J. N., Rozenberg, G. I., Gefen, A., Reinhart-King, C. A., Margulies, S. S., Dembo, M., Boettiger, D., Hammer, D. A., & Weaver, V. M. (2005). Tensional homeostasis and the malignant phenotype. Cancer Cell, 8, 241–254.

    Article  PubMed  CAS  Google Scholar 

  40. Zhang, Z., Hernandez-Lagunas, L., Horne, W. C., & Baron, R. (1999). Cytoskeleton-dependent tyrosine phosphorylation of the p130(Cas) family member HEF1/NEDD9/Cas-L downstream of the G protein-coupled calcitonin receptor. Calcitonin induces the association of HEF1/NEDD9/Cas-L, paxillin, and focal adhesion kinase. Journal of Biological Chemistry, 274, 25093–25098.

    Article  PubMed  CAS  Google Scholar 

  41. Jope, R. S., Song, L., Grimes, C. A., & Zhang, L. (1999). Oxidative stress oppositely modulates protein tyrosine phosphorylation stimulated by muscarinic G protein-coupled and epidermal growth factor receptors. Journal of Neuroscience Research, 55, 329–340.

    Article  PubMed  CAS  Google Scholar 

  42. Sasaki, T., Iwata, S., Okano, H. J., Urasaki, Y., Hamada, J., Tanaka, H., Dang, N. H., Okano, H., & Morimoto, C. (2005). Nedd9 Protein, a Cas-L homologue, is upregulated after transient global ischemia in rats. Possible involvement of Nedd9 in the differentiation of neurons after ischemia. Stroke, 36, 2457–2462.

    Article  PubMed  CAS  Google Scholar 

  43. Merrill, R. A., See, A. W., Wertheim, M. L., & Clagett-Dame, M. (2004). Crk-associated substrate (Cas) family member, NEDD9, is regulated in human neuroblastoma cells and in the embryonic hindbrain by all-trans retinoic acid. Developmental Dynamics, 231, 564–575.

    Article  PubMed  CAS  Google Scholar 

  44. Merrill, R. A., Ahrens, J. M., Kaiser, M. E., Federhart, K. S., Poon, V. Y., & Clagett-Dame, M. (2004). All-trans retinoic acid-responsive genes identified in the human SH-SY5Y neuroblastoma cell line and their regulated expression in the nervous system of early embryos. Biological Chemistry, 385, 605–614.

    Article  PubMed  CAS  Google Scholar 

  45. Richer, J. K., Jacobsen, B. M., Manning, N. G., Abel, M. G., Wolf, D. M., & Horwitz, K. B. (2002). Differential gene regulation by the two progesterone receptor isoforms in human breast cancer cells. Journal of Biological Chemistry, 277, 5209–5218.

    Article  PubMed  CAS  Google Scholar 

  46. Monroe, D. G., Getz, B. J., Johnsen, S. A., Riggs, B. L., Khosla, S., & Spelsberg, T. C. (2003). Estrogen receptor isoform-specific regulation of endogenous gene expression in human osteoblastic cell lines expressing either ERalpha or ERbeta. Journal of Cellular Biochemistry, 90, 315–326.

    Article  PubMed  CAS  Google Scholar 

  47. Buterin, T., Koch, C., & Naegeli, H. (2006). Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis, 27, 1567–1578.

    Article  PubMed  CAS  Google Scholar 

  48. Donninger, H., Bonome, T., Radonovich, M., Pise-Masison, C. A., Brady, J., Shih, J. H., Barrett, J. C., & Birrer, M. J. (2004). Whole genome expression profiling of advance stage papillary serous ovarian cancer reveals activated pathways. Oncogene, 23, 8065–8077.

    Article  PubMed  CAS  Google Scholar 

  49. Boyer, L. A., Lee, T. I., Cole, M. F., Johnstone, S. E., Levine, S. S., Zucker, J. P., Guenther, M. G., Kumar, R. M., Murray, H. L., Jenner, R. G., Gifford, D. K., Melton, D. A., Jaenisch, R., & Young, R. A. (2005). Core transcriptional regulatory circuitry in human embryonic stem cells. Cell, 122, 947–956.

    Article  PubMed  CAS  Google Scholar 

  50. Feng, L., Guedes, S., & Wang, T. (2004). AIP4/hItch is an Ubiquitin E3 ligase For HEF1/NEDD9/Cas-L In TGF-{beta} signaling pathways. Journal of Biological Chemistry, 279, 29681–29690.

    Article  PubMed  CAS  Google Scholar 

  51. Inamoto, S., Iwata, S., Inamoto, T., Nomura, S., Sasaki, T., Urasaki, Y., Hosono, O., Kawasaki, H., Tanaka, H., Dang, N. H., & Morimoto, C. (2006). Crk-associated substrate lymphocyte type regulates transforming growth factor-beta signaling by inhibiting Smad6 and Smad7. Oncogene, 26, 893–904.

    Article  PubMed  CAS  Google Scholar 

  52. Wang, T. (2003). The 26S proteasome system in the signaling pathways of TGF-beta superfamily. Front Bioscience, 8, d1109–d1127.

    Article  CAS  Google Scholar 

  53. Thiery, J. P. (2003). Epithelial-mesenchymal transitions in development and pathologies. Current Opinions in Cell Biology, 15, 740–746.

    Article  CAS  Google Scholar 

  54. Wozniak, M. A., Modzelewska, K., Kwong, L., & Keely, P. J. (2004). Focal adhesion regulation of cell behavior. Biochimica et Biophysica Acta, 1692, 103–119.

    PubMed  CAS  Google Scholar 

  55. Seo, S., Asai, T., Saito, T., Suzuki, T., Morishita, Y., Nakamoto, T., Ichikawa, M., Yamamoto, G., Kawazu, M., Yamagata, T., Sakai, R., Mitani, K., Ogawa, S., Kurokawa, M., Chiba, S., & Hirai, H. (2005). Crk-associated substrate lymphocyte type is required for lymphocyte trafficking and marginal zone B cell maintenance. Journal of Immunology, 175, 3492–3501.

    CAS  Google Scholar 

  56. Fashena, S. J., Einarson, M. B., O’Neill, GM, Patriotis, C. P., & Golemis, E. A. (2002). Dissection of HEF1/NEDD9/Cas-L-dependent functions in motility and transcriptional regulation. Journal of Cell Science, 115, 99–111.

    PubMed  CAS  Google Scholar 

  57. Webb, D. J., Donais, K., Whitmore, L. A., Thomas, S. M., Turner, C. E., Parsons, J. T., & Horwitz, A. F. (2004). FAK-Src signalling through paxillin, ERK and MLCK regulates adhesion disassembly. Nature Cell Biology, 6, 154–161.

    Article  PubMed  CAS  Google Scholar 

  58. Huang, J., Hamasaki, H., Nakamoto, T., Honda, H., Hirai, H., Saito, M., Takato, T., & Sakai, R. (2002). Differential regulation of cell migration, actin stress fiber organization, and cell transformation by functional domains of Crk-associated substrate. Journal of Biological Chemistry, 277, 27265–27272.

    Article  PubMed  CAS  Google Scholar 

  59. van Seventer, G. A., Salman, H. J., Law, S. F., O’Neill, G. M., Mullen, M. M., Franz, A. A., Kanner, S. B., Golemis, E. A., & van Seventer, J. M. (2001). Focal adhesion kinase regulates beta1 integrin dependent migration through an HEF1/NEDD9/Cas-L effector pathway. European Journal of Immunology, 31, 1417–1427.

    Article  PubMed  Google Scholar 

  60. Ohashi, Y., Iwata, S., Kamiguchi, K., & Morimoto, C. (1999). Tyrosine phosphorylation of Crk-associated substrate lymphocyte-type is a critical element in TCR- and beta1 integrin-induced T lymphocyte migration. Journal of Immunology, 163, 3727–3734.

    CAS  Google Scholar 

  61. Iwata, S., Souta-Kuribara, A., Yamakawa, A., Sasaki, T., Shimizu, T., Hosono, O., Kawasaki, H., Tanaka, H., Dang, N. H., Watanabe, T., Arima, N., & Morimoto, C. (2005). HTLV-I Tax induces and associates with Crk-associated substrate lymphocyte type (Cas-L). Oncogene, 24, 1262–1271.

    Article  PubMed  CAS  Google Scholar 

  62. Klemke, R. L., Leng, J., Molander, R., Brooks, P. C., Vuori, K., & Cheresh, D. A. (1998). CAS/Crk coupling serves as a “molecular switch” for induction of cell migration. Journal of Cell Biology, 140, 961–972.

    Article  PubMed  CAS  Google Scholar 

  63. Ridley, A. J. (2001). Rho proteins: Linking signaling with membrane trafficking. Traffic, 2, 303–310.

    Article  PubMed  CAS  Google Scholar 

  64. Smith, L. G., & Li, R. (2004). Actin polymerization: riding the wave. Current Biology, 14, R109–R111.

    Article  PubMed  CAS  Google Scholar 

  65. Cai, D., Iyer, A., Felekkis, K. N., Near, R. I., Luo, Z., Chernoff, J., Albanese, C., Pestell, R. G., & Lerner, A. (2003). AND-34/BCAR3, a GDP exchange factor whose overexpression confers antiestrogen resistance, activates Rac, PAK1, and the cyclin D1 promoter. Cancer Research, 63, 6802–6808.

    PubMed  CAS  Google Scholar 

  66. O’Neill, G. M., Fashena, S. J., & Golemis, E. A. (2000). Integrin signaling: A new Cas(t) of characters enters the stage. Trends in Cell Biology, 10, 111–119.

    Article  PubMed  CAS  Google Scholar 

  67. Cai, D., Felekkis, K. N., Near, R. I., O’Neill, G. M., van Seventer, J. M., Golemis, E. A., & Lerner, A. (2003). The GDP exchange factor AND-34 is expressed in B cells, associates with HEF1/NEDD9/Cas-L, and activates Cdc42. Journal of Immunology, 170, 969–978.

    CAS  Google Scholar 

  68. Gotoh, T., Cai, D., Tian, X., Feig, L. A., & Lerner, A. (2000). p130Cas regulates the activity of AND-34, a novel ral, rap1, and R-Ras guanine nucleotide exchange factor. Journal of Biological Chemistry, 275, 30118–30123.

    Article  PubMed  CAS  Google Scholar 

  69. Sakakibara, A., Hattori, S., Nakamura, S., & Katagiri, T. (2003). A novel hematopoietic adaptor protein, Chat-H, positively regulates T cell receptor-mediated interleukin-2 production by Jurkat cells. Journal of Biological Chemistry, 278, 6012–6017.

    Article  PubMed  CAS  Google Scholar 

  70. Sakakibara, A., & Hattori, S. (2000). Chat, a Cas/HEF1/NEDD9/Cas-L-associated adaptor protein that integrates multiple signaling pathways. Journal of Biological Chemistry, 275, 6404–6410.

    Article  PubMed  CAS  Google Scholar 

  71. Sakakibara, A., Ohba, Y., Kurokawa, K., Matsuda, M., & Hattori, S. (2002). Novel function of Chat in controlling cell adhesion via Cas-Crk-C3G-pathway-mediated Rap1 activation. Journal of Cell Science, 115, 4915–4924.

    Article  PubMed  CAS  Google Scholar 

  72. Regelmann, A. G., Danzl, N. M., Wanjalla, C., & Alexandropoulos, K. (2006). The hematopoietic isoform of cas-HEF1/NEDD9/Cas-L-associated signal transducer regulates chemokine-induced inside-out signaling and T cell trafficking. Immunity, 25, 907–918.

    Article  PubMed  CAS  Google Scholar 

  73. da Silva, J. S., & Dotti, C. G. (2002). Breaking the neuronal sphere: regulation of the actin cytoskeleton in neuritogenesis. Nature Reviews Neuroscience, 3, 694–704.

    Article  PubMed  CAS  Google Scholar 

  74. Ridley, A. J., Schwartz, M. A., Burridge, K., Firtel, R. A., Ginsberg, M. H., Borisy, G., Parsons, J. T., & Horwitz, A. R. (2003). Cell migration: Integrating signals from front to back. Science, 302, 1704–1709.

    Article  PubMed  CAS  Google Scholar 

  75. Dolfi, F., Garcia-Guzman, M., Ojaniemi, M., Nakamura, H., Matsuda, M., & Vuori, K. (1998). The adaptor protein Crk connects multiple cellular stimuli to the JNK signaling pathway. Proceedings of the National Academic Science USA, 95, 15394–15399.

    Article  CAS  Google Scholar 

  76. Kothakota, S., Azuma, T., Reinhard, C., Klippel, A., Tang, J., Chu, K., McGarry, T. J., Kirschner, M. W., Koths, K., Kwiatkowski, D. J., & Williams, L. T. (1997). Caspase-3-generated fragment of gelsolin: Effector of morphological change in apoptosis. Science, 278, 294–298.

    Article  PubMed  CAS  Google Scholar 

  77. Gervais, F. G., Thornberry, N. A., Ruffolo, S. C., Nicholson, D. W., & Roy, S. (1998). Caspases cleave focal adhesion kinase during apoptosis to generate a FRNK-like polypeptide. Journal of Biological Chemistry, 273, 17102–17108.

    Article  PubMed  CAS  Google Scholar 

  78. Kook, S., Shim, S. R., Choi, S. J., Ahnn, J., Kim, J. I., Eom, S. H., Jung, Y. K., Paik, S. G., & Song, W. K. (2000). Caspase-mediated cleavage of p130cas in etoposide-induced apoptotic Rat-1 cells. Molecular Biology of the Cell, 11, 929–939.

    PubMed  CAS  Google Scholar 

  79. Stupack, D. G., Puente, X. S., Boutsaboualoy, S., Storgard, C. M., & Cheresh, D. A. (2001). Apoptosis of adherent cells by recruitment of caspase-8 to unligated integrins. Journal of Cell Biology, 155, 459–470.

    Article  PubMed  CAS  Google Scholar 

  80. Frisch, S. M. (2000). Anoikis. Methods Enzymol, 322, 472–479.

    Article  PubMed  CAS  Google Scholar 

  81. Biscardi, J. S., Belsches, A. P., & Parsons, S. J. (1998). Characterization of human epidermal growth factor receptor and c-Src interactions in human breast tumor cells. Molecular Carcinogenesis, 21, 261–272.

    Article  PubMed  CAS  Google Scholar 

  82. Dadke, D., Jarnik, M., Pugacheva, E. N., Singh, M. K., & Golemis, E. A. (2006). Deregulation of HEF1/NEDD9/Cas-L impairs M-phase progression by disrupting the RhoA activation cycle. Molecular Biology of the Cell, 17, 1204–1217.

    Article  PubMed  CAS  Google Scholar 

  83. Pugacheva, E. N., & Golemis, E. A. (2006). HEF1/NEDD9/Cas-L-aurora A interactions: Points of dialog between the cell cycle and cell attachment signaling networks. Cell Cycle, 5, 384–391.

    PubMed  CAS  Google Scholar 

  84. Fritz, G., & Kaina, B. (2006). Rho GTPases: Promising cellular targets for novel anticancer drugs. Current Cancer Drug Targets, 6, 1–14.

    Article  PubMed  CAS  Google Scholar 

  85. Maddox, A. S., & Burridge, K. (2003). RhoA is required for cortical retraction and rigidity during mitotic cell rounding. Journal of Cell Biology, 160, 255–265.

    Article  PubMed  CAS  Google Scholar 

  86. O’Keefe, L., Somers, W. G., Harley, A., & Saint, R. (2001). The pebble GTP exchange factor and the control of cytokinesis. Cell Structure and Function, 26, 619–626.

    Article  PubMed  CAS  Google Scholar 

  87. Yi, J., Kloeker, S., Jensen, C. C., Bockholt, S., Honda, H., Hirai, H., & Beckerle, M. C. (2002). Members of the zyxin family of LIM proteins interact with members of the p130cas family of signal transducers. Journal of Biological Chemistry, 277, 9580–9589.

    Article  PubMed  CAS  Google Scholar 

  88. Hirota, T., Morisaki, T., Nishiyama, Y., Marumoto, T., Tada, K., Hara, T., Masuko, N., Inagaki, M., Hatakeyama, K., & Saya, H. (2000). Zyxin, a regulator of actin filament assembly, targets the mitotic apparatus by interacting with h-warts/LATS1 tumor suppressor. Journal of Cell Biology, 149, 1073–1086.

    Article  PubMed  CAS  Google Scholar 

  89. Moasser, M. M., Srethapakdi, M., Sachar, K. S., Kraker, A. J., & Rosen, N. (1999). Inhibition of Src kinases by a selective tyrosine kinase inhibitor causes mitotic arrest. Cancer Research, 59, 6145–6152.

    PubMed  CAS  Google Scholar 

  90. Bhatt, A. S., Erdjument-Bromage, H., Tempst, P., Craik, C. S., & Moasser, M. M. (2005). Adhesion signaling by a novel mitotic substrate of src kinases. Oncogene, 24, 5333–5343.

    Article  PubMed  CAS  Google Scholar 

  91. Seo, S., Ichikawa, M., & Kurokawa, M. (2006). Structure and function of Cas-L and integrin-mediated signaling. Critical Reviews in Immunology, 26, 391–406.

    PubMed  CAS  Google Scholar 

  92. Iwata, S., Ohashi, Y., Kamiguchi, K., & Morimoto, C. (2000). Beta 1-integrin-mediated cell signaling in T lymphocytes. Journal of Dermatological Science, 23, 75–86.

    Article  PubMed  CAS  Google Scholar 

  93. Hunter, A. J., & Shimizu, Y. (1997). Alpha 4 beta 1 integrin-mediated tyrosine phosphorylation in human T cells: Characterization of Crk- and Fyn-associated substrates (pp105, pp115, and human enhancer of filamentation-1) and integrin-dependent activation of p59fyn1. Journal of Immunology, 159, 4806–4814.

    CAS  Google Scholar 

  94. Kamiguchi, K., Tachibana, K., Iwata, S., Ohashi, Y., & Morimoto, C. (1999). Cas-L is required for beta 1 integrin-mediated costimulation in human Tcells. Journal of Immunology, 163, 563–568.

    CAS  Google Scholar 

  95. Murata, S., Tanaka, T., & Miyasaka, M. (2002). Lymphocyte binding to MAdCAM-1 via alpha4beta7 integrin activates a signal transduction pathway involving tyrosine phosphorylation of paxillin and p105(Cas-L). Immunology Letters, 81, 223–228.

    Article  PubMed  CAS  Google Scholar 

  96. Astier, A., Manie, S., Avraham, H., Hirai, H., Law, S. F., Zhang, Y.-Z., Golemis, E. A., Fu, Y., Druker, B. J., Haghayeghi, N., Freedman, A. S., & Avraham, S. (1997). The related adhesion focal tyrosine kinase differentially phosphorylates p130Cas and the Cas-Like protein, p105HEF1/NEDD9/Cas-L. Journal of Biological Chemistry, 272, 19719–19730.

    Article  PubMed  CAS  Google Scholar 

  97. Astier, A., Manie, S. N., Law, S. F., Canty, T., Hagheyeghi, N., Druker, B. J., Salgia, R., Golemis, E. A., & Freedman, A. S. (1997). Association of the Cas-Like molecule HEF1/NEDD9/Cas-L with CrkL following integrin and antigen receptor signaling in B cells. Possible relevance to neoplastic lymphohematopoietic cells. Leukemia & Lymphoma, 28, 65–72.

    CAS  Google Scholar 

  98. Manie, S. N., Beck, A. R. P., Astier, A., Law, S. F., Canty, T., Hirai, H., Druker, B. J., Avraham, H., Haghayegi, N., Sattler, M., Salgia, R., Griffin, J. D., Golemis, E. A., & Freedman, A. S. (1997). Involvement of p130Cas and p105HEF1/NEDD9/Cas-L, a novel Cas-Like docking protein, in a cytoskeleton-dependent signaling pathway initiated by ligation of integrin or antigen receptor on human B cells. Journal of Biological Chemistry, 272, 4230–4236.

    Article  PubMed  CAS  Google Scholar 

  99. Sattler, M., Salgia, R., Shrikhande, G., Verma, S., Uemura, N., Law, S. F., Golemis, E. A., & Griffin, J. D. (1997). Differential signaling after beta1 integrin ligation is mediated through binding of CRKL to p120CBL and p110HEF1/NEDD9/Cas-L. Journal of Biological Chemistry, 272, 14320–14326.

    Article  PubMed  CAS  Google Scholar 

  100. Kyono, W. T., de Jong, R., Park, R. K., Liu, Y., Heisterkamp, N., Groffen, J., & Durden, D. L. (1998). Differential interaction of Crkl with Cbl or C3G, Hef-1, and gamma subunit immunoreceptor tyrosine-based activation motif in signaling of myeloid high affinity Fc receptor for IgG (Fc gamma RI). Journal of Immunology, 161, 5555–5563.

    CAS  Google Scholar 

  101. Kanda, H., Mimura, T., Hamasaki, K., Yamamoto, K., Yazaki, Y., Hirai, H., & Nojima, Y. (1999). Fyn and Lck tyrosine kinases regulate tyrosine phosphorylation of p105CasL, a member of the p130Cas docking protein family, in T-cell receptor-mediated signalling. Immunology, 97, 56–61.

    Article  PubMed  CAS  Google Scholar 

  102. Kanda, H., Mimura, T., Morino, N., Hamasaki, K., Nakamoto, T., Hirai, H., Morimoto, C., Yazaki, Y., & Nojima, Y. (1997). Ligation of the T cell antigen receptor induces tyrosine phosphorylation of p105CasL, a member of the p130Cas-related docking protein family, and its subsequent binding to the Src homology 2 domain of c-Crk. European Journal of Immunology, 27, 2113–2117.

    Article  PubMed  CAS  Google Scholar 

  103. Ohashi, Y., Tachibana, K., Kamiguchi, K., Fujita, H., & Morimoto, C. (1998). T cell receptor-mediated tyrosine phosphorylation of Cas-L, a 105-kDa Crk-associated substrate-related protein, and its association of Crk and C3G. Journal of Biological Chemistry, 273, 6446–6451.

    Article  PubMed  CAS  Google Scholar 

  104. Iwata, S., Kobayashi, H., Miyake-Nishijima, R., Sasaki, T., Souta-Kuribara, A., Nori, M., Hosono, O., Kawasaki, H., Tanaka, H., & Morimoto, C. (2002). Distinctive signaling pathways through CD82 and beta1 integrins in human T cells. European Journal of Immunology, 32, 1328–1337.

    Article  PubMed  CAS  Google Scholar 

  105. Felekkis, K., Quilliam, L. A., & Lerner, A. (2005). Characterization of AND-34 function and signaling. Methods Enzymol, 407, 55–63.

    PubMed  Google Scholar 

  106. Dail, M., Kalo, M. S., Seddon, J. A., Cote, J. F., Vuori, K., & Pasquale, E. B. (2004). SHEP1 function in cell migration is impaired by a single amino acid mutation that disrupts association with the scaffolding protein cas but not with Ras GTPases. Journal of Biological Chemistry, 279, 41892–41902.

    Article  PubMed  CAS  Google Scholar 

  107. Cai, D., Clayton, L. K., Smolyar, A., & Lerner, A. (1999). AND-34, a novel p130Cas-binding thymic stromal cell protein regulated by adhesion and inflammatory cytokines. Journal of Immunology, 163, 2104–2112.

    CAS  Google Scholar 

  108. Lang, T. J. (2004). Estrogen as an immunomodulator. Clinical Immunology, 113, 224–230.

    Article  PubMed  CAS  Google Scholar 

  109. de Jong, R., van Wijk, A., Haataja, L., Heisterkamp, N., & Groffen, J. (1997). BCR/ABL-induced leukemogenesis causes phosphorylation of HEF1/NEDD9/Cas-L and its association with Crkl. Journal of Biological Chemistry, 272, 32649–32655.

    Article  PubMed  Google Scholar 

  110. Groffen, J., de Jong, R., Haataja, L., Kaartinen, V., & Heisterkamp, N. (1999). Phosphorylation substrates and altered signalling in leukemias caused by BCR/ABL. Leukemia 13(Suppl 1), S81–S82.

    Article  PubMed  Google Scholar 

  111. Heisterkamp, N., Voncken, J. W., Senadheera, D., Gonzalez-Gomez, I., Reichert, A., Haataja, L., Reinikainen, A., Pattengale, P. K., & Groffen, J. (2000). Reduced oncogenicity of p190 Bcr/Abl F-actin-binding domain mutants. Blood, 96, 2226–2232.

    PubMed  CAS  Google Scholar 

  112. Sattler, M., & Salgia, R. (1998). Role of the adapter protein CRKL in signal transduction of normal hematopoietic and BCR/ABL-transformed cells. Leukemia, 12, 637–644.

    Article  PubMed  CAS  Google Scholar 

  113. Hemmeryckx, B., Reichert, A., Watanabe, M., Kaartinen, V., de Jong, R., Pattengale, P. K., Groffen, J., & Heisterkamp, N. (2002). BCR/ABL P190 transgenic mice develop leukemia in the absence of Crkl. Oncogene, 21, 3225–3231.

    Article  PubMed  CAS  Google Scholar 

  114. Hemmeryckx, B., van Wijk, A., Reichert, A., Kaartinen, V., de Jong, R., Pattengale, P. K., Gonzalez-Gomez, I., Groffen, J., & Heisterkamp, N. (2001). Crkl enhances leukemogenesis in BCR/ABL P190 transgenic mice. Cancer Research, 61, 1398–1405.

    PubMed  CAS  Google Scholar 

  115. O’Dwyer, M. (2002). Multifaceted approach to the treatment of bcr-abl-positive leukemias. Oncologist 7(Suppl 1), 30–38.

    Article  PubMed  CAS  Google Scholar 

  116. Miyake-Nishijima, R., Iwata, S., Saijo, S., Kobayashi, H., Kobayashi, S., Souta-Kuribara, A., Hosono, O., Kawasaki, H., Tanaka, H., Ikeda, E., Okada, Y., Iwakura, Y., & Morimoto, C. (2003). Role of Crk-associated substrate lymphocyte type in the pathophysiology of rheumatoid arthritis in tax transgenic mice and in humans. Arthritis Rheum, 48, 1890–1900.

    Article  PubMed  CAS  Google Scholar 

  117. Sun, S. C., & Yamaoka, S. (2005). Activation of NF-kappaB by HTLV-I and implications for cell transformation. Oncogene, 24, 5952–5964.

    Article  PubMed  CAS  Google Scholar 

  118. Gao, L., Deng, H., Zhao, H., Hirbe, A., Harding, J., Ratner, L., & Weilbaecher, K. (2005). HTLV-1 Tax transgenic mice develop spontaneous osteolytic bone metastases prevented by osteoclast inhibition. Blood, 106, 4294–4302.

    Article  PubMed  CAS  Google Scholar 

  119. Iwakura, Y., Saijo, S., Kioka, Y., Nakayama-Yamada, J., Itagaki, K., Tosu, M., Asano, M., Kanai, Y., & Kakimoto, K. (1995). Autoimmunity induction by human T cell leukemia virus type 1 in transgenic mice that develop chronic inflammatory arthropathy resembling rheumatoid arthritis in humans. Journal of Immunology, 155, 1588–1598.

    CAS  Google Scholar 

  120. McCallum, R. M., Patel, D. D., Moore, J. O., & Haynes, B. F. (1997). Arthritis syndromes associated with human T cell lymphotropic virus type I infection. Medical Clinics of North America, 81, 261–276.

    Article  PubMed  CAS  Google Scholar 

  121. Honda, H., Oda, H., Nakamoto, T., Honda, Z., Sakai, R., Suzuki, T., Saito, T., Nakamura, K., Nakao, K., Ishikawa, T., Katsuki, M., Yazaki, Y., & Hirai, H. (1998). Cardiovascular anomaly, impaired actin bundling and resistance to Src-induced transformation in mice lacking p130Cas. Nature Genetics, 19, 361–365.

    Article  PubMed  CAS  Google Scholar 

  122. Suzuki, T., Nakamoto, T., Ogawa, S., Seo, S., Matsumura, T., Tachibana, K., Morimoto, C., & Hirai, H. (2002). MICAL, a novel CasL interacting molecule, associates with vimentin. Journal of Biological Chemistry, 277, 14933–14941.

    PubMed  CAS  Google Scholar 

  123. Togashi, H., Schmidt, E. F., & Strittmatter, S. M. (2006). RanBPM contributes to Semaphorin3A signaling through plexin-A receptors. Journal of Neuroscience, 26, 4961–4969.

    Article  PubMed  CAS  Google Scholar 

  124. Nef, S., Schaad, O., Stallings, N. R., Cederroth, C. R., Pitetti, J. L., Schaer, G., Malki, S., Dubois-Dauphin, M., Boizet-Bonhoure, B., Descombes, P., Parker, K. L., & Vassalli, J. D. (2005). Gene expression during sex determination reveals a robust female genetic program at the onset of ovarian development. Developmental Biology, 287, 361–377.

    Article  PubMed  CAS  Google Scholar 

  125. van der Flier, S., Brinkman, A., Look, M. P., Kok, E. M., Meijer-Van Gelder, M. E., Klijn, J. G., Dorssers, L. C., & Foekens, J. A. (2000). Bcar1/p130Cas protein and primary breast cancer: Prognosis and response to tamoxifen treatment. Journal of National Cancer Institute, 92, 120–127.

    Article  Google Scholar 

  126. van der Flier, S., van der Kwast, T. H., Claassen, C. J., Timmermans, M., Brinkman, A., Henzen-Logmans, S. C., Foekens, J. A., & Dorssers, L. C. (2001). Immunohistochemical study of the BCAR1/p130Cas protein in non-malignant and malignant human breast tissue. International Journal of Biological Markers, 16, 172–178.

    PubMed  Google Scholar 

  127. Tang, H., Hao, Q., Fitzgerald, T., Sasaki, T., Landon, E. J., & Inagami, T. (2002). Pyk2/CAKbeta tyrosine kinase activity-mediated angiogenesis of pulmonary vascular endothelial cells. Journal of Biological Chemistry, 277, 5441–5447.

    Article  PubMed  CAS  Google Scholar 

  128. Pugacheva, E. N., Roegiers, F., & Golemis, E. A. (2006). Interdependence of cell attachment and cell cycle signaling. Current Opinions in Cell Biology, 18, 507–515.

    Article  CAS  Google Scholar 

  129. Kato-Stankiewicz, J., Hakimi, I., Zhi, G., Zhang, J., Serebriiskii, I., Guo, L., Edamatsu, H., Koide, H., Menon, S., Eckl, R., Sakamuri, S., Lu, Y., Chen, Q. Z., Agarwal, S., Baumbach, W. R., Golemis, E. A., Tamanoi, F., & Khazak, V. (2002). Inhibitors of Ras/Raf-1 interaction identified by two-hybrid screening revert Ras-dependent transformation phenotypes in human cancer cells. Proceedings of National Academic Science USA, 99, 14398–14403.

    Article  CAS  Google Scholar 

  130. Druker, B. J. (2002). Perspectives on the development of a molecularly targeted agent. Cancer Cell, 1, 31–36.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

MKS and EAG were supported by NIH RO1 CA63366, a Department of Defense OCRF IDEA Award, Pennsylvania Tobacco Settlement Funds, and a grant from the Susan B. Komen Foundation (to EAG), and by an Appropriation from the Commonwealth of Pennsylvania, and by NIH core Grant CA-06927 (to Fox Chase Cancer Center). SS was supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and the Ministry of Health, Labor, and Welfare of Japan. GMO’N is the NSW Cancer Council Career Development Fellow. LC is supported by an Australian Post-graduate Award and is a NSW Cancer Institute Scholar.

Author information

Authors and Affiliations

  1. Division of Basic Science, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA, 19111, USA

    Mahendra K. Singh & Erica A. Golemis

  2. Oncology Research Unit, The Children’s Hospital at Westmead, Sydney, NSW, Australia

    Lauren Cowell & Geraldine M. O’Neill

  3. Discipline of Paediatrics and Child Health, The University of Sydney, Sydney, NSW, Australia

    Lauren Cowell & Geraldine M. O’Neill

  4. Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Sachiko Seo

Authors
  1. Mahendra K. Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lauren Cowell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sachiko Seo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Geraldine M. O’Neill
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Erica A. Golemis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Erica A. Golemis.

Additional information

The contribution of Mahendra K. Singh and Lauren Cowell was equivalent.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Singh, M.K., Cowell, L., Seo, S. et al. Molecular basis for HEF1/NEDD9/Cas-L action as a multifunctional co-ordinator of invasion, apoptosis and cell cycle. Cell Biochem Biophys 48, 54–72 (2007). https://doi.org/10.1007/s12013-007-0036-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12013-007-0036-3

Keywords

Search

Navigation