Skip to main content

Advertisement

SpringerLink
Log in

Coordinated dysregulation of cancer progression by the HER family and p21-activated kinases

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Most epithelial cancer types are polygenic in nature and are driven by coordinated dysregulation of multiple regulatory pathways, genes, and protein modifications. The process of coordinated regulation of cancer promoting pathways in response to extrinsic and intrinsic signals facilitates the dysregulation of several pathways with complementary functions, contributing to the hallmarks of cancer. Dysregulation and hyperactivation of cell surface human epidermal growth factor receptors (HERs) and cytoskeleton remodeling by p21-activated kinases (PAKs) are two prominent interconnected aspects of oncogenesis. We briefly discuss the discoveries and significant advances in the area of coordinated regulation of HERs and PAKs in the development and progression of breast and other epithelial cancers. We also discuss how initial studies involving heregulin signaling via HER3-HER2 axis and HER2-overexpressing breast cancer cells not only discovered a mechanistic role of PAK1 in breast cancer pathobiology but also acted as a bridge in generating a broader cancer research interest in other PAK family members and cancer types and catalyzed establishing the role of PAKs in human cancer, at-large. In addition, growth factor stimulation of the PAK pathway also helped to recognize new facets of PAKs, connecting the PAK pathway to oncogenesis, nuclear signaling, gene expression, mitotic progression, DNA damage response, among other phenotypic responses, and shaped the field of PAK cancer research. Finally, we recount some of the current limitations of HER- and PAK-directed therapeutics in counteracting acquired therapeutic resistance and discuss how cancer’s as a polygenic disease may be best targeted with a polygenic approach.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Ghosh, S., Marrocco, I., & Yarden, Y. (2020). Roles for receptor tyrosine kinases in tumor progression and implications for cancer treatment. Advances in Cancer Research, 147, 1–57.

    PubMed  Google Scholar 

  2. Chen, M.-K., Hsu, J. L., & Hung, M.-C. (2020). Nuclear receptor tyrosine kinase transport and functions in cancer. Advances in Cancer Research, 147, 59–107.

    PubMed  Google Scholar 

  3. Kumar, R., George, B., Campbell, M. R., Verma, N., Paul, A. M., Melo-Alvim, C., Ribeiro, L., Pillai, M. R., Marques da Costa, L., & Moasser, M. M. (2020). HER family in cancer progression: From discovery to 2020 and beyond. Advances in Cancer Research, 147, 109–152.

    PubMed  Google Scholar 

  4. Kumar, R., & Mendelsohn, J. (1991). Polypeptide growth factors in the regulation of human tumor cell proliferation. Current Opinion in Oncology, 3(1), 70–74.

    PubMed  CAS  Google Scholar 

  5. Mendelsohn, J. (2000). Blockade of receptors for growth factors: An anticancer therapy - the Fourth Annual Joseph H. Burchenal American Association for Cancer Research Clinical Research Award Lecture. Clinical Cancer Research, 6(3), 747–753.

    PubMed  CAS  Google Scholar 

  6. Kumar, R. (2001). Targeting epidermal growth factor receptor family members for treatment of breast cancer. Biological Therapy of Breast Cancer, 3, 3–6.

    Google Scholar 

  7. Kumar, R., de Vijver, Van, M., Tortora, G., Ciardiello, F., Goldkorn, T., Miller, W. H., & Norton, L. (2019). A tribute to John Mendelsohn: A pioneer in targeted cancer therapy. Cancer Research, 79(17), 4315–4323.

    PubMed  CAS  Google Scholar 

  8. Kumar, R., & Vadlamudi, R. K. (2002). Emerging functions of p21-activated kinases in human cancer cells. Journal of Cellular Physiology, 193(2), 133–144.

    PubMed  CAS  Google Scholar 

  9. Gururaj, A. E., Rayala, S. K., & Kumar, R. (2005). p21-activated kinase signaling in breast cancer. Breast Cancer Research : BCR, 7(1), 5–12.

    PubMed  CAS  Google Scholar 

  10. Kumar, R., Gururaj, A. E., & Barnes, C. J. (2006). p21-activated kinases in cancer. Nature Reviews. Cancer, 6(6), 459–471.

    PubMed  CAS  Google Scholar 

  11. Molli, P. R., Li, D. Q., Murray, B. W., Rayala, S. K., & Kumar, R. (2009). PAK signaling in oncogenesis. Oncogene, 28(28), 2545–2555.

    PubMed  PubMed Central  CAS  Google Scholar 

  12. Kumar, R., & Li, D.-Q. (2016). PAKs in human Cancer progression: From inception to cancer therapeutic to future oncobiology. Advances in Cancer Research, 130, 137–209.

    PubMed  CAS  Google Scholar 

  13. Kumar, R., Sanawar, R., Li, X., & Li, F. (2017). Structure, biochemistry, and biology of PAK kinases. Gene, 605, 20–31.

    PubMed  CAS  Google Scholar 

  14. Cohen, S. (1962). Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new-born animal. The Journal of Biological Chemistry, 237, 1555–1562.

    PubMed  CAS  Google Scholar 

  15. Carpenter, G., King Jr., L., & Cohen, S. (1978). Epidermal growth factor stimulates phosphorylation in membrane preparations in vitro. Nature, 276(5686), 409–410.

    PubMed  CAS  Google Scholar 

  16. Carpenter, G., King Jr., L., & Cohen, S. (1979). Rapid enhancement of protein phosphorylation in A-431 cell membrane preparations by epidermal growth factor. The Journal of Biological Chemistry, 254(11), 4884–4891.

    PubMed  CAS  Google Scholar 

  17. Cohen, S., Carpenter, G., & King Jr., L. (1980). Epidermal growth factor-receptor-protein kinase interactions. Co-purification of receptor and epidermal growth factor-enhanced phosphorylation activity. The Journal of Biological Chemistry, 255(10), 4834–4842.

    PubMed  CAS  Google Scholar 

  18. Semba, K., Kamata, N., Toyoshima, K., & Yamamoto, T. (1985). A v-erbB-related protooncogene, c-erbB-2, is distinct from the c-erbB-1/epidermal growth factor-receptor gene and is amplified in a human salivary gland adenocarcinoma. Proceedings of the National Academy of Sciences of the United States of America, 82(19), 6497–6501.

    PubMed  PubMed Central  CAS  Google Scholar 

  19. Schechter, A. L., Hung, M. C., Vaidyanathan, L., Weinberg, R. A., Yang-Feng, T. L., Francke, U., et al. (1985). The neu gene: An erbB-homologous gene distinct from and unlinked to the gene encoding the EGF receptor. Science (New York, N.Y.), 229(4717), 976–978.

    CAS  Google Scholar 

  20. Hung, M. C., Schechter, A. L., Chevray, P. Y., Stern, D. F., & Weinberg, R. A. (1986). Molecular cloning of the neu gene: Absence of gross structural alteration in oncogenic alleles. Proceedings of the National Academy of Sciences of the United States of America, 83(2), 261–264.

    PubMed  PubMed Central  CAS  Google Scholar 

  21. van de Vijver, M. J., Peterse, J. L., Mooi, W. J., Wisman, P., Lomans, J., Dalesio, O., & Nusse, R. (1988). Neu-protein overexpression in breast cancer. Association with comedo-type ductal carcinoma in situ and limited prognostic value in stage II breast cancer. The New England Journal of Medicine, 319(19), 1239–1245.

    PubMed  Google Scholar 

  22. Slamon, D. J., Godolphin, W., Jones, L. A., Holt, J. A., Wong, S. G., Keith, D. E., et al. (1989). Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science (New York, N.Y.), 244(4905), 707–712.

    CAS  Google Scholar 

  23. Kraus, M. H., Issing, W., Miki, T., Popescu, N. C., & Aaronson, S. A. (1989). Isolation and characterization of ERBB3, a third member of the ERBB/epidermal growth factor receptor family: Evidence for overexpression in a subset of human mammary tumors. Proceedings of the National Academy of Sciences of the United States of America, 86(23), 9193–9197.

    PubMed  PubMed Central  CAS  Google Scholar 

  24. Plowman, G. D., Whitney, G. S., Neubauer, M. G., Green, J. M., McDonald, V. L., Todaro, G. J., & Shoyab, M. (1990). Molecular cloning and expression of an additional epidermal growth factor receptor-related gene. Proceedings of the National Academy of Sciences of the United States of America, 87(13), 4905–4909.

    PubMed  PubMed Central  CAS  Google Scholar 

  25. Plowman, G. D., Culouscou, J. M., Whitney, G. S., Green, J. M., Carlton, G. W., Foy, L., et al. (1993). Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family. Proceedings of the National Academy of Sciences of the United States of America, 90(5), 1746–1750.

    PubMed  PubMed Central  CAS  Google Scholar 

  26. Earp 3rd, H. S., Calvo, B. F., & Sartor, C. I. (2003). The EGF receptor family--multiple roles in proliferation, differentiation, and neoplasia with an emphasis on HER4. Transactions of the American Clinical and Climatological Association, 114, 315–334.

    PubMed  PubMed Central  Google Scholar 

  27. Jones, F. E. (2008). HER4 intracellular domain (4ICD) activity in the developing mammary gland and breast cancer. Journal of Mammary Gland Biology and Neoplasia, 13(2), 247–258.

    PubMed  PubMed Central  Google Scholar 

  28. Pines, G., Köstler, W. J., & Yarden, Y. (2010). Oncogenic mutant forms of EGFR: Lessons in signal transduction and targets for cancer therapy. FEBS Letters, 584(12), 2699–2706.

    PubMed  PubMed Central  CAS  Google Scholar 

  29. Paez, J. G., Jänne, P. A., Lee, J. C., Tracy, S., Greulich, H., Gabriel, S., et al. (2004). EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science (New York, N.Y.), 304(5676), 1497–1500.

    CAS  Google Scholar 

  30. Carey, K. D., Garton, A. J., Romero, M. S., Kahler, J., Thomson, S., Ross, S., et al. (2006). Kinetic analysis of epidermal growth factor receptor somatic mutant proteins shows increased sensitivity to the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib. Cancer Research, 66(16), 8163–8171.

    PubMed  CAS  Google Scholar 

  31. Zhang, K., Cui, J., Xi, H., Bian, S., Ma, L., Shen, W., et al. (2015). Serum HER2 is a potential surrogate for tissue HER2 status in gastric cancer: A systematic review and meta-analysis. PLoS One, 10(8), e0136322–e0136322.

    PubMed  PubMed Central  Google Scholar 

  32. Robichaux, J. P., Elamin, Y. Y., Vijayan, R. S. K., Nilsson, M. B., Hu, L., He, J., et al. (2019). Pan-cancer landscape and analysis of ERBB2 mutations identifies poziotinib as a clinically active inhibitor and enhancer of T-DM1 activity. Cancer Cell, 36(4), 444–457.e7.

    PubMed  CAS  Google Scholar 

  33. Wang, Z. (2017). ErbB receptors and cancer. Methods in Molecular Biology (Clifton, N.J.), 1652, 3–35.

    CAS  Google Scholar 

  34. Baulida, J., Kraus, M. H., Alimandi, M., Di Fiore, P. P., & Carpenter, G. (1996). All ErbB receptors other than the epidermal growth factor receptor are endocytosis impaired. The Journal of Biological Chemistry, 271(9), 5251–5257.

    PubMed  CAS  Google Scholar 

  35. Haslekås, C., Breen, K., Pedersen, K. W., Johannessen, L. E., Stang, E., & Madshus, I. H. (2005). The inhibitory effect of ErbB2 on epidermal growth factor-induced formation of clathrin-coated pits correlates with retention of epidermal growth factor receptor-ErbB2 oligomeric complexes at the plasma membrane. Molecular Biology of the Cell, 16(12), 5832–5842.

    PubMed  PubMed Central  Google Scholar 

  36. Sorkin, A., & von Zastrow, M. (2009). Endocytosis and signalling: Intertwining molecular networks. Nature Reviews. Molecular and Cellular Biology, 10(9), 609–622.

  37. Pedersen, N. M., Madshus, I. H., Haslekås, C., & Stang, E. (2008). Geldanamycin-induced down-regulation of ErbB2 from the plasma membrane is clathrin dependent but proteasomal activity independent. Molecular Cancer Research : MCR, 6(3), 491–500.

    PubMed  CAS  Google Scholar 

  38. Peschard, P., & Park, M. (2003). Escape from Cbl-mediated downregulation: A recurrent theme for oncogenic deregulation of receptor tyrosine kinases. Cancer Cell, 3(6), 519–523.

    PubMed  CAS  Google Scholar 

  39. Pietilä, M., Sahgal, P., Peuhu, E., Jäntti, N. Z., Paatero, I., Närvä, E., et al. (2019). SORLA regulates endosomal trafficking and oncogenic fitness of HER2. Nature Communications, 10(1), 2340.

    PubMed  PubMed Central  Google Scholar 

  40. Wiley, H. S. (2003). Trafficking of the ErbB receptors and its influence on signaling. Experimental Cell Research, 284(1), 78–88.

    PubMed  CAS  Google Scholar 

  41. Waterman, H., Alroy, I., Strano, S., Seger, R., & Yarden, Y. (1999). The C-terminus of the kinase-defective neuregulin receptor ErbB-3 confers mitogenic superiority and dictates endocytic routing. The EMBO Journal, 18(12), 3348–3358.

    PubMed  PubMed Central  CAS  Google Scholar 

  42. Stern, D. F., & Kamps, M. P. (1988). EGF-stimulated tyrosine phosphorylation of p185neu: A potential model for receptor interactions. The EMBO Journal, 7(4), 995–1001.

    PubMed  PubMed Central  CAS  Google Scholar 

  43. King, C. R., Borrello, I., Bellot, F., Comoglio, P., & Schlessinger, J. (1988). Egf binding to its receptor triggers a rapid tyrosine phosphorylation of the erbB-2 protein in the mammary tumor cell line SK-BR-3. The EMBO Journal, 7(6), 1647–1651.

    PubMed  PubMed Central  CAS  Google Scholar 

  44. Wada, T., Qian, X. L., & Greene, M. I. (1990). Intermolecular association of the p185neu protein and EGF receptor modulates EGF receptor function. Cell, 61(7), 1339–1347.

    PubMed  CAS  Google Scholar 

  45. Goldman, R., Levy, R. B., Peles, E., & Yarden, Y. (1990). Heterodimerization of the erbB-1 and erbB-2 receptors in human breast carcinoma cells: A mechanism for receptor transregulation. Biochemistry, 29(50), 11024–11028.

    PubMed  CAS  Google Scholar 

  46. Ferguson, K. M. (2008). Structure-based view of epidermal growth factor receptor regulation. Annual Review of Biophysics, 37, 353–373.

    PubMed  PubMed Central  CAS  Google Scholar 

  47. Linggi, B., & Carpenter, G. (2006). ErbB receptors: New insights on mechanisms and biology. Trends in Cell Biology, 16(12), 649–656.

    PubMed  CAS  Google Scholar 

  48. Jones, R. B., Gordus, A., Krall, J. A., & MacBeath, G. (2006). A quantitative protein interaction network for the ErbB receptors using protein microarrays. Nature, 439(7073), 168–174.

    PubMed  CAS  Google Scholar 

  49. Schulze, W. X., Deng, L., & Mann, M. (2005). Phosphotyrosine interactome of the ErbB-receptor kinase family. Molecular Systems Biology, 1, 2005.0008–2005.0008.

    PubMed  PubMed Central  Google Scholar 

  50. Sweeney, C., Fambrough, D., Huard, C., Diamonti, A. J., Lander, E. S., Cantley, L. C., & Carraway 3rd, K. L. (2001). Growth factor-specific signaling pathway stimulation and gene expression mediated by ErbB receptors. The Journal of Biological Chemistry, 276(25), 22685–22698.

    PubMed  CAS  Google Scholar 

  51. Kawamoto, T., Sato, J. D., Le, A., Polikoff, J., Sato, G. H., & Mendelsohn, J. (1983). Growth stimulation of A431 cells by epidermal growth factor: Identification of high-affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody. Proceedings of the National Academy of Sciences of the United States of America, 80(5), 1337–1341.

    PubMed  PubMed Central  CAS  Google Scholar 

  52. Van de Vijver, M. J., Kumar, R., & Mendelsohn, J. (1991). Ligand-induced activation of A431 cell epidermal growth factor receptors occurs primarily by an autocrine pathway that acts upon receptors on the surface rather than intracellularly. The Journal of Biological Chemistry, 266(12), 7503–7508.

    PubMed  Google Scholar 

  53. Mendelsohn, J. (2000). Jeremiah Metzger Lecture. Targeted cancer therapy. Transactions of the American Clinical and Climatological Association, 111, 95–111.

    PubMed  PubMed Central  CAS  Google Scholar 

  54. Mendelsohn, J., Prewett, M., Rockwell, P., & Goldstein, N. I. (2015). CCR 20th anniversary commentary: A chimeric antibody, C225, inhibits EGFR activation and tumor growth. In Clinical cancer research : An official journal of the American Association for Cancer Research. United: States.

    Google Scholar 

  55. Kumar, R., Murad, F., Bogler, O., O’Malley, B. W., & Hortobagyi, G. N. (2019). John Mendelsohn: A visionary scientist, oncologist and leader. Genes & Cancer, 10(5–6), 109–118.

    CAS  Google Scholar 

  56. Lupu, R., Colomer, R., Zugmaier, G., Sarup, J., Shepard, M., Slamon, D., & Lippman, M. E. (1990). Direct interaction of a ligand for the erbB2 oncogene product with the EGF receptor and p185erbB2. Science (New York, N.Y.), 249(4976), 1552–1555.

    CAS  Google Scholar 

  57. Kumar, R., Shepard, H. M., & Mendelsohn, J. (1991). Regulation of phosphorylation of the c-erbB-2/HER2 gene product by a monoclonal antibody and serum growth factor(s) in human mammary carcinoma cells. Molecular and Cellular Biology, 11(2), 979–986.

    PubMed  PubMed Central  CAS  Google Scholar 

  58. Carter, P., Presta, L., Gorman, C. M., Ridgway, J. B., Henner, D., Wong, W. L., et al. (1992). Humanization of an anti-p185HER2 antibody for human cancer therapy. Proceedings of the National Academy of Sciences of the United States of America, 89(10), 4285–4289.

    PubMed  PubMed Central  CAS  Google Scholar 

  59. Baselga, J., Tripathy, D., Mendelsohn, J., Baughman, S., Benz, C. C., Dantis, L., et al. (1999). Phase II study of weekly intravenous trastuzumab (Herceptin) in patients with HER2/neu-overexpressing metastatic breast cancer. Seminars in Oncology, 26(4 Suppl 12), 78–83.

    PubMed  CAS  Google Scholar 

  60. Adam, L., Vadlamudi, R., Kondapaka, S. B., Chernoff, J., Mendelsohn, J., & Kumar, R. (1998). Heregulin regulates cytoskeletal reorganization and cell migration through the p21-activated kinase-1 via phosphatidylinositol-3 kinase. The Journal of Biological Chemistry, 273(43), 28238–28246.

    PubMed  CAS  Google Scholar 

  61. Kumar, R. (2007). ErbB-dependent signaling as a determinant of trastuzumab resistance. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 13(16), 4657–4659.

    CAS  Google Scholar 

  62. Mills, G. B., & Yarden, Y. (2010). The rebirth of a phoenix: Ovarian cancers are addicted to ErbB-3. Cancer Cell, 17(3), 217–218.

    PubMed  CAS  Google Scholar 

  63. Morrison, M. M., Hutchinson, K., Williams, M. M., Stanford, J. C., Balko, J. M., Young, C., et al. (2013). ErbB3 downregulation enhances luminal breast tumor response to antiestrogens. The Journal of Clinical Investigation, 123(10), 4329–4343.

    PubMed  PubMed Central  CAS  Google Scholar 

  64. Wang, S., Huang, J., Lyu, H., Lee, C.-K., Tan, J., Wang, J., & Liu, B. (2013). Functional cooperation of miR-125a, miR-125b, and miR-205 in entinostat-induced downregulation of erbB2/erbB3 and apoptosis in breast cancer cells. Cell Death & Disease, 4(3), e556–e556.

    CAS  Google Scholar 

  65. Li, X., Xu, Y., Ding, Y., Li, C., Zhao, H., Wang, J., & Meng, S. (2018). Posttranscriptional upregulation of HER3 by HER2 mRNA induces trastuzumab resistance in breast cancer. Molecular Cancer, 17(1), 113.

    PubMed  PubMed Central  Google Scholar 

  66. Kennedy, S. P., Han, J. Z. R., Portman, N., Nobis, M., Hastings, J. F., Murphy, K. J., et al. (2019). Targeting promiscuous heterodimerization overcomes innate resistance to ERBB2 dimerization inhibitors in breast cancer. Breast Cancer Research, 21(1), 43.

    PubMed  Google Scholar 

  67. Cytoskeleton Signaling in Cancer, Editors - Kumar, R. and Hall, A. (2009). Cancer. Metastasis Reviews, 28(1–2), 1–263.

  68. Manser, E., Leung, T., Salihuddin, H., Zhao, Z. S., & Lim, L. (1994). A brain serine/threonine protein kinase activated by Cdc42 and Rac1. Nature, 367(6458), 40–46.

    PubMed  CAS  Google Scholar 

  69. Galisteo, M. L., Chernoff, J., Su, Y. C., Skolnik, E. Y., & Schlessinger, J. (1996). The adaptor protein Nck links receptor tyrosine kinases with the serine-threonine kinase Pak1. The Journal of Biological Chemistry, 271(35), 20997–201000.

    PubMed  CAS  Google Scholar 

  70. Bekri, S., Adélaïde, J., Merscher, S., Grosgeorge, J., Caroli-Bosc, F., Perucca-Lostanlen, D., et al. (1997). Detailed map of a region commonly amplified at 11q13➔q14 in human breast carcinoma. Cytogenet Cell Genet., 79(1–2), 125–131. Methods in Molecular Biology. N.J: Clifton.

    Google Scholar 

  71. Adam, L., Vadlamudi, R., Mandal, M., Chernoff, J., & Kumar, R. (2000). Regulation of microfilament reorganization and invasiveness of breast cancer cells by kinase dead p21-activated kinase-1. The Journal of Biological Chemistry., 275(16), 12041–12050.

    PubMed  CAS  Google Scholar 

  72. Vadlamudi, R. K., Adam, L., Wang, R. A., Mandal, M., Nguyen, D., Sahin, A., et al. (2000). Regulatable expression of p21-activated kinase-1 promotes anchorage-independent growth and abnormal organization of mitotic spindles in human epithelial breast cancer cells. The Journal of Biological Chemistry, 275(46), 36238–36244.

    PubMed  CAS  Google Scholar 

  73. Bagheri-Yarmand, R., Mandal, M., Taludker, A. H., Wang, R. A., Vadlamudi, R. K., Kung, H. J., & Kumar, R. (2001). Etk/Bmx tyrosine kinase activates Pak1 and regulates tumorigenicity of breast cancer cells. The Journal of Biological Chemistry., 276(31), 29403–29409.

    PubMed  CAS  Google Scholar 

  74. Oladimeji, P., Skerl, R., Rusch, C., & Diakonova, M. (2016). Synergistic activation of ERα by estrogen and prolactin in breast cancer cells requires tyrosyl phosphorylation of PAK1. Cancer Research, 76(9), 2600–2611.

    PubMed  PubMed Central  CAS  Google Scholar 

  75. Li, F., Adam, L., Vadlamudi, R. K., Zhou, H., Sen, S., Chernoff, J., & Kumar, R. (2002). p21-activated kinase 1 interacts with and phosphorylates histone H3 in breast cancer cells. EMBO Reports, 3(8), 767–773.

    PubMed  PubMed Central  CAS  Google Scholar 

  76. Singh, R. R., Song, C., Yang, Z., & Kumar, R. (2005). Nuclear localization and chromatin targets of p21-activated kinase 1. The Journal of Biological Chemistry, 280(18), 18130–18137.

    PubMed  CAS  Google Scholar 

  77. Cotteret, S., & Chernoff, J. (2005). Pak GITs to Aurora-A. Developmental Cell, 9(5), 573–574.

    PubMed  CAS  Google Scholar 

  78. Wang, R.-A., Vadlamudi, R. K., Bagheri-Yarmand, R., Beuvink, I., Hynes, N. E., & Kumar, R. (2003). Essential functions of p21-activated kinase 1 in morphogenesis and differentiation of mammary glands. The Journal of Cell Biology, 161(3), 583–592.

    PubMed  PubMed Central  CAS  Google Scholar 

  79. Wang, R.-A., Mazumdar, A., Vadlamudi, R. K., & Kumar, R. (2002). P21-activated kinase-1 phosphorylates and transactivates estrogen receptor-alpha and promotes hyperplasia in mammary epithelium. The EMBO Journal, 21(20), 5437–5447.

    PubMed  PubMed Central  CAS  Google Scholar 

  80. Wang, R.-A., Zhang, H., Balasenthil, S., Medina, D., & Kumar, R. (2006). PAK1 hyperactivation is sufficient for mammary gland tumor formation. Oncogene, 25(20), 2931–2936.

    PubMed  CAS  Google Scholar 

  81. Holm, C., Rayala, S., Jirström, K., Stål, O., Kumar, R., & Landberg, G. (2006). Association between Pak1 expression and subcellular localization and tamoxifen resistance in breast cancer patients. Journal of the National Cancer Institute, 98(10), 671–680.

    PubMed  CAS  Google Scholar 

  82. Rayala, S. K., Molli, P. R., & Kumar, R. (2006). Nuclear p21-activated kinase 1 in breast cancer packs off tamoxifen sensitivity. Cancer Research, 66(12), 5985–5988.

    PubMed  CAS  Google Scholar 

  83. Jordan, V. C. (2006). Pak up your breast tumor--and grow! Journal of the National Cancer. United States: Institute.

    Google Scholar 

  84. Kumar, R., & Hung, M.-C. (2005). Signaling intricacies take center stage in cancer cells. Cancer Research, 65(7), 2511–2515.

    PubMed  CAS  Google Scholar 

  85. Kumar, R., Deivendran, S., Santhosh Kumar, T. R., & Pillai, M. R. (2017). Signaling coupled epigenomic regulation of gene expression. Oncogene, 36(43), 5917–5926.

    PubMed  CAS  Google Scholar 

  86. Balasenthil, S., Barnes, C. J., Rayala, S. K., & Kumar, R. (2004). Estrogen receptor activation at serine 305 is sufficient to upregulate cyclin D1 in breast cancer cells. FEBS Letters, 567(2–3), 243–247.

  87. Balasenthil, S., Sahin, A. A., Barnes, C. J., Wang, R.-A., Pestell, R. G., Vadlamudi, R. K., & Kumar, R. (2004). p21-activated kinase-1 signaling mediates cyclin D1 expression in mammary epithelial and cancer cells. The Journal of Biological Chemistry, 279(2), 1422–1428.

    PubMed  CAS  Google Scholar 

  88. Tharakan, R., Lepont, P., Singleton, D., Kumar, R., & Khan, S. (2008). Phosphorylation of estrogen receptor alpha, serine residue 305 enhances activity. Molecular and Cellular Endocrinology, 295(1–2), 70–78.

    PubMed  CAS  Google Scholar 

  89. Rayala, S. K., Talukder, A. H., Balasenthil, S., Tharakan, R., Barnes, C. J., Wang, R.-A., et al. (2006). P21-activated kinase 1 regulation of estrogen receptor-alpha activation involves serine 305 activation linked with serine 118 phosphorylation. Cancer Research, 66(3), 1694–1701.

    PubMed  CAS  Google Scholar 

  90. Curtis, C., Shah, S. P., Chin, S.-F., Turashvili, G., Rueda, O. M., Dunning, M. J., et al. (2012). The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature, 486(7403), 346–352.

    PubMed  PubMed Central  CAS  Google Scholar 

  91. Mertins, P., Mani, D. R., Ruggles, K. V, Gillette, M. A., Clauser, K. R., Wang, P., et al. (2016). Proteogenomics connects somatic mutations to signalling in breast cancer. Nature, 534(7605), 55–62.

  92. Vadlamudi, R. K., Li, F., Barnes, C. J., Bagheri-Yarmand, R., & Kumar, R. (2004). p41-Arc subunit of human Arp2/3 complex is a p21-activated kinase-1-interacting substrate. EMBO Reports, 5(2), 154–160.

    PubMed  PubMed Central  CAS  Google Scholar 

  93. Molli, P. R., Li, D.-Q., Bagheri-Yarmand, R., Pakala, S. B., Katayama, H., Sen, S., et al. (2010). Arpc1b, a centrosomal protein, is both an activator and substrate of Aurora A. The Journal of Cell Biology, 190(1), 101–114.

    PubMed  PubMed Central  CAS  Google Scholar 

  94. Sánchez-Solana, B., Motwani, M., Li, D.-Q., Eswaran, J., & Kumar, R. (2012). p21-activated kinase-1 signaling regulates transcription of tissue factor and tissue factor pathway inhibitor. The Journal of Biological Chemistry, 287(47), 39291–39302.

    PubMed  PubMed Central  Google Scholar 

  95. Callow, M. G., Clairvoyant, F., Zhu, S., Schryver, B., Whyte, D. B., Bischoff, J. R., et al. (2002). Requirement for PAK4 in the anchorage-independent growth of human cancer cell lines. The Journal of Biological Chemistry, 277(1), 550–558.

    PubMed  CAS  Google Scholar 

  96. Gong, W., An, Z., Wang, Y., Pan, X., Fang, W., Jiang, B., & Zhang, H. (2009). P21-activated kinase 5 is overexpressed during colorectal cancer progression and regulates colorectal carcinoma cell adhesion and migration. International Journal of Cancer, 125(3), 548–555.

    PubMed  CAS  Google Scholar 

  97. Lee, S. R., Ramos, S. M., Ko, A., Masiello, D., Swanson, K. D., Lu, M. L., & Balk, S. P. (2002). AR and ER interaction with a p21-activated kinase (PAK6). Molecular Endocrinology (Baltimore, Md.), 16(1), 85–99.

    CAS  Google Scholar 

  98. Heiser, L. M., Wang, N. J., Talcott, C. L., Laderoute, K. R., Knapp, M., Guan, Y., et al. (2009). Integrated analysis of breast cancer cell lines reveals unique signaling pathways. Genome Biology, 10(3), R31.

    PubMed  PubMed Central  Google Scholar 

  99. Shrestha, Y., Schafer, E. J., Boehm, J. S., Thomas, S. R., He, F., Du, J., et al. (2012). PAK1 is a breast cancer oncogene that coordinately activates MAPK and MET signaling. Oncogene, 31(29), 3397–3408.

    PubMed  CAS  Google Scholar 

  100. Arias-Romero, L. E., Villamar-Cruz, O., Pacheco, A., Kosoff, R., Huang, M., Muthuswamy, S. K., et al. (2010). A Rac-Pak signaling pathway is essential for ErbB2-mediated transformation of human breast epithelial cancer cells. Oncogene, 29(43), 5839–5849.

    PubMed  PubMed Central  CAS  Google Scholar 

  101. Liu, Y., Chen, N., Cui, X., Zheng, X., Deng, L., Price, S., et al. (2010). The protein kinase Pak4 disrupts mammary acinar architecture and promotes mammary tumorigenesis. Oncogene, 29(44), 5883–5894.

    PubMed  PubMed Central  CAS  Google Scholar 

  102. Puto, L. A., Pestonjamasp, K., King, C. C., & Bokoch, G. M. (2003). p21-activated kinase 1 (PAK1) interacts with the Grb2 adapter protein to couple to growth factor signaling. The Journal of Biological Chemistry, 278(11), 9388–9393.

    PubMed  CAS  Google Scholar 

  103. Ohshiro, K., Bui-Nguyen, T. M., Divijendra Natha, R. S., Schwartz, A. M., Levine, P., & Kumar, R. (2012). Thrombin stimulation of inflammatory breast cancer cells leads to aggressiveness via the EGFR-PAR1-Pak1 pathway. The International Journal of Biological Markers, 27(4), e305–e313.

    PubMed  PubMed Central  CAS  Google Scholar 

  104. Long, W., Yi, P., Amazit, L., LaMarca, H. L., Ashcroft, F., Kumar, R., et al. (2010). SRC-3Delta4 mediates the interaction of EGFR with FAK to promote cell migration. Molecular Cell, 37(3), 321–332.

    PubMed  PubMed Central  CAS  Google Scholar 

  105. Ueda, Y., Wang, S., Dumont, N., Yi, J. Y., Koh, Y., & Arteaga, C. L. (2004). Overexpression of HER2 (erbB2) in human breast epithelial cells unmasks transforming growth factor beta-induced cell motility. The Journal of Biological Chemistry, 279(23), 24505–24513.

    PubMed  CAS  Google Scholar 

  106. Vadlamudi, R. K., Li, F., Adam, L., Nguyen, D., Ohta, Y., Stossel, T. P., & Kumar, R. (2002). Filamin is essential in actin cytoskeletal assembly mediated by p21-activated kinase 1. Nature Cell Biology, 4(9), 681–690.

    PubMed  CAS  Google Scholar 

  107. Wang, S. E., Shin, I., Wu, F. Y., Friedman, D. B., & Arteaga, C. L. (2006). HER2/Neu (ErbB2) signaling to Rac1-Pak1 is temporally and spatially modulated by transforming growth factor beta. Cancer Research, 66(19), 9591–9600.

    PubMed  CAS  Google Scholar 

  108. Rafn, B., Nielsen, C. F., Andersen, S. H., Szyniarowski, P., Corcelle-Termeau, E., Valo, E., et al. (2012). ErbB2-driven breast cancer cell invasion depends on a complex signaling network activating myeloid zinc finger-1-dependent cathepsin B expression. Molecular Cell, 45(6), 764–776.

    PubMed  CAS  Google Scholar 

  109. Brix, D. M., Tvingsholm, S. A., Hansen, M. B., Clemmensen, K. B., Ohman, T., Siino, V., et al. (2019). Release of transcriptional repression via ErbB2-induced, SUMO-directed phosphorylation of myeloid zinc finger-1 serine 27 activates lysosome redistribution and invasion. Oncogene, 38(17), 3170–3184.

    PubMed  PubMed Central  CAS  Google Scholar 

  110. Motwani, M., Li, D.-Q., Horvath, A., & Kumar, R. (2013). Identification of novel gene targets and functions of p21-activated kinase 1 during DNA damage by gene expression profiling. PLoS One, 8(8), e66585.

    PubMed  PubMed Central  CAS  Google Scholar 

  111. Berger, A., Hoelbl-Kovacic, A., Bourgeais, J., Hoefling, L., Warsch, W., Grundschober, E., et al. (2014). PAK-dependent STAT5 serine phosphorylation is required for BCR-ABL-induced leukemogenesis. Leukemia, 28(3), 629–641.

    PubMed  CAS  Google Scholar 

  112. Chatterjee, A., Ghosh, J., Ramdas, B., Mali, R. S., Martin, H., Kobayashi, M., et al. (2014). Regulation of Stat5 by FAK and PAK1 in oncogenic FLT3- and KIT-driven leukemogenesis. Cell Reports, 9(4), 1333–1348.

    PubMed  PubMed Central  CAS  Google Scholar 

  113. Meng, Q., Rayala, S. K., Gururaj, A. E., Talukder, A. H., O’Malley, B. W., & Kumar, R. (2007). Signaling-dependent and coordinated regulation of transcription, splicing, and translation resides in a single coregulator, PCBP1. Proceedings of the National Academy of Sciences of the United States of America, 104(14), 5866–5871.

    PubMed  PubMed Central  CAS  Google Scholar 

  114. Li, Y., Shao, Y., Tong, Y., Shen, T., Zhang, J., Li, Y., et al. (2012). Nucleo-cytoplasmic shuttling of PAK4 modulates β-catenin intracellular translocation and signaling. Biochimica et Biophysica Acta, 1823(2), 465–475.

    PubMed  CAS  Google Scholar 

  115. Oladimeji, P., & Diakonova, M. (2016). PAK1 translocates into nucleus in response to prolactin but not to estrogen. Biochemical and Biophysical Research Communications, 473(1), 206–211.

    PubMed  PubMed Central  CAS  Google Scholar 

  116. Pérez-Yépez, E. A., Saldívar-Cerón, H. I., Villamar-Cruz, O., Pérez-Plasencia, C., & Arias-Romero, L. E. (2018). p21 activated kinase 1: Nuclear activity and its role during DNA damage repair. DNA Repair, 65, 42–46.

    PubMed  Google Scholar 

  117. Siu, M. K. Y., Kong, D. S. H., Ngai, S. Y. P., Chan, H. Y., Jiang, L., Wong, E. S. Y., et al. (2015). p21-activated kinases 1, 2 and 4 in endometrial cancers: Effects on clinical outcomes and cell proliferation. PLoS One, 10(7), e0133467.

    PubMed  PubMed Central  Google Scholar 

  118. Zhu, G., Wang, Y., Huang, B., Liang, J., Ding, Y., Xu, A., & Wu, W. (2012). A Rac1/PAK1 cascade controls β-catenin activation in colon cancer cells. Oncogene, 31(8), 1001–1012.

    PubMed  CAS  Google Scholar 

  119. Park, M.-H., Kim, D.-J., You, S.-T., Lee, C.-S., Kim, H. K., Park, S. M., et al. (2012). Phosphorylation of β-catenin at serine 663 regulates its transcriptional activity. Biochemical and Biophysical Research Communications, 419(3), 543–549.

    PubMed  CAS  Google Scholar 

  120. Ding, Q., Xia, W., Liu, J.-C., Yang, J.-Y., Lee, D.-F., Xia, J., et al. (2005). Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin. Molecular Cell, 19(2), 159–170.

    PubMed  CAS  Google Scholar 

  121. Arias-Romero, L. E., Villamar-Cruz, O., Huang, M., Hoeflich, K. P., & Chernoff, J. (2013). Pak1 kinase links ErbB2 to β-catenin in transformation of breast epithelial cells. Cancer Research, 73(12), 3671–3682.

    PubMed  PubMed Central  CAS  Google Scholar 

  122. Adam, L., Vadlamudi, R. K., McCrea, P., & Kumar, R. (2001). Tiam1 overexpression potentiates heregulin-induced lymphoid enhancer factor-1/beta -catenin nuclear signaling in breast cancer cells by modulating the intercellular stability. The Journal of Biological Chemistry, 276(30), 28443–28450.

    PubMed  CAS  Google Scholar 

  123. Bagheri-Yarmand, R., Vadlamudi, R. K., Wang, R. A., Mendelsohn, J., & Kumar, R. (2000). Vascular endothelial growth factor up-regulation via p21-activated kinase-1 signaling regulates heregulin-beta1-mediated angiogenesis. The Journal of Biological Chemistry, 275(50), 39451–39457.

    PubMed  CAS  Google Scholar 

  124. Barnes, C. J., Vadlamudi, R. K., Mishra, S. K., Jacobson, R. H., Li, F., & Kumar, R. (2003). Functional inactivation of a transcriptional corepressor by a signaling kinase. Nature Structural Biology, 10(8), 622–628.

    PubMed  CAS  Google Scholar 

  125. Thomas, J.-L., Moncollin, V., Ravel-Chapuis, A., Valente, C., Corda, D., Méjat, A., & Schaeffer, L. (2015). PAK1 and CtBP1 regulate the coupling of neuronal activity to muscle chromatin and gene expression. Molecular and Cellular Biology, 35(24), 4110–4120.

    PubMed  PubMed Central  CAS  Google Scholar 

  126. Yang, Z., Rayala, S., Nguyen, D., Vadlamudi, R. K., Chen, S., & Kumar, R. (2005). Pak1 phosphorylation of snail, a master regulator of epithelial-to-mesenchyme transition, modulates snail’s subcellular localization and functions. Cancer Research, 65(8), 3179–3184.

    PubMed  CAS  Google Scholar 

  127. Vadlamudi, R. K., Manavathi, B., Singh, R. R., Nguyen, D., Li, F., & Kumar, R. (2005). An essential role of Pak1 phosphorylation of SHARP in Notch signaling. Oncogene, 24(28), 4591–4596.

    PubMed  CAS  Google Scholar 

  128. Roig, J., & Traugh, J. A. (1999). p21-activated protein kinase gamma-PAK is activated by ionizing radiation and other DNA-damaging agents. Similarities and differences to alpha-PAK. The Journal of Biological Chemistry, 274(44), 31119–31122.

    PubMed  CAS  Google Scholar 

  129. Li, D.-Q., Nair, S. S., Ohshiro, K., Kumar, A., Nair, V. S., Pakala, S. B., et al. (2012). MORC2 signaling integrates phosphorylation-dependent, ATPase-coupled chromatin remodeling during the DNA damage response. Cell Reports, 2(6), 1657–1669.

    PubMed  PubMed Central  CAS  Google Scholar 

  130. Advani, S. J., Camargo, M. F., Seguin, L., Mielgo, A., Anand, S., Hicks, A. M., et al. (2015). Kinase-independent role for CRAF-driving tumour radioresistance via CHK2. Nature Communications, 6, 8154.

    PubMed  PubMed Central  Google Scholar 

  131. Millan-Zambrano, G., Santos-Rosa, H., Puddu, F., Robson, S. C., Jackson, S. P., & Kouzarides, T. (2018). Phosphorylation of histone H4T80 triggers DNA damage checkpoint recovery. Molecular Cell, 72(4), 625–635.e4.

    PubMed  PubMed Central  CAS  Google Scholar 

  132. Tsai, C.-F., Wang, Y.-T., Yen, H.-Y., Tsou, C.-C., Ku, W.-C., Lin, P.-Y., et al. (2015). Large-scale determination of absolute phosphorylation stoichiometries in human cells by motif-targeting quantitative proteomics. Nature Communications, 6, 6622.

    PubMed  PubMed Central  CAS  Google Scholar 

  133. Parker, B. L., Yang, G., Humphrey, S. J., Chaudhuri, R., Ma, X., Peterman, S., & James, D. E. (2015). Targeted phosphoproteomics of insulin signaling using data-independent acquisition mass spectrometry. Science Signaling, 8(380), rs6. https://doi.org/10.1126/scisignal.aaa3139.

    Article  PubMed  CAS  Google Scholar 

  134. Chen, T., Wang, T., Liang, W., Zhao, Q., Yu, Q., Ma, C.-M., et al. (2019). PAK4 phosphorylates fumarase and blocks TGFβ-induced cell growth arrest in lung cancer cells. Cancer Research, 79(7), 1383–1397.

    PubMed  CAS  Google Scholar 

  135. Jiang, Y., Qian, X., Shen, J., Wang, Y., Li, X., Liu, R., et al. (2015). Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation. Nature Cell Biology, 17(9), 1158–1168.

    PubMed  PubMed Central  CAS  Google Scholar 

  136. Sedelnikova, O. A., & Bonner, W. M. (2006). GammaH2AX in cancer cells: a potential biomarker for cancer diagnostics, prediction and recurrence. Cell Cycle (Georgetown, Texas), 5(24), 2909–2913.

    CAS  Google Scholar 

  137. Brustmann, H., Hinterholzer, S., & Brunner, A. (2011). Expression of phosphorylated histone H2AX (γ-H2AX) in normal and neoplastic squamous epithelia of the uterine cervix: An immunohistochemical study with epidermal growth factor receptor. International Journal of Gynecological Pathology : Official Journal of the International Society of Gynecological Pathologists, 30(1), 76–83.

    Google Scholar 

  138. Matthaios, D., Foukas, P. G., Kefala, M., Hountis, P., Trypsianis, G., Panayiotides, I. G., et al. (2012). γ-H2AX expression detected by immunohistochemistry correlates with prognosis in early operable non-small cell lung cancer. Oncotargets and Therapy, 5, 309–314.

    PubMed  PubMed Central  CAS  Google Scholar 

  139. Brunner, A. H., Hinterholzer, S., Riss, P., Heinze, G., Weiss, K., & Brustmann, H. (2011). Expression of γ-H2AX in endometrial carcinomas: An immunohistochemical study with p53. Gynecologic Oncology, 121(1), 206–211.

    PubMed  CAS  Google Scholar 

  140. Nagelkerke, A., van Kuijk, S. J. A., Sweep, F. C. G. J., Nagtegaal, I. D., Hoogerbrugge, N., Martens, J. W. M., et al. (2011). Constitutive expression of γ-H2AX has prognostic relevance in triple negative breast cancer. Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology, 101(1), 39–45.

    CAS  Google Scholar 

  141. Gan, J., Zhang, Y., Ke, X., Tan, C., Ren, H., Dong, H., et al. (2015). Dysregulation of PAK1 is associated with DNA damage and is of prognostic importance in primary esophageal small cell carcinoma. International Journal of Molecular Sciences, 16(6), 12035–12050.

    PubMed  PubMed Central  CAS  Google Scholar 

  142. Qing, H., Gong, W., Che, Y., Wang, X., Peng, L., Liang, Y., et al. (2012). PAK1-dependent MAPK pathway activation is required for colorectal cancer cell proliferation. Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine, 33(4), 985–994.

    CAS  Google Scholar 

  143. Walsh, K., McKinney, M. S., Love, C., Liu, Q., Fan, A., Patel, A., et al. (2013). PAK1 mediates resistance to PI3K inhibition in lymphomas. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 19(5), 1106–1115.

    CAS  Google Scholar 

  144. Zhou, W., Jubb, A. M., Lyle, K., Xiao, Q., Ong, C. C., Desai, R., et al. (2014). PAK1 mediates pancreatic cancer cell migration and resistance to MET inhibition. The Journal of Pathology, 234(4), 502–513.

    PubMed  PubMed Central  CAS  Google Scholar 

  145. Villamar Cruz, O., Prudnikova, T. Y., Araiza-Olivera, D., Perez-Plasencia, C., Johnson, N., Bernhardy, A. J., et al. (2016). Reduced PAK1 activity sensitizes FA/BRCA-proficient breast cancer cells to PARP inhibition. Oncotarget, 7(47), 76590–76603.

    PubMed  Google Scholar 

  146. Fu, X., Feng, J., Zeng, D., Ding, Y., Yu, C., & Yang, B. (2014). PAK4 confers cisplatin resistance in gastric cancer cells via PI3K/Akt- and MEK/ERK-dependent pathways. Bioscience Reports, 34(2). https://doi.org/10.1042/BSR20130102.

  147. Moon, S.-U., Kim, J. W., Sung, J. H., Kang, M. H., Kim, S.-H., Chang, H., et al. (2015). p21-activated kinase 4 (PAK4) as a predictive marker of gemcitabine sensitivity in pancreatic cancer cell lines. Cancer Research and Treatment : Official Journal of Korean Cancer Association, 47(3), 501–508.

    CAS  Google Scholar 

  148. Li, D., Yao, X., & Zhang, P. (2013). The overexpression of P21-activated kinase 5 (PAK5) promotes paclitaxel-chemoresistance of epithelial ovarian cancer. Molecular and Cellular Biochemistry, 383(1–2), 191–199.

    PubMed  CAS  Google Scholar 

  149. He, S., Feng, M., Liu, M., Yang, S., Yan, S., Zhang, W., et al. (2014). P21-activated kinase 7 mediates cisplatin-resistance of esophageal squamous carcinoma cells with Aurora-A overexpression. PLoS One, 9(12), e113989.

    PubMed  PubMed Central  Google Scholar 

  150. Chen, J., Lu, H., Yan, D., Cui, F., Wang, X., Yu, F., et al. (2015). PAK6 increase chemoresistance and is a prognostic marker for stage II and III colon cancer patients undergoing 5-FU based chemotherapy. Oncotarget, 6(1), 355–367.

    PubMed  Google Scholar 

  151. Huynh, N., Shulkes, A., Baldwin, G., & He, H. (2016). Up-regulation of stem cell markers by P21-activated kinase 1 contributes to 5-fluorouracil resistance of colorectal cancer. Cancer Biology & Therapy, 17(8), 813–823.

    CAS  Google Scholar 

  152. Yeo, D., He, H., Patel, O., Lowy, A. M., Baldwin, G. S., & Nikfarjam, M. (2016). FRAX597, a PAK1 inhibitor, synergistically reduces pancreatic cancer growth when combined with gemcitabine. BMC Cancer, 16, 24.

    PubMed  PubMed Central  Google Scholar 

  153. Chang, Y., Park, K. H., Lee, J. E., & Han, K.-C. (2018). Phosphoproteomic analysis reveals PAK2 as a therapeutic target for lapatinib resistance in HER2-positive breast cancer cells. Biochemical and Biophysical Research Communications, 505(1), 187–193.

    PubMed  CAS  Google Scholar 

  154. Flis, S., Bratek, E., Chojnacki, T., Piskorek, M., & Skorski, T. (2019). Simultaneous inhibition of BCR-ABL1 tyrosine kinase and PAK1/2 serine/threonine kinase exerts synergistic effect against chronic myeloid leukemia cells. Cancers, 11(10). https://doi.org/10.3390/cancers11101544.

  155. Korobeynikov, V., Borakove, M., Feng, Y., Wuest, W. M., Koval, A. B., Nikonova, A. S., et al. (2019). Combined inhibition of Aurora A and p21-activated kinase 1 as a new treatment strategy in breast cancer. Breast Cancer Research and Treatment, 177(2), 369–382.

    PubMed  PubMed Central  CAS  Google Scholar 

  156. Khan, H. Y., Ge, J., Nagasaka, M., Aboukameel, A., Mpilla, G., Muqbil, I., et al. (2019). Targeting XPO1 and PAK4 in 8505C anaplastic thyroid cancer cells: Putative implications for overcoming lenvatinib therapy resistance. International Journal of Molecular Sciences, 21(1). https://doi.org/10.3390/ijms21010237.

  157. Mpilla, G., Aboukameel, A., Muqbil, I., Kim, S., Beydoun, R., Philip, P. A., et al. (2019). PAK4-NAMPT dual inhibition as a novel strategy for therapy resistant pancreatic neuroendocrine tumors. Cancers, 11(12). https://doi.org/10.3390/cancers11121902.

  158. Li, N., Lopez, M. A., Linares, M., Kumar, S., Oliva, S., Martinez-Lopez, J., et al. (2019). Dual PAK4-NAMPT inhibition impacts growth and survival, and increases sensitivity to DNA-damaging agents in Waldenström Macroglobulinemia. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 25(1), 369–377.

    CAS  Google Scholar 

  159. Zhang, M., Siedow, M., Saia, G., & Chakravarti, A. (2010). Inhibition of p21-activated kinase 6 (PAK6) increases radiosensitivity of prostate cancer cells. The Prostate, 70(8), 807–816.

    PubMed  PubMed Central  CAS  Google Scholar 

  160. Wang, K., Huynh, N., Wang, X., Pajic, M., Parkin, A., Man, J., et al. (2019). PAK inhibition by PF-3758309 enhanced the sensitivity of multiple chemotherapeutic reagents in patient-derived pancreatic cancer cell lines. American Journal of Translational Research, 11(6), 3353–3364.

    PubMed  PubMed Central  CAS  Google Scholar 

  161. Abril-Rodriguez, G., Torrejon, D. Y., Liu, W., et al. (2020). PAK4 inhibition improves PD-1 blockade immunotherapy. Nature Cancer, 1(1), 46–58.

    Google Scholar 

  162. Ong, C. C., Jubb, A. M., Jakubiak, D., Zhou, W., Rudolph, J., Haverty, P. M., et al. (2013). P21-activated kinase 1 (PAK1) as a therapeutic target in BRAF wild-type melanoma. Journal of the National Cancer Institute, 105(9), 606–607.

    PubMed  CAS  Google Scholar 

  163. Babagana, M., Johnson, S., Slabodkin, H., Bshara, W., Morrison, C., & Kandel, E. S. (2017). P21-activated kinase 1 regulates resistance to BRAF inhibition in human cancer cells. Molecular Carcinogenesis, 56(5), 1515–1525.

    PubMed  PubMed Central  CAS  Google Scholar 

  164. Araiza-Olivera, D., Feng, Y., Semenova, G., Prudnikova, T. Y., Rhodes, J., & Chernoff, J. (2018). Suppression of RAC1-driven malignant melanoma by group A PAK inhibitors. Oncogene, 37(7), 944–952.

    PubMed  CAS  Google Scholar 

  165. Montero-Conde, C., Ruiz-Llorente, S., Dominguez, J. M., Knauf, J. A., Viale, A., Sherman, E. J., et al. (2013). Relief of feedback inhibition of HER3 transcription by RAF and MEK inhibitors attenuates their antitumor effects in BRAF-mutant thyroid carcinomas. Cancer Discovery, 3(5), 520–533.

    PubMed  PubMed Central  CAS  Google Scholar 

  166. Kugel 3rd, C. H., Hartsough, E. J., Davies, M. A., Setiady, Y. Y., & Aplin, A. E. (2014). Function-blocking ERBB3 antibody inhibits the adaptive response to RAF inhibitor. Cancer Research, 74(15), 4122–4132.

    PubMed  PubMed Central  CAS  Google Scholar 

  167. Kaneko, M., Saito, Y., Saito, H., Matsumoto, T., Matsuda, Y., Vaught, J. L., et al. (1997). Neurotrophic 3,9-bis[(alkylthio)methyl]-and-bis(alkoxymethyl)-K-252a derivatives. Journal of Medicinal Chemistry, 40(12), 1863–1869.

    PubMed  CAS  Google Scholar 

  168. Zhu, J., Huang, J.-W., Tseng, P.-H., Yang, Y.-T., Fowble, J., Shiau, C.-W., et al. (2004). From the cyclooxygenase-2 inhibitor celecoxib to a novel class of 3-phosphoinositide-dependent protein kinase-1 inhibitors. Cancer Research, 64(12), 4309–4318.

    PubMed  CAS  Google Scholar 

  169. Bradshaw-Pierce, E. L., Pitts, T. M., Tan, A.-C., McPhillips, K., West, M., Gustafson, D. L., et al. (2013). Tumor P-glycoprotein correlates with efficacy of PF-3758309 in in vitro and in vivo models of colorectal cancer. Frontiers in Pharmacology, 4, 22. https://doi.org/10.3389/fphar.2013.00022.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  170. Ndubaku, C., & Tsui, V. (2015). Inhibiting the deubiquitinating enzymes (DUBs). Journal of Medicinal Chemistry, 58(4), 1581–1595.

    PubMed  CAS  Google Scholar 

  171. Rudolph, J., Murray, L. J., Ndubaku, C. O., O’Brien, T., Blackwood, E., Wang, W., et al. (2016). Chemically diverse group I p21-activated kinase (PAK) inhibitors impart acute cardiovascular toxicity with a narrow therapeutic window. Journal of Medicinal Chemistry, 59(11), 5520–5541.

    PubMed  CAS  Google Scholar 

  172. Kim, D.-J., Choi, C.-K., Lee, C.-S., Park, M.-H., Tian, X., Kim, N. D., et al. (2016). Small molecules that allosterically inhibit p21-activated kinase activity by binding to the regulatory p21-binding domain. Experimental & Molecular Medicine, 48(4), e229. https://doi.org/10.1038/emm.2016.13.

    Article  CAS  Google Scholar 

  173. Fattore, L., Marra, E., Pisanu, M. E., Noto, A., de Vitis, C., Belleudi, F., et al. (2013). Activation of an early feedback survival loop involving phospho-ErbB3 is a general response of melanoma cells to RAF/MEK inhibition and is abrogated by anti-ErbB3 antibodies. Journal of Translational Medicine, 11, 180.

    PubMed  PubMed Central  CAS  Google Scholar 

  174. Herr, R., Halbach, S., Heizmann, M., Busch, H., Boerries, M., & Brummer, T. (2018). BRAF inhibition upregulates a variety of receptor tyrosine kinases and their downstream effector Gab2 in colorectal cancer cell lines. Oncogene, 37(12), 1576–1593.

    PubMed  CAS  Google Scholar 

  175. Cruz, O. V., Prudnikova, T. Y., Araiza-Olivera, D., Perez-Plasencia, C., Johnson, N., Bernhardy, A. J., et al. (2016). Reduced PAK1 activity sensitizes FA/BRCA-proficient breast cancer cells to PARP inhibition. Oncotarget, 7(47), 76590–76603.

    PubMed Central  Google Scholar 

  176. Cerami, E., Gao, J., Dogrusoz, U., Gross, B. E., Sumer, S. O., Aksoy, B. A., et al. (2012). The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data. Cancer Discovery, 2(5), 401–404.

    PubMed  Google Scholar 

  177. Gao, J., Aksoy, B. A., Dogrusoz, U., Dresdner, G., Gross, B., Sumer, S. O., et al. (2013). Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Science Signaling, 6, l1.

    Google Scholar 

Download references

Acknowledgments

The authors wish to apologize to several of their colleagues for not discussing additional research findings here due to the paucity of space in the present article.

Author information

Authors and Affiliations

  1. Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Trivandrum, Kerala, India

    Rakesh Kumar, Aswathy Mary Paul, Ravikumar Amjesh, Bijesh George & M. Radhakrishna Pillai

  2. Department of Medicine, Division of Hematology & Oncology, Rutgers New Jersey Medical School, Newark, NJ, USA

    Rakesh Kumar

  3. Department of Human and Molecular Genetics, Virginia Commonwealth University Medical Center, Richmond, VA, USA

    Rakesh Kumar

  4. PhD Program in Biotechnology, Manipal Academy of Higher Education, Manipal, India

    Aswathy Mary Paul & Bijesh George

Authors
  1. Rakesh Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aswathy Mary Paul
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ravikumar Amjesh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bijesh George
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Radhakrishna Pillai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Rakesh Kumar or M. Radhakrishna Pillai.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kumar, R., Paul, A.M., Amjesh, R. et al. Coordinated dysregulation of cancer progression by the HER family and p21-activated kinases. Cancer Metastasis Rev 39, 583–601 (2020). https://doi.org/10.1007/s10555-020-09922-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-020-09922-6

Keywords

Search

Navigation