Exploring CDKs, Ras-ERK, and PI3K-Akt in Abnormal Signaling and Cancer


  • Sisir Nandi Department of Pharmaceutical Chemistry, Global Institute of Pharmaceutical Education and Research, Kashipur-244713, India
  • Manish C. Bagchi Formerly of Indian Institute of Chemical Biology (CSIR), Kolkata-700032, India




CDKs, Ras-ERK, PI3K-Akt, abnormal signaling, Cancer


Cancer or malignancy can be defined as abnormal growth and cell division. Malignancies spread, through metastasis invasion, or implantation into distant sites by which cancer cells can move through the bloodstream or lymphatic system to distant locations. The body cells follow the mitotic cell division process. Normal cell division occurs through the normal signal transduction through proto-oncogenes responsible for cell proliferation and differentiation. Mutation of these proto-oncogene leads to oncogene which can modify the gene expression and function through abnormal signal transduction, making uncontrolled growth of cells. The mitotic cell cycle is regulated by signal transduction through the cyclin-dependent kinases (CDKs), Ras-ERK, and PI3K-Akt. Abnormal signaling occurs through the mutation of these genes leading to cancer. The present review shortly reported the role of these proteins in abnormal signal transduction and cancer.


Sciacovelli M, Schmidt C, Maher ER, Frezza C. Metabolic Drivers in Hereditary Cancer Syndromes. Annu Rev Cancer Biol 2020; 4: 77-97. https://doi.org/10.1146/annurev-cancerbio-030419-033612

Sever R, Brugge JS. Signal Transduction in Cancer. Cold Spring Harbor Perspectives in Medicine 2015; 5: a006098-a006098. https://doi.org/10.1101/cshperspect.a006098

Wang Q. Cancer predisposition genes: molecular mechanisms and clinical impact on personalized cancer care: examples of Lynch and HBOC syndromes. Acta Pharmacol Sin 2016; 37: 143-9. https://doi.org/10.1038/aps.2015.89

Roux PP, Blenis J. ERK and p38 MAPK-Activated Protein Kinases: a Family of Protein Kinases with Diverse Biological Functions. MicrobiolMolBiol Rev 2004; 68: 320-44. https://doi.org/10.1128/MMBR.68.2.320-344.2004

Wodarz D, Newell AC, Komarova NL. Passenger mutations can accelerate tumour suppressor gene inactivation in cancer evolution. J R Soc Interface 2018; 15: 20170967. https://doi.org/10.1098/rsif.2017.0967

Park M-T, Lee S-J. Cell Cycle and Cancer. BMB Reports 2003; 36: 60-5. https://doi.org/10.5483/BMBRep.2003.36.1.060

Cheng N, Chytil A, Shyr Y, Joly A, Moses HL. Transforming Growth Factor-β Signaling-Deficient Fibroblasts Enhance Hepatocyte Growth Factor Signaling in Mammary Carcinoma Cells to Promote Scattering and Invasion. Molecular Cancer Research 2008; 6: 1521-33. https://doi.org/10.1158/1541-7786.MCR-07-2203

Bhowmick NA, Neilson EG, Moses HL. Stromal fibroblasts in cancer initiation and progression. Nature 2004; 432: 332-7. https://doi.org/10.1038/nature03096

Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell 2011; 144: 646-74. https://doi.org/10.1016/j.cell.2011.02.013

Roy DM, Walsh LA, Chan TA. Driver mutations of cancer epigenomes. Protein Cell 2014; 5: 265-96. https://doi.org/10.1007/s13238-014-0031-6

Mair B, Konopka T, Kerzendorfer C, et al. Gain- and Loss-of-Function Mutations in the Breast Cancer Gene GATA3 Result in Differential Drug Sensitivity. PLoS Genet 2016; 12: e1006279. https://doi.org/10.1371/journal.pgen.1006279

Quinlan MP, Settleman J. Isoform-specific ras functions in development and cancer. Future Oncology 2009; 5: 105-16. https://doi.org/10.2217/14796694.5.1.105

Li L, Zhao G-D, Shi Z, Qi L-L, Zhou L-Y, Fu Z-X. The Ras/Raf/MEK/ERK signaling pathway and its role in the occurrence and development of HCC. Oncology Letters 2016; 12: 3045-50. https://doi.org/10.3892/ol.2016.5110

Chang F, Steelman LS, Lee JT, et al. Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention. Leukemia 2003; 17: 1263-93. https://doi.org/10.1038/sj.leu.2402945

Levine MS, Holland AJ. The impact of mitotic errors on cell proliferation and tumorigenesis. Genes Dev 2018; 32: 620-38. https://doi.org/10.1101/gad.314351.118

Hunter T, Pines J. Cyclins and cancer II: Cyclin D and CDK inhibitors come of age. Cell 1994; 79: 573-82. https://doi.org/10.1016/0092-8674(94)90543-6

Chotiner JY, Wolgemuth DJ, Wang PJ. Functions of cyclins and CDKs in mammalian gametogenesis†. Biology of Reproduction 2019; 101: 591-601. https://doi.org/10.1093/biolre/ioz070

DeVita VT, Chu E. A History of Cancer Chemotherapy. Cancer Research 2008; 68: 8643-53. https://doi.org/10.1158/0008-5472.CAN-07-6611

Kamb A. Cell-cycle regulators and cancer. Trends in Genetics 1995; 11: 136-40. https://doi.org/10.1016/S0168-9525(00)89027-7

Risal S, Adhikari D, Liu K. Animal Models for Studying the In vivo Functions of Cell Cycle CDKs. In: Orzáez M, Sancho Medina M, Pérez-Payá E, editors. Cyclin-Dependent Kinase (CDK) Inhibitors, vol. 1336, New York, NY: Springer New York 2016; pp. 155-66. https://doi.org/10.1007/978-1-4939-2926-9_13

Morgan DO. Principles of CDK regulation. Nature 1995; 374: 131-4. https://doi.org/10.1038/374131a0

Heichman KA, Roberts JM. Rules to replicate by. Cell 1994; 79: 557-62. https://doi.org/10.1016/0092-8674(94)90541-X

Lim S, Kaldis P. Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development 2013; 140: 3079-93. https://doi.org/10.1242/dev.091744

Sherr CJ, Roberts JM. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev 1995; 9: 1149-63. https://doi.org/10.1101/gad.9.10.1149

Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes & Development 1999; 13: 1501-12. https://doi.org/10.1101/gad.13.12.1501

Galaktionov K, Chen X, Beach D. Cdc25 cell-cycle phosphatase as a target of c-myc. Nature 1996; 382: 511-7. https://doi.org/10.1038/382511a0

Nilsson I, Hoffmann I. Cell cycle regulation by the Cdc25 phosphatase family. In: Meijer L, Jézéquel A, Ducommun B, editors. Progress in Cell Cycle Research, Boston, MA: Springer US 2000; pp. 107-14. https://doi.org/10.1007/978-1-4615-4253-7_10

Bretones G, Delgado MD, León J. Myc and cell cycle control. Biochimica et BiophysicaActa (BBA) - Gene Regulatory Mechanisms 2015; 1849: 506-16. https://doi.org/10.1016/j.bbagrm.2014.03.013

Easton J, Wei T, Lahti JM, Kidd VJ. Disruption of the cyclin D/cyclin-dependent kinase/INK4/retinoblastoma protein regulatory pathway in human neuroblastoma. Cancer Res 1998; 58: 2624-32.

Wölfel T, Hauer M, Schneider J, et al. A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science 1995; 269: 1281-4. https://doi.org/10.1126/science.7652577

Canavese M, Santo L, Raje N. Cyclin dependent kinases in cancer. Cancer Biology & Therapy 2012; 13: 451-7. https://doi.org/10.4161/cbt.19589

El-Deiry WS, Tokino T, Velculescu VE, et al. WAF1, a potential mediator of p53 tumor suppression. Cell 1993; 75: 817-25. https://doi.org/10.1016/0092-8674(93)90500-P

Ko LJ, Prives C. p53: puzzle and paradigm. Genes Dev 1996; 10: 1054-72. https://doi.org/10.1101/gad.10.9.1054

Vermeulen K, Van Bockstaele DR, Berneman ZN. The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif2003; 36: 131-49. https://doi.org/10.1046/j.1365-2184.2003.00266.x

Motokura T, Bloom T, Kim HG, et al. A novel cyclin encoded by a bcl1-linked candidate oncogene. Nature 1991; 350: 512-5. https://doi.org/10.1038/350512a0

Li Y, Wei J, Xu C, Zhao Z, You T. Prognostic Significance of Cyclin D1 Expression in Colorectal Cancer: A Meta-Analysis of Observational Studies. PLOS ONE 2014; 9: e94508. https://doi.org/10.1371/journal.pone.0094508

Comstock CES, Revelo MP, Buncher CR, Knudsen KE. Impact of differential cyclin D1 expression and localisation in prostate cancer. Br J Cancer 2007; 96: 970-9. https://doi.org/10.1038/sj.bjc.6603615

Casimiro MC, Crosariol M, Loro E, Li Z, Pestell RG. Cyclins and cell cycle control in cancer and disease. Genes Cancer 2012; 3: 649-57. https://doi.org/10.1177/1947601913479022

Sherr CJ, McCormick F. The RB and p53 pathways in cancer. Cancer Cell 2002; 2: 103-12. https://doi.org/10.1016/s1535-6108(02)00102-2

Israels ED, Israels LG. The cell cycle. Oncologist 2000; 5: 510-3. https://doi.org/10.1634/theoncologist.5-6-510

Miller C, Koeffler HP. P53 mutations in human cancer. Leukemia 1993; 7(Suppl 2): S18-21.

Greenblatt MS, Bennett WP, Hollstein M, Harris CC. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 1994; 54: 4855-78.

Nataraj AJ, Trent JC, Ananthaswamy HN. p53 gene mutations and photocarcinogenesis. Photochem Photobiol 1995; 62: 218-30. https://doi.org/10.1111/j.1751-1097.1995.tb05262.x

Møller MB, Ino Y, Gerdes AM, Skjødt K, Louis DN, Pedersen NT. Aberrations of the p53 pathway components p53, MDM2 and CDKN2A appear independent in diffuse large B cell lymphoma. Leukemia1999; 13: 453-9. https://doi.org/10.1038/sj.leu.2401315

Bueso-Ramos CE, Manshouri T, Haidar MA, Huh YO, Keating MJ, Albitar M. Multiple patterns of MDM-2 deregulation in human leukemias: implications in leukemogenesis and prognosis. Leuk Lymphoma 1995; 17: 13-8. https://doi.org/10.3109/10428199509051698

Bueso-Ramos CE, Manshouri T, Haidar MA, et al. Abnormal expression of MDM-2 in breast carcinomas. Breast Cancer Res Treat 1996; 37: 179-88. https://doi.org/10.1007/BF01806499

Wakasugi E, Kobayashi T, Tamaki Y, et al. p21(Waf1/Cip1) and p53 protein expression in breast cancer. Am J Clin Pathol 1997; 107: 684-91. https://doi.org/10.1093/ajcp/107.6.684

Kang Z-J, Liu Y-F, Xu L-Z, et al. The Philadelphia chromosome in leukemogenesis. Chin J Cancer 2016; 35: 48. https://doi.org/10.1186/s40880-016-0108-0

Sawyers CL. 3 Signal transduction pathways involved in BCR-ABL transformation. Baillière’s Clinical Haematology 1997; 10: 223-31. https://doi.org/10.1016/S0950-3536(97)80004-2

Gabay M, Li Y, Felsher DW. MYC activation is a hallmark of cancer initiation and maintenance. Cold Spring HarbPerspect Med 2014; 4: a014241. https://doi.org/10.1101/cshperspect.a014241

Cheung M, Testa JR. Diverse mechanisms of AKT pathway activation in human malignancy. Curr Cancer Drug Targets 2013; 13: 234-44. https://doi.org/10.2174/1568009611313030002

Cheon D-J, Orsulic S. Mouse models of cancer. Annu Rev Pathol2011; 6: 95-119. https://doi.org/10.1146/annurev.pathol.3.121806.154244

Bellacosa A, Kumar CC, Di Cristofano A, Testa JR. Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res 2005; 94: 29-86. https://doi.org/10.1016/S0065-230X(05)94002-5

Korkaya H, Paulson A, Charafe-Jauffret E, et al. Regulation of mammary stem/progenitor cells by PTEN/Akt/beta-catenin signaling. PLoSBiol 2009; 7: e1000121. https://doi.org/10.1371/journal.pbio.1000121

Ma L, Zhang G, Miao X-B, et al. Cancer stem-like cell properties are regulated by EGFR/AKT/β-catenin signaling and preferentially inhibited by gefitinib in nasopharyngeal carcinoma. FEBS J 2013; 280: 2027-41. https://doi.org/10.1111/febs.12226

Chalhoub N, Baker SJ. PTEN and the PI3-kinase pathway in cancer. Annu Rev Pathol 2009; 4: 127-50. https://doi.org/10.1146/annurev.pathol.4.110807.092311

Neshat MS, Mellinghoff IK, Tran C, et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci U S A 2001; 98: 10314-9. https://doi.org/10.1073/pnas.171076798

Alayev A, Holz MK. mTORsignaling for biological control and cancer. J Cell Physiol2013; 228: 1658-64. https://doi.org/10.1002/jcp.24351




How to Cite

Nandi, S., & Bagchi, M. C. (2022). Exploring CDKs, Ras-ERK, and PI3K-Akt in Abnormal Signaling and Cancer. Journal of Cancer Research Updates, 11, 63–69. https://doi.org/10.30683/1929-2279.2022.11.09