Skip to main content

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

  • Review Article
  • Published:

Phosphoinositide signalling in cancer: beyond PI3K and PTEN

Key Points

  • The phosphoinositide signalling system can be viewed as a network of interconverting enzymes, phospholipid messengers and their binding proteins. Interactions between phosphoinositides and their binding proteins are key to their regulatory actions.

  • Control of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) signals in cell survival, proliferation and growth is frequently dysfunctional in cancer, resulting in enhanced PtdIns(3,4,5)P3 signalling. The phosphoinositide enzymes PI3KIα and 3-phosphatase PTEN stringently control this signalling.

  • Some important downstream targets of PtdIns(3,4,5)P3, such as the protein kinase Akt, are also regulated by PtdIns(3,4)P2. The phosphoinositide enzymes that generate PtdIns(3,4)P2 from PtdIns(3,4,5)P3, phosphoinositide 5-phosphatases, and enzymes that degrade PtdIns(3,4)P2 to PtdIns3P, phosphoinositide 4-phosphatases, are also implicated in cancer.

  • The most abundant phosphoinositide, PtdIns(4,5)P2, binds to proteins important for actin polymerization, formation and turnover of focal contacts and cell–cell adhesion. These proteins could be regulated by local changes in the PtdIns(4,5)P2 levels through the action of enzymes such as PtdIns4P-5 kinases (PIPKIγ) and PLC (PLCγ) that are implicated in the regulation of cancer cell motility.

  • In addition to the local regulation of PtdIns(4,5)P2 levels, diverse functions of PLC enzymes in cancer could be mediated by the generation of the second messengers diacylglycerol and inositol-1,4,5-trisphosphate or in some instances by their function as signalling scaffolds.

  • The most important outstanding task is to further evaluate the role and extent of involvement of different phosphoinositide enzymes in the generation and progression of human tumours.

Abstract

There are numerous studies that suggest multiple links between the cellular phosphoinositide system and cancer. As key roles in cancer have been established for PI3K and PTEN — enzymes that regulate the levels of phosphatidylinositol-3,4,5-trisphosphate — compounds targeting this pathway are entering the clinic at a rapid pace. Several other phosphoinositide-modifying enzymes, including phosphoinositide kinases, phosphatases and phospholipase C enzymes, have been implicated in the generation and progression of tumours. Studies of these enzymes are providing new insights into the mechanisms and the extent of their involvement in cancer, highlighting new potential targets for therapeutic intervention.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: The phosphoinositide metabolic cycle and target proteins.
Figure 2: Some phosphoinositide-modifying enzymes relevant to human cancer.
Figure 3: Signalling through PtdIns(3,4,5)P3.
Figure 4: Diverse functions of phospholipase C (PLC) enzymes in cancer.

Similar content being viewed by others

References

  1. Sasaki, T. et al. Mammalian phosphoinositide kinases and phosphatases. Prog. Lipid Res. 48, 307–343 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. Katan, M. New insights into the families of PLC enzymes: looking back and going forward. Biochem. J. 391, e7–e9 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lemmon, M. A. Phosphoinositide recognition domains. Traffic 4, 201–213 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Lemmon, M. A. Membrane recognition by phospholipid-binding domains. Nature Rev. Mol. Cell Biol. 9, 99–111 (2008).

    Article  CAS  Google Scholar 

  5. Behnia, R. & Munro, S. Organelle identity and the signposts for membrane traffic. Nature 438, 597–604 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Di Paolo, G. & De Camilli, P. Phosphoinositides in cell regulation and membrane dynamics. Nature 443, 651–657 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Mora, A., Komander, D., van Aalten, D. M. & Alessi, D. R. PDK1, the master regulator of AGC kinase signal transduction. Semin. Cell Dev. Biol. 15, 161–170 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. D'Angelo, G., Vicinanza, M., Di Campli, A. & De Matteis, M. A. The multiple roles of PtdIns(4)P — not just the precursor of PtdIns(4, 5)P2. J. Cell Sci. 121, 1955–1963 (2008).

    Article  CAS  PubMed  Google Scholar 

  9. Zoncu, R. et al. Loss of endocytic clathrin-coated pits upon acute depletion of phosphatidylinositol 4, 5-bisphosphate. Proc. Natl Acad. Sci. USA 104, 3793–3798 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yin, H. L. & Janmey, P. A. Phosphoinositide regulation of the actin cytoskeleton. Annu. Rev. Physiol. 65, 761–789 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Di Paolo, G. et al. Impaired PtdIns(4, 5)P2 synthesis in nerve terminals produces defects in synaptic vesicle trafficking. Nature 431, 415–422 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Katso, R. et al. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu. Rev. Cell Dev. Biol. 17, 615–675 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Engelman, J. A., Luo, J. & Cantley, L. C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nature Rev. Genet. 7, 606–619 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Leslie, N. R., Batty, I. H., Maccario, H., Davidson, L. & Downes, C. P. Understanding PTEN regulation: PIP2, polarity and protein stability. Oncogene 27, 5464–5476 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Ooms, L. M. et al. The role of the inositol polyphosphate 5-phosphatases in cellular function and human disease. Biochem. J. 419, 29–49 (2009).

    Article  CAS  PubMed  Google Scholar 

  16. Majerus, P. W., Kisseleva, M. V. & Norris, F. A. The role of phosphatases in inositol signaling reactions. J. Biol. Chem. 274, 10669–10672 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Michell, R. H., Heath, V. L., Lemmon, M. A. & Dove, S. K. Phosphatidylinositol 3,5-bisphosphate: metabolism and cellular functions. Trends Biochem. Sci. 31, 52–63 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Clarke, J. H., Richardson, J. P., Hinchliffe, K. A. & Irvine, R. F. Type II PtdInsP kinases: location, regulation and function. Biochem. Soc. Symp. 74, 149–159 (2007).

    Article  CAS  Google Scholar 

  19. Vicinanza, M., D'Angelo, G., Di Campli, A. & De Matteis, M. A. Phosphoinositides as regulators of membrane trafficking in health and disease. Cell. Mol. Life Sci. 65, 2833–2841 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Krauss, M. & Haucke, V. Phosphoinositide-metabolizing enzymes at the interface between membrane traffic and cell signalling. EMBO Rep. 8, 241–246 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wymann, M. P. & Schneiter, R. Lipid signalling in disease. Nature Rev. Mol. Cell Biol. 9, 162–176 (2008).

    Article  CAS  Google Scholar 

  22. Yuan, T. L. & Cantley, L. C. PI3K pathway alterations in cancer: variations on a theme. Oncogene 27, 5497–5510 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Liu, P., Cheng, H., Roberts, T. M. & Zhao, J. J. Targeting the phosphoinositide 3-kinase pathway in cancer. Nature Rev. Drug Discov. 8, 627–644 (2009).

    Article  CAS  Google Scholar 

  24. Engelman, J. A. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nature Rev. Cancer 9, 550–562 (2009).

    Article  CAS  Google Scholar 

  25. Ali, I. U., Schriml, L. M. & Dean, M. Mutational spectra of PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase activity. J. Natl Cancer Inst. 91, 1922–1932 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (2004). This study reported the discovery that somatic mutations in PIK3CA are a common event in human cancers.

    Article  CAS  PubMed  Google Scholar 

  27. Jaiswal, B. S. et al. Somatic mutations in p85α promote tumorigenesis through class IA PI3K activation. Cancer Cell 16, 463–474 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Samuels, Y. & Velculescu, V. E. Oncogenic mutations of PIK3CA in human cancers. Cell Cycle 3, 1221–1224 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Ikenoue, T. et al. Functional analysis of PIK3CA gene mutations in human colorectal cancer. Cancer Res. 65, 4562–4567 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Kang, S., Bader, A. G. & Vogt, P. K. Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc. Natl Acad. Sci. USA 102, 802–807 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Suzuki, A., Nakano, T., Mak, T. W. & Sasaki, T. Portrait of PTEN: messages from mutant mice. Cancer Sci. 99, 209–213 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Chalhoub, N. & Baker, S. J. PTEN and the PI3-kinase pathway in cancer. Annu. Rev. Pathol. 4, 127–150 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Maehama, T. PTEN: its deregulation and tumorigenesis. Biol. Pharm. Bull. 30, 1624–1627 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Franke, T. F., Kaplan, D. R., Cantley, L. C. & Toker, A. Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate. Science 275, 665–668 (1997). This study described regulation of Akt by PtdIns(3, 4)P 2.

    Article  CAS  PubMed  Google Scholar 

  35. Ma, K., Cheung, S. M., Marshall, A. J. & Duronio, V. PI(3, 4, 5)P3 and PI(3, 4)P2 levels correlate with PKB/akt phosphorylation at Thr308 and Ser473, respectively; PI(3, 4)P2 levels determine PKB activity. Cell. Signal. 20, 684–694 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Scheid, M. P. et al. Phosphatidylinositol (3,4,5)P3 is essential but not sufficient for protein kinase B (PKB) activation; phosphatidylinositol (3,4)P2 is required for PKB phosphorylation at Ser-473: studies using cells from SH2-containing inositol-5-phosphatase knockout mice. J. Biol. Chem. 277, 9027–9035 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Leung, W. H., Tarasenko, T. & Bolland, S. Differential roles for the inositol phosphatase SHIP in the regulation of macrophages and lymphocytes. Immunol. Res. 43, 243–251 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rohrschneider, L. R., Fuller, J. F., Wolf, I., Liu, Y. & Lucas, D. M. Structure, function, and biology of SHIP proteins. Genes Dev. 14, 505–520 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Helgason, C. D. et al. Targeted disruption of SHIP leads to hemopoietic perturbations, lung pathology, and a shortened life span. Genes Dev. 12, 1610–1620 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sattler, M. et al. BCR/ABL directly inhibits expression of SHIP, an SH2-containing polyinositol-5-phosphatase involved in the regulation of hematopoiesis. Mol. Cell. Biol. 19, 7473–7480 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Horn, S. et al. Restoration of SHIP activity in a human leukemia cell line downregulates constitutively activated phosphatidylinositol 3-kinase/Akt/GSK-3β signaling and leads to an increased transit time through the G1 phase of the cell cycle. Leukemia 18, 1839–1849 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Fukuda, R. et al. Alteration of phosphatidylinositol 3-kinase cascade in the multilobulated nuclear formation of adult T cell leukemia/lymphoma (ATLL). Proc. Natl Acad. Sci. USA 102, 15213–15218 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ong, C. J. et al. Small-molecule agonists of SHIP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells. Blood 110, 1942–1949 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Kennah, M. et al. Activation of SHIP via a small molecule agonist kills multiple myeloma cells. Exp. Hematol. 37, 1274–1283 (2009).

    Article  CAS  PubMed  Google Scholar 

  45. Garcia-Palma, L. et al. Up-regulation of the T cell quiescence factor KLF2 in a leukaemic T-cell line after expression of the inositol 5′-phosphatase SHIP-1. Br. J. Haematol. 131, 628–631 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Luo, J. M. et al. Mutation analysis of SHIP gene in acute leukemia. Zhongguo Shi Yan Xue Ye Xue Za Zhi 12, 420–426 (2004).

    CAS  PubMed  Google Scholar 

  47. Luo, J. M. et al. Possible dominant-negative mutation of the SHIP gene in acute myeloid leukemia. Leukemia 17, 1–8 (2003).

    Article  CAS  PubMed  Google Scholar 

  48. Prasad, N. K., Tandon, M., Badve, S., Snyder, P. W. & Nakshatri, H. Phosphoinositol phosphatase SHIP2 promotes cancer development and metastasis coupled with alterations in EGF receptor turnover. Carcinogenesis 29, 25–34 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Prasad, N. K. SHIP2 phosphoinositol phosphatase positively regulates EGFR-Akt pathway, CXCR4 expression, and cell migration in MDA-MB-231 breast cancer cells. Int. J. Oncol. 34, 97–105 (2009).

    CAS  PubMed  Google Scholar 

  50. Sleeman, M. W. et al. Absence of the lipid phosphatase SHIP2 confers resistance to dietary obesity. Nature Med. 11, 199–205 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. Calle, E. E. & Kaaks, R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nature Rev. Cancer 4, 579–591 (2004).

    Article  CAS  Google Scholar 

  52. Prasad, N. Two diseases with one hit: inhibiting a potential diabetes target to reduce cancer risk and to improve anti-cancer therapy. Curr. Cancer Ther. Rev. 5, 111–121 (2009).

    Article  CAS  Google Scholar 

  53. Yoon, J. H. et al. cDNA microarray analysis of gene expression profiles associated with cervical cancer. Cancer Res. Treat 35, 451–459 (2003).

    Article  PubMed  Google Scholar 

  54. Chow, K. U. et al. In vivo drug-response in patients with leukemic non-Hodgkin's lymphomas is associated with in vitro chemosensitivity and gene expression profiling. Pharmacol. Res. 53, 49–61 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Quade, B. J. et al. Molecular pathogenesis of uterine smooth muscle tumors from transcriptional profiling. Genes Chromosom. Cancer 40, 97–108 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Akada, M. et al. Intrinsic chemoresistance to gemcitabine is associated with decreased expression of BNIP3 in pancreatic cancer. Clin. Cancer Res. 11, 3094–3101 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Kim, B. et al. Expression profiling and subtype-specific expression of stomach cancer. Cancer Res. 63, 8248–8255 (2003).

    CAS  PubMed  Google Scholar 

  58. Ramaswamy, S., Ross, K. N., Lander, E. S. & Golub, T. R. A molecular signature of metastasis in primary solid tumors. Nature Genet. 33, 49–54 (2003).

    Article  CAS  PubMed  Google Scholar 

  59. Gruvberger, S. et al. Estrogen receptor status in breast cancer is associated with remarkably distinct gene expression patterns. Cancer Res. 61, 5979–5984 (2001).

    CAS  PubMed  Google Scholar 

  60. van 't Veer, L. J. et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 415, 530–536 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Ooms, L. M. et al. The inositol polyphosphate 5-phosphatase, PIPP, Is a novel regulator of phosphoinositide 3-kinase-dependent neurite elongation. Mol. Biol. Cell 17, 607–622 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kisseleva, M. V., Cao, L. & Majerus, P. W. Phosphoinositide-specific inositol polyphosphate 5-phosphatase IV inhibits Akt/protein kinase B phosphorylation and leads to apoptotic cell death. J. Biol. Chem. 277, 6266–6272 (2002).

    Article  CAS  PubMed  Google Scholar 

  63. Gewinner, C. et al. Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling. Cancer Cell 16, 115–125 (2009). This study showed involvement of a phosphoinositide 4-phosphatase in tumour suppression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Barnache, S., Le Scolan, E., Kosmider, O., Denis, N. & Moreau-Gachelin, F. Phosphatidylinositol 4-phosphatase type II is an erythropoietin-responsive gene. Oncogene 25, 1420–1423 (2006).

    Article  CAS  PubMed  Google Scholar 

  65. Naylor, T. L. et al. High resolution genomic analysis of sporadic breast cancer using array-based comparative genomic hybridization. Breast Cancer Res. 7, R1186–R1198 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bergamaschi, A. et al. Distinct patterns of DNA copy number alteration are associated with different clinicopathological features and gene-expression subtypes of breast cancer. Genes Chromosom. Cancer 45, 1033–1040 (2006).

    Article  CAS  PubMed  Google Scholar 

  67. Chin, S. F. et al. Using array-comparative genomic hybridization to define molecular portraits of primary breast cancers. Oncogene 26, 1959–1970 (2007).

    Article  CAS  PubMed  Google Scholar 

  68. Johannsdottir, H. K. et al. Deletions on chromosome 4 in sporadic and BRCA mutated tumors and association with pathological variables. Anticancer Res. 24, 2681–2687 (2004).

    CAS  PubMed  Google Scholar 

  69. Ivetac, I. et al. Regulation of PI(3)K/Akt signalling and cellular transformation by inositol polyphosphate 4-phosphatase-1. EMBO Rep. 10, 487–493 (2009). This study shows that phosphoinositide 4-phosphatase can control the activation of Akt and thereby cell proliferation, survival and tumourigenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Anderson, R. A., Boronenkov, I. V., Doughman, S. D., Kunz, J. & Loijens, J. C. Phosphatidylinositol phosphate kinases, a multifaceted family of signaling enzymes. J. Biol. Chem. 274, 9907–9910 (1999).

    Article  CAS  PubMed  Google Scholar 

  71. Heck, J. N. et al. A conspicuous connection: structure defines function for the phosphatidylinositol-phosphate kinase family. Crit. Rev. Biochem. Mol. Biol. 42, 15–39 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. McLaughlin, S., Wang, J., Gambhir, A. & Murray, D. PIP2 and proteins: interactions, organization, and information flow. Annu. Rev. Biophys Biomol. Struct. 31, 151–175 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. van den Bout, I. & Divecha, N. PIP5K-driven PtdIns(4,5)P2 synthesis: regulation and cellular functions. J. Cell Sci. 122, 3837–3850 (2009).

    Article  CAS  PubMed  Google Scholar 

  74. Mao, Y. S. & Yin, H. L. Regulation of the actin cytoskeleton by phosphatidylinositol 4-phosphate 5 kinases. Pflugers Arch. 455, 5–18 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Ling, K., Schill, N. J., Wagoner, M. P., Sun, Y. & Anderson, R. A. Movin' on up: the role of PtdIns(4,5)P2 in cell migration. Trends Cell Biol. 16, 276–284 (2006).

    Article  CAS  PubMed  Google Scholar 

  76. Ling, K., Doughman, R. L., Firestone, A. J., Bunce, M. W. & Anderson, R. A. Type I gamma phosphatidylinositol phosphate kinase targets and regulates focal adhesions. Nature 420, 89–93 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Di Paolo, G. et al. Recruitment and regulation of phosphatidylinositol phosphate kinase type 1γ by the FERM domain of talin. Nature 420, 85–89 (2002). References 76 and 77 identified the role of local PtdIns(4,5)P 2 synthesis in regulation of focal adhesions.

    Article  CAS  PubMed  Google Scholar 

  78. Ginsberg, M. H., Partridge, A. & Shattil, S. J. Integrin regulation. Curr. Opin. Cell Biol. 17, 509–516 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Yap, A. S., Crampton, M. S. & Hardin, J. Making and breaking contacts: the cellular biology of cadherin regulation. Curr. Opin. Cell Biol. 19, 508–514 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Collins, B. M., McCoy, A. J., Kent, H. M., Evans, P. R. & Owen, D. J. Molecular architecture and functional model of the endocytic AP2 complex. Cell 109, 523–535 (2002).

    Article  CAS  PubMed  Google Scholar 

  81. Ling, K. et al. Type Iγ phosphatidylinositol phosphate kinase modulates adherens junction and E-cadherin trafficking via a direct interaction with μ1B adaptin. J. Cell Biol. 176, 343–353 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Akiyama, C. et al. Phosphatidylinositol-4-phosphate 5-kinase γ is associated with cell–cell junction in A431 epithelial cells. Cell Biol. Int. 29, 514–520 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Wang, Y., Lian, L., Golden, J. A., Morrisey, E. E. & Abrams, C. S. PIP5KIγ is required for cardiovascular and neuronal development. Proc. Natl Acad. Sci. USA 104, 11748–11753 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Polyak, K. & Weinberg, R. A. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nature Rev. Cancer 9, 265–273 (2009).

    Article  CAS  Google Scholar 

  85. Yabuta, T. et al. E-cadherin gene variants in gastric cancer families whose probands are diagnosed with diffuse gastric cancer. Int. J. Cancer 101, 434–441 (2002).

    Article  CAS  PubMed  Google Scholar 

  86. Suriano, G. et al. The intracellular E-cadherin germline mutation V832 M lacks the ability to mediate cell-cell adhesion and to suppress invasion. Oncogene 22, 5716–5719 (2003).

    Article  CAS  PubMed  Google Scholar 

  87. Wodarz, A. & Nathke, I. Cell polarity in development and cancer. Nature Cell Biol. 9, 1016–1024 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Katan, M., Rodriguez, R., Matsuda, M., Newbatt, Y. M. & Aherne, G. W. Structural and mechanistic aspects of phospholipase Cγ regulation. Adv. Enzyme Regul. 43, 77–85 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. Mouneimne, G. et al. Phospholipase C and cofilin are required for carcinoma cell directionality in response to EGF stimulation. J. Cell Biol. 166, 697–708 (2004). This study described the connection between cofilin-regulation and activation of PLC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Andrianantoandro, E. & Pollard, T. D. Mechanism of actin filament turnover by severing and nucleation at different concentrations of ADF/cofilin. Mol. Cell 24, 13–23 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Wang, W., Eddy, R. & Condeelis, J. The cofilin pathway in breast cancer invasion and metastasis. Nature Rev. Cancer 7, 429–440 (2007).

    Article  CAS  Google Scholar 

  92. Song, X. et al. Initiation of cofilin activity in response to EGF is uncoupled from cofilin phosphorylation and dephosphorylation in carcinoma cells. J. Cell Sci. 119, 2871–2881 (2006).

    Article  CAS  PubMed  Google Scholar 

  93. van Rheenen, J. et al. EGF-induced PIP2 hydrolysis releases and activates cofilin locally in carcinoma cells. J. Cell Biol. 179, 1247–1259 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Frantz, C. et al. Cofilin is a pH sensor for actin free barbed end formation: role of phosphoinositide binding. J. Cell Biol. 183, 865–879 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Leyman, S. et al. Unbalancing the phosphatidylinositol-4, 5-bisphosphate-cofilin interaction impairs cell steering. Mol. Biol. Cell 20, 4509–4523 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Gorbatyuk, V. Y. et al. Mapping the phosphoinositide-binding site on chick cofilin explains how PIP2 regulates the cofilin-actin interaction. Mol. Cell 24, 511–522 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Ghosh, M. et al. Cofilin promotes actin polymerization and defines the direction of cell motility. Science 304, 743–746 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Mouneimne, G. et al. Spatial and temporal control of cofilin activity is required for directional sensing during chemotaxis. Curr. Biol. 16, 2193–2205 (2006).

    Article  CAS  PubMed  Google Scholar 

  99. Meira, M. et al. Memo is a cofilin-interacting protein that influences PLCγ1 and cofilin activities, and is essential for maintaining directionality during ErbB2-induced tumor-cell migration. J. Cell Sci. 122, 787–797 (2009).

    Article  CAS  PubMed  Google Scholar 

  100. Jones, N. P., Peak, J., Brader, S., Eccles, S. A. & Katan, M. PLCγ1 is essential for early events in integrin signalling required for cell motility. J. Cell Sci. 118, 2695–2706 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. Jones, N. P. & Katan, M. Role of phospholipase Cγ1 in cell spreading requires association with a beta-Pix/GIT1-containing complex, leading to activation of Cdc42 and Rac1. Mol. Cell. Biol. 27, 5790–5805 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Sun, C. X., Magalhaes, M. A. & Glogauer, M. Rac1 and Rac2 differentially regulate actin free barbed end formation downstream of the fMLP receptor. J. Cell Biol. 179, 239–245 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Noh, D. Y. et al. Elevated content of phospholipase C-γ 1 in colorectal cancer tissues. Cancer 73, 36–41 (1994).

    Article  CAS  PubMed  Google Scholar 

  104. Arteaga, C. L. et al. Elevated content of the tyrosine kinase substrate phospholipase C-γ 1 in primary human breast carcinomas. Proc. Natl Acad. Sci. USA 88, 10435–10439 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Nomoto, K. et al. Expression of phospholipases γ1, β1, and δ1 in primary human colon carcinomas and colon carcinoma cell lines. Mol. Carcinog. 12, 146–152 (1995).

    Article  CAS  PubMed  Google Scholar 

  106. Park, J. G. et al. Overexpression of phospholipase C-γ 1 in familial adenomatous polyposis. Cancer Res. 54, 2240–2244 (1994).

    CAS  PubMed  Google Scholar 

  107. Thomas, S. M. et al. Epidermal growth factor receptor-stimulated activation of phospholipase Cγ-1 promotes invasion of head and neck squamous cell carcinoma. Cancer Res. 63, 5629–5635 (2003).

    CAS  PubMed  Google Scholar 

  108. Shepard, C. R., Kassis, J., Whaley, D. L., Kim, H. G. & Wells, A. PLCγ contributes to metastasis of in situ-occurring mammary and prostate tumors. Oncogene 26, 3020–3026 (2007).

    Article  CAS  PubMed  Google Scholar 

  109. Sala, G. et al. Phospholipase Cγ1 is required for metastasis development and progression. Cancer Res. 68, 10187–10196 (2008).

    Article  CAS  PubMed  Google Scholar 

  110. Yu, P. et al. Autoimmunity and inflammation due to a gain-of-function mutation in phospholipase Cγ2 that specifically increases external Ca2+ entry. Immunity 22, 451–465 (2005).

    Article  PubMed  CAS  Google Scholar 

  111. Everett, K. L. et al. Characterization of phospholipase Cγ enzymes with gain-of-function mutations. J. Biol. Chem. 284, 23083–23093 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Hynes, N. E. & MacDonald, G. ErbB receptors and signaling pathways in cancer. Curr. Opin. Cell Biol. 21, 177–184 (2009).

    Article  CAS  PubMed  Google Scholar 

  113. Suh, P. G. et al. Multiple roles of phosphoinositide-specific phospholipase C isozymes. BMB Rep. 41, 415–434 (2008).

    Article  CAS  PubMed  Google Scholar 

  114. Bunney, T. D. & Katan, M. Phospholipase C epsilon: linking second messengers and small GTPases. Trends Cell Biol. 16, 640–648 (2006).

    Article  CAS  PubMed  Google Scholar 

  115. Bai, Y. et al. Crucial role of phospholipase Cepsilon in chemical carcinogen-induced skin tumor development. Cancer Res. 64, 8808–8810 (2004).

    Article  CAS  PubMed  Google Scholar 

  116. Ikuta, S., Edamatsu, H., Li, M., Hu, L. & Kataoka, T. Crucial role of phospholipase C epsilon in skin inflammation induced by tumor-promoting phorbol ester. Cancer Res. 68, 64–72 (2008).

    Article  CAS  PubMed  Google Scholar 

  117. Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Li, M., Edamatsu, H., Kitazawa, R., Kitazawa, S. & Kataoka, T. Phospholipase Cɛ promotes intestinal tumorigenesis of ApcMin/+ mice through augmentation of inflammation and angiogenesis. Carcinogenesis 30, 1424–1432 (2009).

    Article  CAS  PubMed  Google Scholar 

  119. Yuan, T. L. et al. Class 1A PI3K regulates vessel integrity during development and tumorigenesis. Proc. Natl Acad. Sci. USA 105, 9739–9744 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Xiao, W. et al. Tumor suppression by phospholipase C-β3 via SHP-1-mediated dephosphorylation of Stat5. Cancer Cell 16, 161–171 (2009). This study showed a tumour suppressor role of a PLC enzyme, functioning as a signalling scaffold.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Van Etten, R. A. & Shannon, K. M. Focus on myeloproliferative diseases and myelodysplastic syndromes. Cancer Cell 6, 547–552 (2004).

    Article  CAS  PubMed  Google Scholar 

  122. Follo, M. Y. et al. Phosphoinositide-phospholipase C β1 mono-allelic deletion is associated with myelodysplastic syndromes evolution into acute myeloid leukemia. J. Clin. Oncol. 27, 782–790 (2009).

    Article  PubMed  Google Scholar 

  123. Kolsch, V., Charest, P. G. & Firtel, R. A. The regulation of cell motility and chemotaxis by phospholipid signaling. J. Cell Sci. 121, 551–559 (2008).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Matilda Katan.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Matilda Katan's homepages

Matilda Katan's homepages

Catalogue of Somatic Mutations in Cancer

Glossary

Focal adhesion complex

A multiprotein complex of more than 150 distinct components that links the extracellular matrix to the actin cytoskeleton.

Actin-nucleation activity

Property of a protein to generate new free high-affinity actin filament ends, also known as free barbed ends, which are required for actin polymerization.

On-rate

A rate of association (binding), the measurement of which allows the determination of the association (Ka) constant.

Off-rate

A rate of dissociation, the measurement of which allows the determination of the dissociation (Kd) constant.

Barbed-end transient

A tightly regulated time period when barbed ends (free high-affinity actin filament ends) are formed.

Caged cofilin

A protein or compound, in this case cofilin, conjugated with a chromophore that allows for the controlled photorelease of a biologically active protein or compound with high temporal and spatial precision.

De novo nucleation

One of three well-defined mechanisms of actin assembly through the formation of barbed ends (free high-affinity actin filament ends); de novo nucleation is mainly mediated by the Arp2/3 complex.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bunney, T., Katan, M. Phosphoinositide signalling in cancer: beyond PI3K and PTEN. Nat Rev Cancer 10, 342–352 (2010). https://doi.org/10.1038/nrc2842

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc2842

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer