FAK Acts as a Suppressor of RTK-MAP Kinase Signalling in Epithelia and Human Cancer Cells


Due to their deregulation in cancer and their potential to be inhibited by small chemical compounds, tyrosine kinases are among the most important targets under consideration for cancer therapeutics. One such oncogenic tyrosine kinase is FAK, which is known to regulate cellular signalling downstream of Integrins and Receptor Tyrosine Kinases (RTK) at the cell surface. In this study, however, we report that FAK can act as a suppressor of oncogenic Receptor Tyrosine Kinases. This mechanism was observed in fruit fly tissues in vivo and human cancer-derived cells in vitro, which additionally suggests it is an evolutionary conserved mechanism in humans. FAK mediated this inhibition by controlling the sub-cellular localisation of receptors, via suppression of receptor recycling to the cell surface. These results suggest that in some particular cancer contexts such as RTK-driven tumours, FAK may act as a tumour suppressor and therefore, may not be a valid drug target.


Vyšlo v časopise: FAK Acts as a Suppressor of RTK-MAP Kinase Signalling in Epithelia and Human Cancer Cells. PLoS Genet 10(3): e32767. doi:10.1371/journal.pgen.1004262
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pgen.1004262

Souhrn

Due to their deregulation in cancer and their potential to be inhibited by small chemical compounds, tyrosine kinases are among the most important targets under consideration for cancer therapeutics. One such oncogenic tyrosine kinase is FAK, which is known to regulate cellular signalling downstream of Integrins and Receptor Tyrosine Kinases (RTK) at the cell surface. In this study, however, we report that FAK can act as a suppressor of oncogenic Receptor Tyrosine Kinases. This mechanism was observed in fruit fly tissues in vivo and human cancer-derived cells in vitro, which additionally suggests it is an evolutionary conserved mechanism in humans. FAK mediated this inhibition by controlling the sub-cellular localisation of receptors, via suppression of receptor recycling to the cell surface. These results suggest that in some particular cancer contexts such as RTK-driven tumours, FAK may act as a tumour suppressor and therefore, may not be a valid drug target.


Zdroje

1. VidalM, CaganRL (2006) Drosophila models for cancer research. Curr Opin Genet Dev 16: 10–16.

2. TenenbaumD (2003) What's All the Buzz? Fruit Flies Provide Unique Model for Cancer Research. J Natl Cancer Inst 95: 1742–1744.

3. EdgarBA (2006) From cell structure to transcription: Hippo forges a new path. Cell 124: 267–273.

4. KarimFD, ChangHC, TherrienM, WassarmanDA, LavertyT, et al. (1996) A screen for genes that function downstream of Ras1 during Drosophila eye development. Genetics 143: 315–329.

5. DicksonBJ, van der StratenA, DominguezM, HafenE (1996) Mutations Modulating Raf signaling in Drosophila eye development. Genetics 142: 163–171.

6. TherrienM, MorrisonDK, WongAM, RubinGM (2000) A genetic screen for modifiers of a kinase suppressor of Ras-dependent rough eye phenotype in Drosophila. Genetics 156: 1231–1242.

7. RebayI, ChenF, HsiaoF, KolodziejPA, KuangBH, et al. (2000) A genetic screen for novel components of the Ras/Mitogen-activated protein kinase signaling pathway that interact with the yan gene of Drosophila identifies split ends, a new RNA recognition motif-containing protein. Genetics 154: 695–712.

8. ParsonsJT (2003) Focal adhesion kinase: the first ten years. J Cell Sci 116: 1409–1416.

9. GelmanIH (2003) Pyk 2 FAKs, any two FAKs. Cell Biol Int 27: 507–510.

10. SiesserPM, HanksSK (2006) The signaling and biological implications of FAK overexpression in cancer. Clin Cancer Res 12: 3233–3237.

11. ZhaoJ, GuanJL (2009) Signal transduction by focal adhesion kinase in cancer. Cancer Metastasis Rev 28: 35–49.

12. FujimotoJ, SawamotoK, OkabeM, TakagiY, TezukaT, et al. (1999) Cloning and characterization of Dfak56, a homolog of focal adhesion kinase, in Drosophila melanogaster. J Biol Chem 274: 29196–29201.

13. PalmerRH, FesslerLI, EdeenPT, MadiganSJ, McKeownM, et al. (1999) DFak56 is a novel Drosophila melanogaster focal adhesion kinase. J Biol Chem 274: 35621–35629.

14. FoxGL, RebayI, HynesRO (1999) Expression of DFak56, a Drosophila homolog of vertebrate focal adhesion kinase, supports a role in cell migration in vivo. Proc Natl Acad Sci USA 96: 14978–14983.

15. MurakamiS, UmetsuD, MaeyamaY, SatoM, YoshidaS, et al. (2007) Focal adhesion kinase controls morphogenesis of the Drosophila optic stalk. Development 134: 1539–1548.

16. TsaiP-I, KaoH-H, GrabbeC, LeeY-T, GhoseA, et al. (2008) Fak56 functions downstream of integrin alphaPS3betanu and suppresses MAPK activation in neuromuscular junction growth. Neural development 3: 26.

17. GrabbeC, ZervasCG, HunterT, BrownNH, PalmerRH (2004) Focal adhesion kinase is not required for integrin function or viability in Drosophila. Development 131: 5795–5805.

18. UedaA, GrabbeC, LeeJ, LeeJ, PalmerRH, et al. (2008) Mutation of Drosophila focal adhesion kinase induces bang-sensitive behavior and disrupts glial function, axonal conduction and synaptic transmission. Eur J Neurosci 27: 2860–2870.

19. ReadRD, GoodfellowPJ, MardisER, NovakN, ArmstrongJR, et al. (2005) A Drosophila model of multiple endocrine neoplasia type 2. Genetics 171: 1057–1081.

20. VidalM, WellsS, RyanA, CaganR (2005) ZD6474 suppresses oncogenic RET isoforms in a Drosophila model for type 2 multiple endocrine neoplasia syndromes and papillary thyroid carcinoma. Cancer Res 65: 3538–3541.

21. DasT, CaganR (2010) Drosophila as a novel therapeutic discovery tool for thyroid cancer. Thyroid 20: 689–695.

22. JhiangSM (2000) The RET proto-oncogene in human cancers. Oncogene 19: 5590–5597.

23. LeboulleuxS, BaudinE, TravagliJP, SchlumbergerM (2004) Medullary thyroid carcinoma. Clin Endocrinol (Oxf) 61: 299–310.

24. GriecoM, SantoroM, BerlingieriMT, MelilloRM, DonghiR, et al. (1990) PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 60: 557–563.

25. BongarzoneI, ButtiMG, CoronelliS, BorrelloMG, SantoroM, et al. (1994) Frequent activation of ret protooncogene by fusion with a new activating gene in papillary thyroid carcinomas. Cancer Res 54: 2979–2985.

26. SantoroM, RosatiR, GriecoM, BerlingieriMT, D'AmatoGL, et al. (1990) The ret proto-oncogene is consistently expressed in human pheochromocytomas and thyroid medullary carcinomas. Oncogene 5: 1595–1598.

27. BoulayA, BreuleuxM, StephanC, FuxC, BriskenC, et al. (2008) The Ret receptor tyrosine kinase pathway functionally interacts with the ERalpha pathway in breast cancer. Cancer Res 68: 3743–3751.

28. ChenSY, ChenHC (2006) Direct interaction of focal adhesion kinase (FAK) with Met is required for FAK to promote hepatocyte growth factor-induced cell invasion. Mol Cell Biol 26: 5155–5167.

29. SiegDJ, HauckCR, IlicD, KlingbeilCK, SchaeferE, et al. (2000) FAK integrates growth-factor and integrin signals to promote cell migration. Nat Cell Biol 2: 249–256.

30. Plaza-MenachoI, MorandiA, MologniL, BoenderP, Gambacorti-PasseriniC, et al. (2011) Focal adhesion kinase (FAK) binds RET kinase via its FERM domain, priming a direct and reciprocal RET-FAK transactivation mechanism. J Biol Chem 286: 17292–17302.

31. SandilandsE, SerrelsB, WilkinsonS, FrameMC (2012) Src-dependent autophagic degradation of Ret in FAK-signalling-defective cancer cells. EMBO Rep 13: 733–740.

32. CorderoJ, JassimO, BaoS, CaganR (2004) A role for wingless in an early pupal cell death event that contributes to patterning the Drosophila eye. Mech Dev 121: 1523–1530.

33. DarAC, DasTK, ShokatKM, CaganRL (2012) Chemical genetic discovery of targets and anti-targets for cancer polypharmacology. Nature 486: 80–84.

34. SpeicherSA, ThomasU, HinzU, KnustE (1994) The Serrate locus of Drosophila and its role in morphogenesis of the wing imaginal discs: control of cell proliferation. Development 120: 535–544.

35. GleichaufR (1936) Anatomie und Variabilitat des Geschlechtapparates von Drosophila melanogaster (Meigen).. ZWissZool 148: 1–66.

36. AdamG, PerrimonN, NoselliS (2003) The retinoic-like juvenile hormone controls the looping of left-right asymmetric organs in Drosophila. Development 130: 2397–2406.

37. FrameMC, PatelH, SerrelsB, LiethaD, EckMJ (2010) The FERM domain: organizing the structure and function of FAK. Nat Rev Mol Cell Biol 11: 802–814.

38. ZhaoX, PengX, SunS, ParkAY, GuanJL (2010) Role of kinase-independent and -dependent functions of FAK in endothelial cell survival and barrier function during embryonic development. J Cell Biol 189: 955–965.

39. SawamotoK, TaguchiA, HirotaY, YamadaC, JinMH, et al. (1998) Argos induces programmed cell death in the developing Drosophila eye by inhibition of the Ras pathway. Cell Death Differ 5: 262–270.

40. BergmannA, AgapiteJ, McCallK, StellerH (1998) The Drosophila gene hid is a direct molecular target of Ras-dependent survival signaling. Cell 95: 331–341.

41. KuradaP, WhiteK (1998) Ras promotes cell survival in Drosophila by downregulating hid expression. Cell 95: 319–329.

42. GretherME, AbramsJM, AgapiteJ, WhiteK, StellerH (1995) The head involution defective gene of Drosophila melanogaster functions in programmed cell death. Genes Dev 9: 1694–1708.

43. BlochlingerK, JanLY, JanYN (1993) Postembryonic patterns of expression of cut, a locus regulating sensory organ identity in Drosophila. Development 117: 441–450.

44. VerduJ, BuratovichMA, WilderEL, BirnbaumMJ (1999) Cell-autonomous regulation of cell and organ growth in Drosophila by Akt/PKB. Nat Cell Biol 1: 500–506.

45. LongW, YiP, AmazitL, LamarcaHL, AshcroftF, et al. (2010) SRC-3Delta4 Mediates the Interaction of EGFR with FAK to Promote Cell Migration. Molecular cell 37: 321–332.

46. Diaz-BenjumeaFJ, HafenE (1994) The sevenless signalling cassette mediates Drosophila EGF receptor function during epidermal development. Development 120: 569–578.

47. CorkeryB, CrownJ, ClynesM, O'DonovanN (2009) Epidermal growth factor receptor as a potential therapeutic target in triple-negative breast cancer. Ann Oncol 20: 862–867.

48. PriceJT, TiganisT, AgarwalA, DjakiewD, ThompsonEW (1999) Epidermal growth factor promotes MDA-MB-231 breast cancer cell migration through a phosphatidylinositol 3′-kinase and phospholipase C-dependent mechanism. Cancer Res 59: 5475–5478.

49. OwensLV, XuL, CravenRJ, DentGA, WeinerTM, et al. (1995) Overexpression of the focal adhesion kinase (p125FAK) in invasive human tumors. Cancer Res 55: 2752–2755.

50. AgochiyaM, BruntonVG, OwensDW, ParkinsonEK, ParaskevaC, et al. (1999) Increased dosage and amplification of the focal adhesion kinase gene in human cancer cells. Oncogene 18: 5646–5653.

51. SigismundS, ArgenzioE, TosoniD, CavallaroE, PoloS, et al. (2008) Clathrin-mediated internalization is essential for sustained EGFR signaling but dispensable for degradation. Dev Cell 15: 209–219.

52. MiaczynskaM, ChristoforidisS, GinerA, ShevchenkoA, Uttenweiler-JosephS, et al. (2004) APPL proteins link Rab5 to nuclear signal transduction via an endosomal compartment. Cell 116: 445–456.

53. SadowskiL, PileckaI, MiaczynskaM (2009) Signaling from endosomes: location makes a difference. Exp Cell Res 315: 1601–1609.

54. MarshallCJ (1995) Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80: 179–185.

55. IrwinME, MuellerKL, BohinN, GeY, BoernerJL (2011) Lipid raft localization of EGFR alters the response of cancer cells to the EGFR tyrosine kinase inhibitor gefitinib. J Cell Physiol 226: 2316–2328.

56. MaciaE, EhrlichM, MassolR, BoucrotE, BrunnerC, et al. (2006) Dynasore, a cell-permeable inhibitor of dynamin. Dev Cell 10: 839–850.

57. MesakiK, TanabeK, ObayashiM, OeN, TakeiK (2011) Fission of tubular endosomes triggers endosomal acidification and movement. PLoS One 6: e19764.

58. HenriksenL, GrandalMV, KnudsenSL, van DeursB, GrovdalLM (2013) Internalization mechanisms of the epidermal growth factor receptor after activation with different ligands. PLoS One 8: e58148.

59. RizzolioS, RabinowiczN, RaineroE, LanzettiL, SeriniG, et al. (2012) Neuropilin-1-dependent regulation of EGF-receptor signaling. Cancer Res 72: 5801–5811.

60. RaineroE, NormanJC (2013) Late endosomal and lysosomal trafficking during integrin-mediated cell migration and invasion: cell matrix receptors are trafficked through the late endosomal pathway in a way that dictates how cells migrate. Bioessays 35: 523–532.

61. RobertsM, BarryS, WoodsA, van der SluijsP, NormanJ (2001) PDGF-regulated rab4-dependent recycling of alphavbeta3 integrin from early endosomes is necessary for cell adhesion and spreading. Curr Biol 11: 1392–1402.

62. ChenT-H, ChanP-C, ChenC-L, ChenH-C (2011) Phosphorylation of focal adhesion kinase on tyrosine 194 by Met leads to its activation through relief of autoinhibition. Oncogene 30: 153–166.

63. HalfarK, RommelC, StockerH, HafenE (2001) Ras controls growth, survival and differentiation in the Drosophila eye by different thresholds of MAP kinase activity. Development 128: 1687–1696.

64. MatsuoT, TakahashiK, KondoS, KaibuchiK, YamamotoD (1997) Regulation of cone cell formation by Canoe and Ras in the developing Drosophila eye. Development 124: 2671–2680.

65. SandilandsE, SerrelsB, McEwanDG, MortonJP, MacagnoJP, et al. (2012) Autophagic targeting of Src promotes cancer cell survival following reduced FAK signalling. Nat Cell Biol 14: 51–60.

66. SchlaepferDD, HanksSK, HunterT, van der GeerP (1994) Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase. Nature 372: 786–791.

67. CanceWG, KurenovaE, MarloweT, GolubovskayaV (2013) Disrupting the scaffold to improve focal adhesion kinase-targeted cancer therapeutics. Sci Signal 6: pe10.

68. InfanteJR, CamidgeDR, MileshkinLR, ChenEX, HicksRJ, et al. (2012) Safety, pharmacokinetic, and pharmacodynamic phase I dose-escalation trial of PF-00562271, an inhibitor of focal adhesion kinase, in advanced solid tumors. J Clin Oncol 30: 1527–1533.

69. GabrielB, zur HausenA, StickelerE, DietzC, GitschG, et al. (2006) Weak expression of focal adhesion kinase (pp125FAK) in patients with cervical cancer is associated with poor disease outcome. Clin Cancer Res 12: 2476–2483.

70. AyakiM, KomatsuK, MukaiM, MurataK, KameyamaM, et al. (2001) Reduced expression of focal adhesion kinase in liver metastases compared with matched primary human colorectal adenocarcinomas. Clin Cancer Res 7: 3106–3112.

71. OhtaR, YamashitaY, TaketomiA, KitagawaD, KurodaY, et al. (2006) Reduced expression of focal adhesion kinase in intrahepatic cholangiocarcinoma is associated with poor tumor differentiation. Oncology 71: 417–422.

72. LuZ, JiangG, Blume-JensenP, HunterT (2001) Epidermal growth factor-induced tumor cell invasion and metastasis initiated by dephosphorylation and downregulation of focal adhesion kinase. Mol Cell Biol 21: 4016–4031.

73. ZhengY, LuZ (2009) Paradoxical roles of FAK in tumor cell migration and metastasis. Cell Cycle 8: 3474–3479.

74. HayBA, MaileR, RubinGM (1997) P element insertion-dependent gene activation in the Drosophila eye. Proc Natl Acad Sci U S A 94: 5195–5200.

75. FreemanM (1996) Reiterative use of the EGF receptor triggers differentiation of all cell types in the Drosophila eye. Cell 87: 651–660.

76. BradfordMM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248–254.

77. RaineroE, CaswellPT, MullerPA, GrindlayJ, McCaffreyMW, et al. (2012) Diacylglycerol kinase alpha controls RCP-dependent integrin trafficking to promote invasive migration. J Cell Biol 196: 277–295.

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2014 Číslo 3

Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Eozinofilní granulomatóza s polyangiitidou
nový kurz

Betablokátory a Ca antagonisté z jiného úhlu
Autori: prof. MUDr. Michal Vrablík, Ph.D., MUDr. Petr Janský

Autori: doc. MUDr. Petr Čáp, Ph.D.

Farmakoterapie akutní a chronické bolesti

Získaná hemofilie - Povědomí o nemoci a její diagnostika

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Nemáte účet?  Registrujte sa

Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa