BPGAP1 spatially integrates JNK/ERK signaling crosstalk in oncogenesis

Article metrics

Abstract

Simultaneous hyperactivation of stress-activated protein kinase/c-Jun N-terminal protein kinase (SAPK/JNK) and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signaling cascades has been reported in carcinogenesis. However, how they are integrated to promote oncogenesis remains unknown. By analyzing breast invasive carcinoma database (The Cancer Genome Altas), we found that the mRNA expression levels of both JNK1 and ERK2 are positively correlated with the mRNA level of EEA1, an endosome associated protein, indicating the potential JNK/ERK crosstalk at endosome. Unbiased screen of different endosome-associated Rab GTPases reveals that late endosome serves as a unique platform to integrate JNK/ERK signaling. Furthermore, we identify that BPGAP1 (a BCH domain-containing, Cdc42GAP-like Rho GTPase-activating protein) promotes MEK partner 1 (MP1)-induced ERK activation on late endosome through scaffolding MP1/MEK1 complex. This regulatory function requires phosphorylation of BPGAP1 by JNK at its C terminal tail (Ser424) to unlock its autoinhibitory conformation. Consequently, phosphorylated BPGAP1 facilitates endosomal ERK signaling transduction to the nucleus, driving cell proliferation and transformation via the ERK–Myc–CyclinA axis. BPGAP1 therefore provides a crucial spatiotemporal checkpoint where JNK and MP1/MEK1 work in concert to regulate endosomal and nuclear ERK signaling in cell proliferation control.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

References

  1. 1

    Arthur JS, Ley SC . Mitogen-activated protein kinases in innate immunity. Nat Rev Immunol 2013; 13: 679–692.

  2. 2

    Ma CX, Reinert T, Chmielewska I, Ellis MJ . Mechanisms of aromatase inhibitor resistance. Nat Rev Cancer 2015; 15: 261–275.

  3. 3

    Zhang W, Liu HT . MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res 2002; 12: 9–18.

  4. 4

    Shen YH, Godlewski J, Zhu J, Sathyanarayana P, Leaner V, Birrer MJ et al. Cross-talk between JNK/SAPK and ERK/MAPK pathways. J Biol Chem 2003; 278: 26715–26721.

  5. 5

    Lopez-Bergami P, Huang C, Goydos JS, Yip D, Bar-Eli M, Herlyn M et al. Rewired ERK-JNK signaling pathways in melanoma. Cancer Cell 2007; 11: 447–460.

  6. 6

    Ramirez A, Boulaiz H, Morata-Tarifa C, Peran M, Jimenez G, Picon-Ruiz M et al. HER2-signaling pathway, JNK and ERKs kinases, and cancer stem-like cells are targets of Bozepinib small compound. Oncotarget 2014; 5: 3590–3606.

  7. 7

    Grijelmo C, Rodrigue C, Svrcek M, Bruyneel E, Hendrix A, de Wever O et al. Proinvasive activity of BMP-7 through SMAD4/src-independent and ERK/Rac/JNK-dependent signaling pathways in colon cancer cells. Cell Signal 2007; 19: 1722–1732.

  8. 8

    Vieira AV, Lamaze C, Schmid SL . Control of EGF receptor signaling by clathrin-mediated endocytosis. Science 1996; 274: 2086–2089.

  9. 9

    Pennock S, Wang Z . Stimulation of cell proliferation by endosomal epidermal growth factor receptor as revealed through two distinct phases of signaling. Mol Cell Biol 2003; 23: 5803–5815.

  10. 10

    Wang Y, Pennock S, Chen X, Wang Z . Endosomal signaling of epidermal growth factor receptor stimulates signal transduction pathways leading to cell survival. Mol Cell Biol 2002; 22: 7279–7290.

  11. 11

    Parameswaran N, Enyindah-Asonye G, Bagheri N, Shah NB, Gupta N . Spatial coupling of JNK activation to the B cell antigen receptor by tyrosine-phosphorylated Ezrin. J Immunol 2013; 190: 2017–2026.

  12. 12

    Taniguchi CM, Emanuelli B, Kahn CR . Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol 2006; 7: 85–96.

  13. 13

    Hornberg JJ, Bruggeman FJ, Westerhoff HV, Lankelma J . Cancer: a systems biology disease. Bio Systems 2006; 83: 81–90.

  14. 14

    Palfy M, Remenyi A, Korcsmaros T . Endosomal crosstalk: meeting points for signaling pathways. Trends Cell Biol 2012; 22: 447–456.

  15. 15

    Schaeffer HJ, Catling AD, Eblen ST, Collier LS, Krauss A, Weber MJ . MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade. Science 1998; 281: 1668–1671.

  16. 16

    Sharma C, Vomastek T, Tarcsafalvi A, Catling AD, Schaeffer HJ, Eblen ST et al. MEK partner 1 (MP1): regulation of oligomerization in MAP kinase signaling. J Cell Biochem 2005; 94: 708–719.

  17. 17

    Teis D, Wunderlich W, Huber LA . Localization of the MP1-MAPK scaffold complex to endosomes is mediated by p14 and required for signal transduction. Dev Cell 2002; 3: 803–814.

  18. 18

    Teis D, Taub N, Kurzbauer R, Hilber D, de Araujo ME, Erlacher M et al. p14-MP1-MEK1 signaling regulates endosomal traffic and cellular proliferation during tissue homeostasis. J Cell Biol 2006; 175: 861–868.

  19. 19

    Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM . Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 2010; 141: 290–303.

  20. 20

    Pullikuth A, McKinnon E, Schaeffer HJ, Catling AD . The MEK1 scaffolding protein MP1 regulates cell spreading by integrating PAK1 and Rho signals. Mol Cell Biol 2005; 25: 5119–5133.

  21. 21

    Song P, Wang W, Tao G, Chu H, Wang M, Wu D et al. A miR-29c binding site genetic variant in the 3'-untranslated region of LAMTOR3 gene is associated with gastric cancer risk. Biomed Pharmacother 2015; 69: 70–75.

  22. 22

    De Araujo ME, Erhart G, Buck K, Muller-Holzner E, Hubalek M, Fiegl H et al. Polymorphisms in the gene regions of the adaptor complex LAMTOR2/LAMTOR3 and their association with breast cancer risk. PLoS One 2013; 8: e53768.

  23. 23

    Jun S, Lee S, Kim HC, Ng C, Schneider AM, Ji H et al. PAF-mediated MAPK signaling hyperactivation via LAMTOR3 induces pancreatic tumorigenesis. Cell Rep 2013; 5: 314–322.

  24. 24

    Jaffe AB, Hall A . Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol 2005; 21: 247–269.

  25. 25

    Vega FM, Ridley AJ . Rho GTPases in cancer cell biology. FEBS Lett 2008; 582: 2093–2101.

  26. 26

    Shang X, Zhou YT, Low BC . Concerted regulation of cell dynamics by BNIP-2 and Cdc42GAP homology/Sec14p-like, Proline-rich, and GTPase-activating protein domains of a novel Rho GTPase-activating protein, BPGAP1. J Biol Chem 2003; 278: 45903–45914.

  27. 27

    Alsayed Y, Timm M, Leontovich A, Santos D, Ho A, Singha U et al. Proteomic analysis of Waldenstrom Macroglobulinemia (WM) using nanoscale protein micorarray techniques. Blood 2005; 106: 150A–151A.

  28. 28

    Johnstone CN, Castellvi-Bel S, Chang LM, Bessa X, Nakagawa H, Harada H et al. ARHGAP8 is a novel member of the RHOGAP family related to ARHGAP1/CDC42GAP/p50RHOGAP: mutation and expression analyses in colorectal and breast cancers. Gene 2004; 336: 59–71.

  29. 29

    Song JY, Lee JK, Lee NW, Jung HH, Kim SH, Lee KW . Microarray analysis of normal cervix, carcinomain situ,and invasive cervical cancer: identification of candidate genes in pathogenesis of invasion in cervical cancer. Int J Gynecol Cancer 2008; 18: 1051–1059.

  30. 30

    Pan CQ, Liou YC, Low BC . Active Mek2 as a regulatory scaffold that promotes Pin1 binding to BPGAP1 to suppress BPGAP1-induced acute Erk activation and cell migration. J Cell Sci 2010; 123: 903–916.

  31. 31

    Lua BL, Low BC . Activation of EGF receptor endocytosis and ERK1/2 signaling by BPGAP1 requires direct interaction with EEN/endophilin II and a functional RhoGAP domain. J Cell Sci 2005; 118: 2707–2721.

  32. 32

    Mingo-Sion AM, Marietta PM, Koller E, Wolf DM, Van Den Berg CL . Inhibition of JNK reduces G2/M transit independent of p53, leading to endoreduplication, decreased proliferation, and apoptosis in breast cancer cells. Oncogene 2004; 23: 596–604.

  33. 33

    Fujii S, Tokita K, Wada N, Ito K, Yamauchi C, Ito Y et al. MEK-ERK pathway regulates EZH2 overexpression in association with aggressive breast cancer subtypes. Oncogene 2011; 30: 4118–4128.

  34. 34

    Brown MD, Sacks DB . Protein scaffolds in MAP kinase signalling. Cell Signal 2009; 21: 462–469.

  35. 35

    West RJH, Lu YB, Marie B, Gao FB, Sweeney ST . Rab8, POSH, and TAK1 regulate synaptic growth in a Drosophila model of frontotemporal dementia. J Cell Biol 2015; 208: 931–947.

  36. 36

    Hutagalung AH, Novick PJ . Role of Rab GTPases in membrane traffic and cell physiology. Physiol Rev 2011; 91: 119–149.

  37. 37

    Miaczynska M . Effects of membrane trafficking on signaling by receptor tyrosine kinases. Cold Spring Harb Perspect Biol 2013; 5: a009035.

  38. 38

    Sorkin A, von Zastrow M . Endocytosis and signalling: intertwining molecular networks. Nat Rev Mol Cell Biol 2009; 10: 609–622.

  39. 39

    Chang F, Steelman LS, Lee JT, Shelton JG, Navolanic PM, Blalock WL 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: 1263–1293.

  40. 40

    Dang CV . c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol Cell Biol 1999; 19: 1–11.

  41. 41

    Yam CH, Fung TK, Poon RY . Cyclin A in cell cycle control and cancer. Cell Mol Life Sci 2002; 59: 1317–1326.

  42. 42

    Good MC, Zalatan JG, Lim WA . Scaffold proteins: hubs for controlling the flow of cellular information. Science 2011; 332: 680–686.

  43. 43

    White CD, Brown MD, Sacks DB . IQGAPs in cancer: a family of scaffold proteins underlying tumorigenesis. FEBS Lett 2009; 583: 1817–1824.

  44. 44

    Pan CQ, Low BC . Functional plasticity of the BNIP-2 and Cdc42GAP homology (BCH) domain in cell signaling and cell dynamics. FEBS Lett 2012; 586: 2674–2691.

  45. 45

    Vomastek T, Iwanicki MP, Schaeffer HJ, Tarcsafalvi A, Parsons JT, Weber MJ . RACK1 targets the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway to link integrin engagement with focal adhesion disassembly and cell motility. Mol Cell Biol 2007; 27: 8296–8305.

  46. 46

    Pan CQ, Sudol M, Sheetz M, Low BC . Modularity and functional plasticity of scaffold proteins as p(l)acemakers in cell signaling. Cell Signal 2012; 24: 2143–2165.

  47. 47

    Sirokmany G, Szidonya L, Kaldi K, Gaborik Z, Ligeti E, Geiszt M . Sec14 homology domain targets p50RhoGAP to endosomes and provides a link between Rab and Rho GTPases. J Biol Chem 2006; 281: 6096–6105.

  48. 48

    Kang JS, Bae GU, Yi MJ, Yang YJ, Oh JE, Takaesu G et al. A Cdo-Bnip-2-Cdc42 signaling pathway regulates p38 alpha/beta MAPK activity and myogenic differentiation. J Cell Biol 2008; 182: 497–507.

  49. 49

    Engstrom W, Ward A, Moorwood K . The role of scaffold proteins in JNK signalling. Cell Prolif 2010; 43: 56–66.

  50. 50

    Lanzetti L, Rybin V, Malabarba MG, Christoforidis S, Scita G, Zerial M et al. The Eps8 protein coordinates EGF receptor signalling through Rac and trafficking through Rab5. Nature 2000; 408: 374–377.

  51. 51

    de Graauw M, Cao L, Winkel L, van Miltenburg MHAM, le Devedec SE, Klop M et al. Annexin A2 depletion delays EGFR endocytic trafficking via cofilin activation and enhances EGFR signaling and metastasis formation. Oncogene 2014; 33: 2610–2619.

  52. 52

    Coso OA, Chiariello M, Yu JC, Teramoto H, Crespo P, Xu N et al. The small GTP-binding proteins Rac1 and Cdc42 regulate the activity of the JNK/SAPK signaling pathway. Cell 1995; 81: 1137–1146.

  53. 53

    Minden A, Lin AN, Claret FX, Abo A, Karin M . Selective activation of the jnk signaling cascade and c-jun transcriptional activity by the small GTPases Rac and Cdc42hs. Cell 1995; 81: 1147–1157.

  54. 54

    Adler V, Qu YX, Smith SJ, Izotova L, Pestka S, Kung HF et al. Functional interactions of Raf and MEK with jun-N-terminal kinase (JNK) result in a positive feedback loop on the oncogenic ras signaling pathway. Biochemistry 2005; 44: 10784–10795.

  55. 55

    Lopez-Bergami P, Ronai Z . Requirements for PKC-augmented JNK activation by MKK4/7. Int J Biochem Cell Biol 2008; 40: 1055–1064.

  56. 56

    Taub N, Teis D, Ebner HL, Hess MW, Huber LA . Late endosomal traffic of the epidermal growth factor receptor ensures spatial and temporal fidelity of mitogen-activated protein kinase signalling. Mol Biol Cell 2007; 18: 4698–4710.

  57. 57

    Wu P, Wee P, Jiang J, Chen X, Wang Z . Differential regulation of transcription factors by location-specific EGF receptor signaling via a spatio-temporal interplay of ERK activation. PLoS One 2012; 7: e41354.

  58. 58

    Skarpen E, Flinder LI, Rosseland CM, Orstavik S, Wierod L, Oksvold MP et al. MEK1 and MEK2 regulate distinct functions by sorting ERK2 to different intracellular compartments. FASEB J 2008; 22: 466–476.

  59. 59

    Koyano F, Okatsu K, Kosako H, Tamura Y, Go E, Kimura M et al. Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature 2014; 510: 162–166.

Download references

Acknowledgements

This work was supported by an NUS Research Scholarship (to TJ), a Ministry of Education Tier 2 grant (R154-000-236-112 to BCL) and the Mechanobiology Institute of Singapore (to BCL), funded through the National Research Foundation and the Ministry of Education Singapore. This work was also supported by National Medical Research Council, CBRG New Investigator Grant (CBRG-NIG) (R-714-000-115-511 to CQP). We thank Proteins and Proteomics Center (National University of Singapore) for mass spectrometric analysis. We thank Nisha Mohd Rafiq (National University of Singapore) for the technical support. We also thank Professor Andrew Catling (LSU Health Sciences Center), Professor Kanga Sabapathy (National Cancer Center, Singapore), and Professor Yih-Cherng Liou (National University of Singapore) for providing MP1, phospho-JNK1, CyclinA and CyclinE antibodies, respectively.

Author contributions

TJ designed and performed the experiments. TJ and CQP analyzed the data. TJ and CQP wrote the paper. BCL designed experiments, analyzed data and wrote the paper.

Author information

Correspondence to C Q Pan or B C Low.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Further reading