Skip to main content

PEBP1/RKIP behavior: a mirror of actin-membrane organization


Phosphatidylethanolamine-binding protein 1 (PEBP1), a small 21 kDa protein, is implicated in several key processes of the living cell. The deregulation of PEBP1, especially its downregulation, leads to major diseases such as cancer and Alzheimer’s disease. PEBP1 was found to interact with numerous proteins, especially kinases and GTPases, generally inhibiting their activity. To understand the basic functionality of this amazing small protein, we have considered several known processes that it modulates and we have discussed the role of each molecular target in these processes. Here, we propose that cortical actin organization, associated with membrane changes, is involved in the majority of the processes modulated by PEBP1. Furthermore, based on recent data, we summarize some key PEBP1-interacting proteins, and we report their respective functions and focus on their relationships with actin organization. We suggest that, depending on the cell status and environment, PEBP1 is an organizer of the actin-membrane composite material.

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

Fig. 1
Fig. 2


  1. 1.

    Bernier I, Tresca JP, Jollès P (1986) Ligand-binding studies with a 23 kDa protein purified from bovine brain cytosol. Biochim Biophys Acta 871(1):19–23

    CAS  PubMed  Google Scholar 

  2. 2.

    Schoentgen F, Saccoccio F, Jollès J, Bernier I, Jollès P (1987) Complete amino acid sequence of a basic 21-kDa protein from bovine brain cytosol. Eur J Biochem 166(2):333–338

    CAS  PubMed  Google Scholar 

  3. 3.

    Serre L, Vallée B, Bureaud N, Schoentgen F, Zelwer C (1998) Crystal structure of the Phosphatidylethanolamine-binding protein from bovine brain: a novel structural class of phospholipid-binding proteins. Structure 6(10):1255–1265

    CAS  PubMed  Google Scholar 

  4. 4.

    Banfield MJ, Barker JJ, Perry AC, Brady RL (1998) Function from structure? The crystal structure of human phosphatidylethanolamine-binding protein suggests a role in membrane signal transduction. Structure 6(10):1245–1254

    CAS  PubMed  Google Scholar 

  5. 5.

    Lamiman K, Keller JM, Mizokami A, Zhang J, Keller ET (2014) Survey of Raf kinase inhibitor protein (RKIP) in multiple cancer types. Crit Rev Oncog 19(6):455–468

    PubMed  Google Scholar 

  6. 6.

    Keller ET, Fu Z, Yeung K, Brennan M (2004) Raf kinase inhibitor protein: a prostate cancer metastasis suppressor gene. Cancer Lett 207(2):131–137

    CAS  PubMed  Google Scholar 

  7. 7.

    Schoentgen F, Jonic S (2018) PEBP1/RKIP: from multiple functions to a common role in cellular processes. arXiv:1802.02378 [q-bio.SC]

  8. 8.

    Rajkumar K, Nichita A, Anoor PK, Raju S, Singh SS, Burgula S (2016) Understanding perspectives of signalling mechanisms regulating PEBP1 function. Cell Biochem Funct 34(6):394–403

    CAS  PubMed  Google Scholar 

  9. 9.

    Yeung K, Seitz T, Li S, Janosch P, McFerran B, Kaiser C, Fee F, Katsanakis KD, Rose DW, Mischak H, Sedivy JM, Kolch W (1999) Suppression of Raf-1 kinase activity and MAP kinase signaling by RKIP. Nature 401(6749):173–177

    CAS  PubMed  Google Scholar 

  10. 10.

    Tang H, Park S, Sun SC, Trumbly R, Ren G, Tsung E, Yeung KC (2010) RKIP inhibits NF-kappaB in cancer cells by regulating upstream signaling components of the IkappaB kinase complex. FEBS Lett 584(4):662–668

    CAS  PubMed  Google Scholar 

  11. 11.

    Maresch J, Birner P, Zakharinov M, Toumangelova-Uzeir K, Natchev S, Guentchev M (2011) Additive effect on survival of Raf kinase inhibitor protein and signal transducer and activator of transcription 3 in high-grade glioma. Cancer 117(11):2499–2504

    CAS  PubMed  Google Scholar 

  12. 12.

    Wall AA, Luo L, Hung Y, Tong SJ, Condon ND, Blumenthal A, Sweet MJ, Stow JL (2017) Small GTPase Rab8a-recruited phosphatidylinositol 3-kinase γ regulates signaling and cytokine outputs from endosomal Toll-like receptors. J Biol Chem 292(11):4411–4422

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Al-Mulla F, Bitar MS, Taqi Z, Yeung KC (2013) RKIP: much more than Raf kinase inhibitory protein. J Cell Physiol 228(8):1688–1702

    CAS  PubMed  Google Scholar 

  14. 14.

    Shin SY, Rath O, Zebisch A, Choo SM, Kolch W, Cho KH (2010) Functional roles of multiple feedback loops in extracellular signal-regulated kinase and Wnt signaling pathways that regulate epithelial-mesenchymal transition. Cancer Res 70(17):6715–6724

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Lin X, Bai F, Nie J, Lu S, Lu C, Zhu X, Wei J, Lu Z, Huang Q (2016) Didymin alleviates hepatic fibrosis through inhibiting ERK and PI3K/Akt pathways via regulation of Raf kinase inhibitor protein. Cell Physiol Biochem 40(6):1422–1432

    CAS  PubMed  Google Scholar 

  16. 16.

    Lai R, Gu M, Jiang W, Lin W, Xu P, Liu Z, Huang H, An H, Wang X (2017) Raf kinase inhibitor protein preferentially promotes TLR3-triggered signaling and inflammation. J Immunol 198(10):4086–4095

    CAS  PubMed  Google Scholar 

  17. 17.

    Noh HS, Hah YS, Ha JH, Kang MY, Zada S, Rha SY, Kang SS, Kim HJ, Park JY, Byun JH, Hahm JR, Shin JK, Jeong SH, Lee YJ, Kim DR (2016) Regulation of the epithelial to mesenchymal transition and metastasis by Raf kinase inhibitory protein-dependent Notch1 activity. Oncotarget 7(4):4632–4646

    PubMed  Google Scholar 

  18. 18.

    Al-Mulla F, Bitar MS, Al-Maghrebi M, Behbehani AI, Al-Ali W, Rath O, Doyle B, Tan KY, Pitt A, Kolch W (2011) Raf kinase inhibitor protein RKIP enhances signaling by glycogen synthase kinase-3β. Cancer Res 71(4):1334–1343

    CAS  PubMed  Google Scholar 

  19. 19.

    Gavilán E, Sánchez-Aguayo I, Daza P, Ruano D (2013) GSK-3β signaling determines autophagy activation in the breast tumor cell line MCF7 and inclusion formation in the non-tumor cell line MCF10A in response to proteasome inhibition. Cell Death Dis 4:e572.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Gu H, Zhan X, Zhang G, Yan L, Cho WC, Li M, Liu T, Chen Z (2013) Mapping the interactome of overexpressed RAF kinase inhibitor protein in a gastric cancer cell line. BMC cancer.

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Li H, Yang HS, Wu TJ, Zhang XY, Jiang WH, Ma QL, Chen YX, Xu Y, Li S, Hua ZC (2010) Proteomic analysis of early-response to mechanical stress in neonatal rat mandibular condylar chondrocytes. J Cell Physiol 223(3):610–622

    CAS  PubMed  Google Scholar 

  22. 22.

    Demidem A, Morvan D, Madelmont JC (2006) Bystander effects are induced by CENU treatment and associated with altered protein secretory activity of treated tumor cells: a relay for chemotherapy? Int J Cancer 119(5):992–1004

    CAS  PubMed  Google Scholar 

  23. 23.

    Huang Q, Liang C, Wei L, Nie J, Lu S, Lu C, Zhuo L, Lu Z, Lin X (2016) Raf kinase inhibitory protein down-expression exacerbates hepatic fibrosis in vivo and in vitro. Cell Physiol Biochem 40(1–2):49–61

    CAS  PubMed  Google Scholar 

  24. 24.

    van Haastert PJ, Keizer-Gunnink I, Kortholt A (2017) Coupled excitable Ras and F-actin activation mediates spontaneous pseudopod formation and directed cell movement. Mol Biol Cell 28(7):922–934

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Nobes CD, Hall A (1995) Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell 81(1):53–62

    CAS  PubMed  Google Scholar 

  26. 26.

    Yesilkanal AE, Rabe DC, Tiwari P, Frankenberger C, Johnson GL, Rosner M (2018) A novel approach for antimetastatic therapies against TNBC utilizing a physiologic suppressor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 78(13 Suppl):Abstract nr 4179

  27. 27.

    Upadhyay G, Goessling W, North TE, Xavier R, Zon LI, Yajnik V (2008) Molecular association between β-catenin degradation complex and Rac guanine exchange factor DOCK4 is essential for Wnt/β-catenin signaling. Oncogene 27(44):5845–5855

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Abraham S, Scarcia M, Bagshaw RD, McMahon K, Grant G, Harvey T, Yeo M, Esteves FO, Thygesen HH, Jones PF, Speirs V, Hanby AM, Selby PJ, Lorger M, Dear TN, Pawson T, Marshall CJ, Mavria G (2015) A Rac/Cdc42 exchange factor complex promotes formation of lateral filopodia and blood vessel lumen morphogenesis. Nat Commun.

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Yu JR, Tai Y, Jin Y, Hammell MC, Wilkinson JE, Roe JS, Vakoc CR, Van Aelst L (2015) TGFb/ Smad signaling through DOCK4 facilitates lung adenocarcinoma metastasis. Genes Dev 29(3):250–261

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Hiramoto-Yamaki N, Takeuchi S, Ueda S, Harada K, Fujimoto S, Negishi M, Katoh H (2010) Ephexin4 and EphA2 mediate cell migration through a RhoG-dependent mechanism. J Cell Biol 190(3):461–477

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Yan D, Li F, Hall ML, Sage C, Hu WH, Giallourakis C, Upadhyay G, Ouyang XM, Du LL, Bethea JR, Chen ZY, Yajnik V, Liu XZ (2006) An isoform of GTPase regulator DOCK4 localizes to the stereocilia in the inner ear and binds to harmonin (USH1C). J Mol Biol 357(3):755–764

    CAS  PubMed  Google Scholar 

  32. 32.

    Xiao Y, Peng Y, Wan J, Tang G, Chen Y, Tang J, Ye WC, Ip NY, Shi L (2013) The atypical guanine nucleotide exchange factor Dock4 regulates neurite differentiation through modulation of Rac1 GTPase and actin dynamics. J Biol Chem 288(27):20034–20045

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Newell-Litwa KA, Horwitz R, Lamers ML (2015) Non-muscle myosin II in disease: mechanisms and therapeutic opportunities. Dis Model Mech 8(12):1495–1515

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Shutova MS, Svitkina TM (2018) Common and specific functions of non-muscle Myosin II paralogs in cells. Biochemistry (Mosc) 83(12):1459–1468

    CAS  Google Scholar 

  35. 35.

    Betapudi V (2010) Myosin II motor proteins with different functions determine the fate of lamellipodia extension during cell spreading. PLoS ONE 5(1):e8560.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Ahmed M, Lai TH, Zada S, Hwang JS, Pham TM, Yun M, Kim DR (2018) Functional linkage of RKIP to the epithelial to mesenchymal transition and autophagy during the development of prostate cancer. Cancers (Basel).

    Article  PubMed Central  Google Scholar 

  37. 37.

    Borg Distefano M, Hofstad Haugen L, Wang Y, Perdreau-Dahl H, Kjos I, Jia D, Morth JP, Neefjes J, Bakke O, Progida C (2018) TBC1D5 controls the GTPase cycle of Rab7b. J Cell Sci.

    Article  PubMed  Google Scholar 

  38. 38.

    Borg M, Bakke O, Progida C (2014) A novel interaction between Rab7b and actomyosin reveals a dual role in intracellular transport and cell migration. J Cell Sci.

    Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Vallée B, Doudeau M, Godin F, Gombault A, Tchalikian A, de Tauzia ML, Bénédetti H (2012) Nf1 RasGAP inhibition of LIMK2 mediates a new cross-talk between Ras and Rho pathways. PLoS ONE.

    Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Visvikis O, Boyer L, Torrino S, Doye A, Lemonnier M, Lorès P, Rolando M, Flatau G, Mettouchi A, Bouvard D, Veiga E, Gacon G, Cossart P, Lemichez E (2011) Escherichia coli producing CNF1 toxin hijacks Tollip to trigger Rac1-dependent cell invasion. Traffic 12(5):579–590

    CAS  PubMed  Google Scholar 

  41. 41.

    Rotoli D, Morales M, Ávila J, Maeso MDC, García MDP, Mobasheri A, Martín-Vasallo P (2017) Commitment of scaffold proteins in the onco-biology of human colorectal cancer and liver metastases after oxaliplatin-based chemotherapy Int J Mol Sci.

    Article  PubMed  Google Scholar 

  42. 42.

    Benseñor LB, Kan HM, Wang N, Wallrabe H, Davidson LA, Cai Y, Schafer DA, Bloom GS (2007) IQGAP1 regulates cell motility by linking growth factor signaling to actin assembly. J Cell Sci 120(Pt 4):658–669

    PubMed  Google Scholar 

  43. 43.

    Corbit KC, Trakul N, Eves EM, Diaz B, Marshall M, Rosner MR (2003) Activation of Raf-1 signaling by protein kinase C through a mechanism involving Raf kinase inhibitory protein. J Biol Chem 278:13061–13068

    CAS  PubMed  Google Scholar 

  44. 44.

    Lorenz K, Lohse MJ, Quitterer U (2003) Protein kinase C switches the Raf kinase inhibitor from Raf-1 to GRK-2. Nature 426(6966):574–579

    CAS  PubMed  Google Scholar 

  45. 45.

    Foerster F, Braig S, Moser C, Kubisch R, Busse J, Wagner E, Schmoeckel E, Mayr D, Schmitt S, Huettel S, Zischka H, Mueller R, Vollmar AM (2014) Targeting the actin cytoskeleton: selective antitumor action via trapping PKCε. Cell Death Dis.

    Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Penela P, Murga C, Ribas C, Lafarga V (2010) Mayor F Jr (2010) The complex G protein-coupled receptor kinase 2 (GRK2) interactome unveils new physiopathological targets. Br J Pharmacol 160(4):821–832

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Penela P, Nogués L, Mayor F Jr (2014) Role of G protein-coupled receptor kinases in cell migration. Curr Opin Cell Biol 27:10–17

    CAS  PubMed  Google Scholar 

  48. 48.

    Kahsai AW, Zhu S (1803) Fenteany G (2010) G protein-coupled receptor kinase 2 activates radixin, regulating membrane protrusion and motility in epithelial cells. Biochim Biophys Acta 2:300–310

    Google Scholar 

  49. 49.

    Lafarga V, Mayor F Jr, Penela P (2012) The interplay between G protein-coupled receptor kinase 2 (GRK2) and histone deacetylase 6 (HDAC6) at the crossroads of epithelial cell motility. Cell Adh Migr 6(6):495–501

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    Crassini K, Pyke T, Shen Y, Stevenson WS, Christopherson RI, Mulligan SP, Best OG (2018) Inhibition of the Raf-1 kinase inhibitory protein (RKIP) by locostatin induces cell death and reduces the CXCR4-mediated migration of chronic lymphocytic leukemia cells. Leuk Lymphoma.

    Article  PubMed  Google Scholar 

  51. 51.

    Calebiro D, Godbole A (2018) Internalization of G-protein-coupled receptors: implication in receptor function, physiology and diseases. Best Pract Res Clin Endocrinol Metab 32(2):83–91

    CAS  PubMed  Google Scholar 

  52. 52.

    Jin T (2013) Gradient sensing during chemotaxis. Curr Opin Cell Biol 25(5):532–537

    CAS  PubMed  Google Scholar 

  53. 53.

    Xu X, Jin T (2017) ELMO proteins transduce G protein-coupled receptor signal to control reorganization of actin cytoskeleton in chemotaxis of eukaryotic cells. Small GTPases.

    Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Murga-Zamalloa CA, Ghosh AK, Patil SB, Reed NA, Chan LS, Davuluri S, Peränen J, Hurd TW, Rachel RA, Khanna H (2011) Accumulation of the Raf-1 kinase inhibitory protein (RKIP) is associated with Cep290-mediated photoreceptor degeneration in ciliopathies. J Biol Chem 286(32):28276–28286

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Satir P, Pedersen LB, Christensen ST (2010) The primary cilium at a glance. J Cell Sci 123(Pt 4):499–503

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Singla V, Reiter JF (2006) The primary cilium as the cell's antenna: signaling at a sensory organelle. Science 313(5787):629–633

    CAS  PubMed  Google Scholar 

  57. 57.

    Wheway G, Nazlamova L, Hancock JT (2018) signaling through the primary cilium. Front Cell Dev Biol 6:8.

    Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Lee S, Tan HY, Geneva II, Kruglov A, Calvert PD (2018) Actin filaments partition primary cilia membranes into distinct fluid corrals. J Cell Biol 217(8):2831–2849

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Seeger-Nukpezah T, Golemis EA (2012) The extracellular matrix and ciliary signaling. Curr Opin Cell Biol 24(5):652–661

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Sas KM, Janech MG, Favre E, Arthur JM, Bell PD (2011) Cilia movement regulates expression of the Raf-1 kinase inhibitor protein. Am J Physiol Renal Physiol 300(5):F1163–1170

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Pampliega O, Orhon I, Patel B, Sridhar S, Díaz-Carretero A, Beau I, Codogno P, Satir BH, Satir P, Cuervo AM (2013) functional interaction between autophagy and ciliogenesis. Nature 502(7470):194–200

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Higgins M, Obaidi I, McMorrow T (2019) Primary cilia and their role in cancer. Oncol Lett 17(3):3041–3047

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Al-Mulla F, Bitar MS, Taqi Z, Rath O, Kolch W (2011) Raf kinase inhibitory protein (RKIP) modulates cell cycle kinetics and motility. Mol Biosyst 7(3):928–941

    CAS  PubMed  Google Scholar 

  64. 64.

    Noh HS, Hah YS, Zada S, Ha JH, Sim G, Hwang JS, Lai TH, Nguyen HQ, Park JY, Kim HJ, Byun JH, Hahm JR, Kang KR, Kim DR (2016) PEBP1, a Raf kinase inhibitory protein, negatively regulates starvation-induced autophagy by direct interaction with LC3. Autophagy 12(11):2183–2196

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Kenific CM, Wittmann T, Debnath J (2016) autophagy in adhesion and migration. J Cell Sci 129(20):3685–3693

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Mi N, Chen Y, Wang S, Chen M, Zhao M, Yang G, Ma M, Su Q, Luo S, Shi J, Xu J, Guo Q, Gao N, Sun Y, Chen Z, Yu L (2015) CapZ regulates autophagosomal membrane shaping by promoting actin assembly inside the isolation membrane. Nat Cell Biol 17(9):1112–1123

    CAS  PubMed  Google Scholar 

  67. 67.

    Hu X, Mullins RD (2019) LC3 and STRAP regulate actin filament assembly by JMY during autophagosome formation. J Cell Biol 218(1):251–266

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Liu X, Klionsky DJ (2019) Regulation of JMY’s actin nucleation activity by TTC5/STRAP and LC3 during autophagy. Autophagy 15(3):373–374

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Corbier C, Sellier C (2017) C9ORF72 is a GDP/GTP exchange factor for Rab8 and Rab39 and regulates autophagy. Small GTPases 8(3):181–186

    CAS  PubMed  Google Scholar 

  70. 70.

    Keller ET (2004) Metastasis suppressor genes: a role for Raf kinase inhibitor protein (RKIP). Anticancer Drugs 15(7):663–669

    CAS  PubMed  Google Scholar 

  71. 71.

    He QY, Yi HM, Yi H, Xiao T, Qu JQ, Yuan L, Zhu JF, Li JY, Wang YY, Li LN, Feng J, Lu SS, Xiao ZQ (2015) Reduction of RKIP expression promotes nasopharyngeal carcinoma invasion and metastasis by activating Stat3 signaling. Oncotarget 6(18):16422–16436

    PubMed  PubMed Central  Google Scholar 

  72. 72.

    Bement WM (2005) A role for RKIP in cell motility. Chem Biol 12(9):953–954

    CAS  PubMed  Google Scholar 

  73. 73.

    Sheetz MP, Felsenfeld D, Galbraith CG, Choquet D (1999) Cell migration as a five-step cycle. Biochem Soc Symp 65:233–243

    CAS  PubMed  Google Scholar 

  74. 74.

    Mc Henry KT, Montesano R, Zhu S, Beshir AB, Tang HH, Yeung KC, Fenteany G (2008) Raf kinase inhibitor protein positively regulates cell-substratum adhesion while negatively regulating cell-cell adhesion. J Cell Biochem 103(3):972–985

    CAS  PubMed  Google Scholar 

  75. 75.

    Das SK, Bhutia SK, Sokhi UK, Azab B, Su ZZ, Boukerche H, Anwar T, Moen EL, Chatterjee D, Pellecchia M, Sarkar D, Fisher PB (2012) Raf kinase inhibitor RKIP inhibits MDA-9/syntenin-mediated metastasis in melanoma. Cancer Res 72(23):6217–6226

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Alblazi KM, Siar CH (2015) Cellular protrusions - lamellipodia, filopodia, invadopodia and podosomes—and their roles in progression of orofacial tumours: current understanding. Asian Pac J Cancer Prev 16(6):2187–2191

    PubMed  Google Scholar 

  77. 77.

    Revach OY, Geiger B (2014) The interplay between the proteolytic, invasive, and adhesive domains of invadopodia and their roles in cancer invasion. Cell Adh Migr 8(3):215–225

    PubMed  Google Scholar 

  78. 78.

    Bravo-Cordero JJ, Cordani M, Soriano SF, Díez B, Muñoz-Agudo C, Casanova-Acebes M, Boullosa C, Guadamillas MC, Ezkurdia I, González-Pisano D, Del Pozo MA, Montoya MC (2016) A novel high-content analysis tool reveals Rab8-driven cytoskeletal reorganization through Rho GTPases, calpain and MT1-MMP. J Cell Sci 129(8):1734–1749

    CAS  PubMed  Google Scholar 

  79. 79.

    Bi J, Wang R, Zeng X (2018) Lipid rafts regulate the lamellipodia formation of melanoma A375 cells via actin cytoskeleton-mediated recruitment of β1 and β3 integrin. Oncol Lett 16(5):6540–6546

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Juanes MA, Bouguenina H, Eskin JA, Jaiswal R, Badache A, Goode BL (2017) Adenomatous polyposis coli nucleates actin assembly to drive cell migration and microtubule-induced focal adhesion turnover. J Cell Biol 216(9):2859–2875

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Okada K, Bartolini F, Deaconescu AM, Moseley JB, Dogic Z, Grigorieff N, Gundersen GG, Goode BL (2010) Adenomatous polyposis coli protein nucleates actin assembly and synergizes with the formin mDia1. J Cell Biol 189(7):1087–1096

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Tirnauer JS (2004) A new cytoskeletal connection for APC: linked to actin through IQGAP. Dev Cell 7(6):778–780

    CAS  PubMed  Google Scholar 

  83. 83.

    Eves EM, Shapiro P, Naik K, Klein UR, Trakul N, Rosner MR (2006) Raf kinase inhibitory protein regulates aurora B kinase and the spindle checkpoint. Mol Cell 23(4):561–574

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Eves EM, Rosner MR (2010) MAP kinase regulation of the mitotic spindle checkpoint. Methods Mol Biol 661:497–505

    CAS  PubMed  Google Scholar 

  85. 85.

    Rosner MR (2007) MAP kinase meets mitosis: a role for Raf Kinase Inhibitory Protein in spindle checkpoint regulation. Cell Div 2:1.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Bordeleau F, Myrand Lapierre ME, Sheng Y, Marceau N (2012) Keratin 8/18 regulation of cell stiffness-extracellular matrix interplay through modulation of Rho-mediated actin cytoskeleton dynamics. PLoS ONE.

    Article  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Moch M, Windoffer R, Schwarz N, Pohl R, Omenzetter A, Schnakenberg U, Herb F, Chaisaowong K, Merhof D, Ramms L, Fabris G, Hoffmann B, Merkel R, Leube RE (2016) Effects of plectin depletion on keratin network dynamics and organization. PLoS ONE.

    Article  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Tavel L, Jaquillard L, Karsisiotis AI, Saab F, Jouvensal L, Brans A, Delmas AF, Schoentgen F, Cadene M, Damblon C (2012) Ligand binding study of human PEBP1/RKIP: interaction with nucleotides and Raf-1 peptides evidenced by NMR and mass spectrometry. PLoS ONE.

    Article  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Park S, Rath O, Beach S, Xiang X, Kelly SM, Luo Z, Kolch W, Yeung KC (2006) Regulation of RKIP binding to the N-region of the Raf-1 kinase. FEBS Lett 580(27):6405–6412

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Skinner JJ, Wang S, Lee J, Ong C, Sommese R, Sivaramakrishnan S, Koelmel W, Hirschbeck M, Schindelin H, Kisker C, Lorenz K, Sosnick TR, Rosner MR (2017) Conserved salt-bridge competition triggered by phosphorylation regulates the protein interactome. Proc Natl Acad Sci USA 114(51):13453–13458

    CAS  PubMed  Google Scholar 

  91. 91.

    Martin J, Lavery R (2012) Arbitrary protein-protein docking targets biologically relevant interfaces. BMC Biophys.

    Article  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Nishi H, Fong JH, Chang C, Teichmann SA, Panchenko AR (2013) Regulation of protein-protein binding by coupling between phosphorylation and intrinsic disorder: analysis of human protein complexes. Mol Biosyst 9(7):1620–1626

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Köster DV, Mayor S (2016) Cortical actin and the plasma membrane: inextricably intertwined. Curr Opin Cell Biol 38:81–89

    PubMed  Google Scholar 

  94. 94.

    Peränen J (2011) Rab8 GTPase as a regulator of cell shape. Cytoskeleton (Hoboken) 68(10):527–539

    Google Scholar 

  95. 95.

    Ling HH, Mendoza-Viveros L, Mehta N, Cheng HY (2014) Raf kinase inhibitory protein (RKIP): functional pleiotropy in the mammalian brain. Crit Rev Oncog 19(6):505–516

    PubMed  PubMed Central  Google Scholar 

  96. 96.

    Sagisaka T, Matsukawa N, Toyoda T, Uematsu N, Kanamori T, Wake H, Borlongan CV, Ojika K (2010) Directed neural lineage differentiation of adult hippocampal progenitor cells via modulation of hippocampal cholinergic neurostimulating peptide precursor expression. Brain Res 1327:107–117

    CAS  PubMed  Google Scholar 

  97. 97.

    Wei J, Jiang H, Gao H, Wang G (2015) Raf-1 Kinase Inhibitory Protein (RKIP) promotes retinal ganglion cell survival and axonal regeneration following optic nerve Crush. J Mol Neurosci 57(2):243–248

    CAS  PubMed  Google Scholar 

  98. 98.

    Hellmann J, Rommelspacher H, Mühlbauer E, Wernicke C (2010) Raf kinase inhibitor protein enhances neuronal differentiation in human SH-SY5Y cells. Dev Neurosci 32(1):33–46

    CAS  PubMed  Google Scholar 

  99. 99.

    Bildyug N (2016) Matrix metalloproteinases: an emerging role in regulation of actin microfilament system. Biomol Concepts 7(5–6):321–329

    CAS  PubMed  Google Scholar 

  100. 100.

    Buckley CD, Tan J, Anderson KL, Hanein D, Volkmann N, Weis WI, Nelson WJ, Dunn AR (2014) The minimal cadherin–catenin complex binds to actin filaments under force. Science.

    Article  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Li J, Tanhehco EJ, Russell B (2014) Actin dynamics is rapidly regulated by the PTEN and PIP2 signaling pathways leading to myocyte hypertrophy. Am J Physiol Heart Circ Physiol 307(11):H1618–1625

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Papakonstanti EA, Stournaras C (2008) Cell responses regulated by early reorganization of actin cytoskeleton. FEBS Lett 582(14):2120–2127

    CAS  PubMed  Google Scholar 

  103. 103.

    Graziano BR, Weiner OD (2014) Self-organization of protrusions and polarity during eukaryotic chemotaxis. Curr Opin Cell Biol 30:60–67

    CAS  PubMed  Google Scholar 

  104. 104.

    Shvartsur A, Givechian KB, Garban H, Bonavida B (2017) Overexpression of RKIP and its cross-talk with several regulatory gene products in multiple myeloma. J Exp Clin Cancer Res.

    Article  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Németh ZH, Deitch EA, Davidson MT, Szabó C, Vizi ES, Haskó G (2004) Disruption of the actin cytoskeleton results in nuclear factor-kappaB activation and inflammatory mediator production in cultured human intestinal epithelial cells. J Cell Physiol 200(1):71–81

    PubMed  Google Scholar 

  106. 106.

    Zhang B, Shi L, Lu S, Sun X, Liu Y, Li H, Wang X, Zhao C, Zhang H, Wang Y (2015) Autocrine IL-8 promotes F-actin polymerization and mediate mesenchymal transition via ELMO1-NF-kB-Snail signaling in glioma. Cancer Biol Ther 16(6):898–911

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Favot L, Hall SM, Haworth SG, Kemp PR (2005) Cytoplasmic YY1 is associated with increased smooth muscle-specific gene expression. Implications for neonatal pulmonary hypertension. Am J Pathol 167(6):1497–1509

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Kreis P, Hendricusdottir R, Kay L, Papageorgiou IE, van Diepen M, Mack T, Ryves J, Harwood A, Leslie NR, Kann O, Parsons M, Eickholt BJ (2013) Phosphorylation of the actin binding protein Drebrin at S647 is regulated by neuronal activity and PTEN. PLoS ONE.

    Article  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Steffen A, Stradal TE, Rottner K (2017) Signalling pathways controlling cellular actin organization. Handb Exp Pharmacol 235:153–178

    CAS  PubMed  Google Scholar 

Download references


We thank Isabelle Callebaut (IMPMC) for helpful comments and fruitful remarks. We sincerely thank William Sacks (IMPMC) for critical reading and improvement of the manuscript. We thank also the members of the “Canceropôle du grand Ouest” for stimulating and constructive discussions throughout these last few years.

Author information



Corresponding author

Correspondence to Françoise Schoentgen.

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

Verify currency and authenticity via CrossMark

Cite this article

Schoentgen, F., Jonic, S. PEBP1/RKIP behavior: a mirror of actin-membrane organization. Cell. Mol. Life Sci. 77, 859–874 (2020).

Download citation


  • Actin
  • Cytoskeleton
  • Membrane
  • Cell shape
  • Motility