Eph receptor and ephrin function in breast, gut, and skin epithelia

Cell Adhesion and Migration

Volumn 8, Issue 4, 2014, Pages 327-338

  White, Bethany E Perez ^a   Getsios, Spiro ^a  

^a NORTHWESTERN UNIVERSITY   (United States)

Author keywords

Breast; Cell cell; Eph receptor; Ephrin; Epithelial; Intestine; Receptor tyrosine kinase; Skin; Stem cell

Indexed keywords

EPHRIN; EPHRIN RECEPTOR;

ATTENUATION; BREAST CANCER; BREAST EPITHELIUM; CELL COMMUNICATION; EPIDERMIS; EPITHELIUM CELL; GASTROINTESTINAL DISEASE; GASTROINTESTINAL TRACT; HAIR FOLLICLE; HOMEOSTASIS; HUMAN; INTESTINE EPITHELIUM; MAMMARY GLAND; NONHUMAN; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; SIGNAL TRANSDUCTION; SKIN DISEASE; SKIN EPITHELIUM; ANIMAL; BREAST TUMOR; CELL DIFFERENTIATION; CELL PROLIFERATION; GENETICS; METABOLISM; MOUSE; PATHOPHYSIOLOGY; PHYSIOLOGY;

ANIMALS; BREAST NEOPLASMS; CELL COMMUNICATION; CELL DIFFERENTIATION; CELL PROLIFERATION; EPHRINS; EPITHELIAL CELLS; GASTROINTESTINAL DISEASES; HOMEOSTASIS; HUMANS; MICE; RECEPTORS, EPH FAMILY; SIGNAL TRANSDUCTION; SKIN DISEASES;

EID: 84919883546     PISSN: 19336918     EISSN: 19336926     Source Type: Journal    
DOI: 10.4161/19336918.2014.970012     Document Type: Review

References (144)

1. Gale NW, Holland SJ, Valenzuela DM, Flenniken A, Pan L, Ryan TE, Henkemeyer M, Strebhardt K, Hirai H, Wilkinson DG, et al. Eph receptors and ligands comprise two major specificity subclasses and are reciprocally compartmentalized during embryogenesis. Neuron 1996;17:9-19; PMID:8755474; http://dx.doi.org/10.1016/S0896-6273 (00) 80276-7
2. Eph Nomenclature Committee. Unified nomenclature for Eph family receptors and their ligands, the ephrins. Cell 1997;90:403-4; PMID:9267020; http://dx.doi.org/10.1016/S0092-8674 (00) 80500-0
3. Himanen JP, Chumley MJ, Lackmann M, Li C, Barton WA, Jeffrey PD, Vearing C, Geleick D, Feldheim DA, Boyd AW, et al. Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling. Nat Neurosci 2004;7:501-9; PMID:15107857; http://dx. doi.org/10.1038/nn1237
4. Alford S, Watson-Hurthig A, Scott N, Carette A, Lorimer H, Bazowski J, Howard PL. Soluble ephrin a1 is necessary for the growth of HeLa and SK-BR3 cells. Cancer Cell Int 2010;10:1475-2867; http://dx.doi.org/10.1186/1475-2867-10-41
5. Beauchamp A, Lively MO, Mintz A, Gibo D, Wykosky J, Debinski W. EphrinA1 is released in three forms from cancer cells by matrix metalloproteases. Mol Cell Biol 2012;32:3253-64; PMID:22688511; http://dx.doi.org/10.1128/MCB.06791-11
6. Himanen JP, Yermekbayeva L, Janes PW, Walker JR, Xu K, Atapattu L, Rajashankar KR, Mensinga A, Lackmann M, Nikolov DB, et al. Architecture of Eph receptor clusters. Proc Natl Acad Sci U S A 2010;107:10860-5; PMID:20505120; http://dx.doi.org/10.1073/pnas.1004148107
7. Janes PW, Nievergall E, Lackmann M. Concepts and consequences of Eph receptor clustering. Semin Cell Dev Biol 2012;23:43-50; PMID:22261642; http://dx.doi.org/10.1016/j.semcdb.2012.01.001
8. Singh A, Winterbottom E, Daar IO. Ephephrin signaling in cell-cell and cell-substrate adhesion. Front Biosci 2012;17:473-97; http://dx.doi.org/10.2741/3939
9. Coulthard MG, Morgan M, Woodruff TM, Arumugam TV, Taylor SM, Carpenter TC, Lackmann M, Boyd AW. EphEphrin signaling in injury and inflammation. Am J Pathol 2012;181:1493-503; PMID:23021982; http://dx.doi.org/10.1016/j.ajpath.2012.06.043
10. Merlos-Suarez A, Batlle E. Eph-ephrin signalling in adult tissues and cancer. Curr Opin Cell Biol 2008;20:194-200; PMID:18353626; http://dx.doi.org/10.1016/j.ceb.2008.01.011
11. Nievergall E, Lackmann M, Janes PW. Eph-dependent cell-cell adhesion and segregation in development and cancer. Cell Mol Life Sci 2012;69:1813-42; PMID:22204021; http://dx.doi.org/10.1007/s00018-011-0900-6
12. Kandouz M. The EphEphrin family in cancer metastasis: communication at the service of invasion. Cancer Metastasis Rev 2012;31:353-73; PMID:22549394; http://dx. doi.org/10.1007/s10555-012-9352-1
13. Frisen J, Barbacid M. Genetic analysis of the role of Eph receptors in the development of the mammalian nervous system. Cell Tissue Res 1997;290:209-15; PMID:9321682; http://dx.doi.org/10.1007/s004410050925
14. Ivanov AI, Romanovsky AA. Putative dual role of ephrin-Eph receptor interactions in inflammation. IUBMB Life 2006;58:389-94; PMID:16801213; http://dx.doi.org/10.1080/15216540600756004
15. Arvanitis D, Davy A. Ephephrin signaling: networks. Genes Dev 2008;22:416-29; PMID:18281458; http://dx.doi.org/10.1101/gad.1630408
16. Miao H, Wang B. Ephephrin signaling in epithelial development and homeostasis. Int J Biochem Cell Biol 2009;41:762-70; PMID:18761422; http://dx. doi.org/10.1016/j.biocel.2008.07.019
17. Gucciardo E, Sugiyama N, Lehti K. Eph- and ephrindependent mechanisms in tumor and stem cell dynamics. Cell Mol Life Sci 2014;4:4.
18. Lin S, Wang B, Getsios S. Ephephrin signaling in epidermal differentiation and disease. Semin Cell Dev Biol 2012;23:92-101; PMID:22040910; http://dx. doi.org/10.1016/j.semcdb.2011.10.017
19. Genander M. Eph and ephrins in epithelial stem cell niches and cancer. Cell Adh Migr 2012;6:126-30; PMID:22568955; http://dx.doi.org/10.4161/cam.18932
20. Genander M, Frisen J. Ephrins and Eph receptors in stem cells and cancer. Curr Opin Cell Biol 2010;22:611-6; PMID:20810264; http://dx.doi.org/10.1016/j.ceb.2010.08.005
21. Kalo MS, Pasquale EB. Multiple in vivo tyrosine phosphorylation sites in EphB receptors. Biochemistry 1999;38:14396-408; PMID:10572014; http://dx. doi.org/10.1021/bi991628t
22. Binns KL, Taylor PP, Sicheri F, Pawson T, Holland SJ. Phosphorylation of tyrosine residues in the kinase domain and juxtamembrane region regulates the biological and catalytic activities of Eph receptors. Mol Cell Biol 2000;20:4791-805; PMID:10848605; http://dx.doi.org/10.1128/MCB.20.13.4791-4805.2000
23. Wybenga-Groot LE, Baskin B, Ong SH, Tong J, Pawson T, Sicheri F. Structural basis for autoinhibition of the Ephb2 receptor tyrosine kinase by the unphosphorylated juxtamembrane region. Cell 2001;106:745-57; PMID:11572780; http://dx.doi.org/10.1016/S0092-8674 (01) 00496-2
24. Bartley TD, Hunt RW, Welcher AA, Boyle WJ, Parker VP, Lindberg RA, Lu HS, Colombero AM, Elliott RL, Guthrie BA, et al. B61 is a ligand for the ECK receptor protein-tyrosine kinase. Nature 1994;368:558-60; PMID:8139691; http://dx.doi.org/10.1038/368558a0
25. Fang WB, Brantley-Sieders DM, Hwang Y, Ham AJ, Chen J. Identification and functional analysis of phosphorylated tyrosine residues within EphA2 receptor tyrosine kinase. J Biol Chem 2008;283:16017-26; PMID:18387945; http://dx.doi.org/10.1074/jbc. M709934200
26. Hock B, Bohme B, Karn T, Feller S, Rubsamen-Waigmann H, Strebhardt K. Tyrosine-614, the major autophosphorylation site of the receptor tyrosine kinase HEK2, functions as multi-docking site for SH2-domain mediated interactions. Oncogene 1998;17:255-60; PMID:9674711; http://dx.doi.org/10.1038/sj. onc.1201907
27. Zisch AH, Kalo MS, Chong LD, Pasquale EB. Complex formation between EphB2 and Src requires phosphorylation of tyrosine 611 in the EphB2 juxtamembrane region. Oncogene 1998;16:2657-70; PMID:9632142; http://dx.doi.org/10.1038/sj. onc.1201823
28. Thanos CD, Goodwill KE, Bowie JU. Oligomeric structure of the human EphB2 receptor SAM domain. Science 1999;283:833-6; PMID:9933164; http://dx. doi.org/10.1126/science.283.5403.833
29. Wimmer-Kleikamp SH, Janes PW, Squire A, Bastiaens PI, Lackmann M. Recruitment of Eph receptors into signaling clusters does not require ephrin contact. J Cell Biol 2004;164:661-6; PMID:14993233; http://dx.doi.org/10.1083/jcb.200312001
30. Sharonov GV, Bocharov EV, Kolosov PM, Astapova MV, Arseniev AS, Feofanov AV. Point mutations in dimerization motifs of transmembrane domain stabilize active or inactive state of the EphA2 receptor tyrosine kinase. J Biol Chem 2014;14:14.
31. Salaita K, Nair PM, Petit RS, Neve RM, Das D, Gray JW, Groves JT. Restriction of receptor movement alters cellular response: physical force sensing by EphA2. Science 2010;327:1380-5; PMID:20223987; http://dx. doi.org/10.1126/science.1181729
32. Janes PW, Griesshaber B, Atapattu L, Nievergall E, Hii LL, Mensinga A, Chheang C, Day BW, Boyd AW, Bastiaens PI, et al. Eph receptor function is modulated by heterooligomerization of A and B type Eph receptors. J Cell Biol 2011;195:1033-45; PMID:22144690; http://dx.doi.org/10.1083/jcb.201104037
33. Fox BP, Kandpal RP. A paradigm shift in EPH receptor interaction: biological relevance of EPHB6 interaction with EPHA2 and EPHB2 in breast carcinoma cell lines. Cancer Genomics Proteomics 2011;8:185-93; PMID:21737611
34. Bruckner K, Pasquale EB, Klein R. Tyrosine phosphorylation of transmembrane ligands for Eph receptors. Science 1997;275:1640-3; PMID:9054357; http://dx.doi.org/10.1126/science.275.5306.1640
35. Palmer A, Zimmer M, Erdmann KS, Eulenburg V, Porthin A, Heumann R, Deutsch U, Klein R. EphrinB phosphorylation and reverse signaling: regulation by Src kinases and PTP-BL phosphatase. Mol Cell 2002;9:725-37; PMID:11983165; http://dx.doi.org/10.1016/S1097-2765 (02) 00488-4
36. Parker M, Roberts R, Enriquez M, Zhao X, Takahashi T, Pat Cerretti D, Daniel T, Chen J. Reverse endocytosis of transmembrane ephrin-B ligands via a clathrin-mediated pathway. Biochem Biophys Res Commun 2004;323:17-23; PMID:15351694; http://dx.doi.org/10.1016/j.bbrc.2004.07.209
37. Cowan CA, Henkemeyer M. The SH2SH3 adaptor Grb4 transduces B-ephrin reverse signals. Nature 2001;413:174-9; PMID:11557983; http://dx.doi.org/10.1038/35093123
38. Qiu R, Wang J, Tsark W, Lu Q. Essential role of PDZ-RGS3 in the maintenance of neural progenitor cells. Stem Cells 2010;28:1602-10; PMID:20629178; http://dx.doi.org/10.1002/stem.478
39. Lin D, Gish GD, Songyang Z, Pawson T. The carboxyl terminus of B class ephrins constitutes a PDZ domain binding motif. J Biol Chem 1999;274:3726-33; PMID:9920925; http://dx.doi.org/10.1074/jbc.274.6.3726
40. Essmann CL, Martinez E, Geiger JC, Zimmer M, Traut MH, Stein V, Klein R, Acker-Palmer A. Serine phosphorylation of ephrinB2 regulates trafficking of synaptic AMPA receptors. Nat Neurosci 2008;11:1035-43; PMID:19160501; http://dx.doi.org/10.1038/nn. 2171
41. Gauthier LR, Robbins SM. Ephrin signaling: One raft to rule them all? One raft to sort them? One raft to spread their call and in signaling bind them? Life Sci 2003;74:207-16; PMID:14607248; http://dx.doi.org/10.1016/j.lfs.2003.09.029
42. Nievergall E, Janes PW, Stegmayer C, Vail ME, Haj FG, Teng SW, Neel BG, Bastiaens PI, Lackmann M. PTP1B regulates Eph receptor function and trafficking. J Cell Biol 2010;191:1189-203; PMID:21135139; http://dx. doi.org/10.1083/jcb.201005035
43. Parri M, Buricchi F, Taddei ML, Giannoni E, Raugei G, Ramponi G, Chiarugi P. EphrinA1 repulsive response is regulated by an EphA2 tyrosine phosphatase. J Biol Chem 2005;280:34008-18; PMID:16051609; http://dx.doi.org/10.1074/jbc. M502879200
44. Boissier P, Chen J, Huynh-Do U. EphA2 signaling following endocytosis: role of Tiam1. Traffic 2013;14:1255-71; PMID:24112471; http://dx.doi.org/10.1111/tra.12123
45. Yoo S, Shin J, Park S. EphA8-ephrinA5 signaling and clathrin-mediated endocytosis is regulated by Tiam-1, a Rac-specific guanine nucleotide exchange factor. Mol Cells 2010;29:603-9; PMID:20496116; http://dx.doi.org/10.1007/s10059-010-0075-2
46. Zhuang G, Hunter S, Hwang Y, Chen J. Regulation of EphA2 receptor endocytosis by SHIP2 lipid phosphatase via phosphatidylinositol 3-Kinase-dependent Rac1 activation. J Biol Chem 2007;282:2683-94; PMID:17135240; http://dx.doi.org/10.1074/jbc. M608509200
47. Janes PW, Wimmer-Kleikamp SH, Frangakis AS, Treble K, Griesshaber B, Sabet O, Grabenbauer M, Ting AY, Saftig P, Bastiaens PI, et al. Cytoplasmic relaxation of active Eph controls ephrin shedding by ADAM10. PLoS Biol 2009;7:13; http://dx.doi.org/10.1371/journal.pbio.1000215
48. Sugiyama N, Gucciardo E, Tatti O, Varjosalo M, Hyytiainen M, Gstaiger M, Lehti K. EphA2 cleavage by MT1-MMP triggers single cancer cell invasion via homotypic cell repulsion. J Cell Biol 2013;201:467-84; PMID:23629968; http://dx.doi.org/10.1083/jcb.201205176
49. Walker-Daniels J, Riese DJ 2nd, Kinch MS. c-Cbldependent EphA2 protein degradation is induced by ligand binding. Mol Cancer Res 2002;1:79-87; PMID:12496371
50. Wang Y, Ota S, Kataoka H, Kanamori M, Li Z, Band H, Tanaka M, Sugimura H. Negative regulation of EphA2 receptor by Cbl. Biochem Biophys Res Commun 2002;296:214-20; PMID:12147253; http://dx. doi.org/10.1016/S0006-291X (02) 00806-9
51. Kim J, Lee H, Kim Y, Yoo S, Park E, Park S. The SAM domains of Anks family proteins are critically involved in modulating the degradation of EphA receptors. Mol Cell Biol 2010;30:1582-92; PMID:20100865; http://dx.doi.org/10.1128/MCB.01605-09
52. Shin J, Gu C, Park E, Park S. Identification of phosphotyrosine binding domain-containing proteins as novel downstream targets of the EphA8 signaling function. Mol Cell Biol 2007;27:8113-26; PMID:17875921; http://dx.doi.org/10.1128/MCB.00794-07
53. Naudin C, Sirvent A, Leroy C, Larive R, Simon V, Pannequin J, Bourgaux JF, Pierre J, Robert B, Hollande F, et al. SLAP displays tumour suppressor functions in colorectal cancer via destabilization of the SRC substrate EPHA2. Nat Commun 2014;5:3159; PMID:24457997; http://dx.doi.org/10.1038/ncomms4159
54. Smith GH, Chepko G. Mammary epithelial stem cells. Microsc Res Tech 2001;52:190-203; PMID:11169867; http://dx.doi.org/10.1002/1097-0029 (20010115) 52:2%3c190::AID-JEMT1005%3e3.0. CO;2-O
55. Vaught D, Chen J, Brantley-Sieders DM. Regulation of mammary gland branching morphogenesis by EphA2 receptor tyrosine kinase. Mol Biol Cell 2009;20:2572-81; PMID:19321667; http://dx.doi.org/10.1091/mbc. E08-04-0378
56. Kouros-Mehr H, Werb Z. Candidate regulators of mammary branching morphogenesis identified by genome-wide transcript analysis. Dev Dyn 2006;235:3404-12; PMID:17039550; http://dx.doi.org/10.1002/dvdy.20978
57. Nikolova Z, Djonov V, Zuercher G, Andres AC, Ziemiecki A. Cell-type specific and estrogen dependent expression of the receptor tyrosine kinase EphB4 and its ligand ephrin-B2 during mammary gland morphogenesis. J Cell Sci 1998;111:2741-51; PMID:9718367
58. Zelinski DP, Zantek ND, Walker-Daniels J, Peters MA, Taparowsky EJ, Kinch MS. Estrogen and Myc negatively regulate expression of the EphA2 tyrosine kinase. J Cell Biochem 2002;85:714-20; PMID:11968011; http://dx. doi.org/10.1002/jcb.10186
59. Gokmen-Polar Y, Toroni RA, Hocevar BA, Badve S, Zhao Q, Shen C, Bruckheimer E, Kinch MS, Miller KD. Dual targeting of EphA2 and ER restores tamoxifen sensitivity in EREphA2-positive breast cancer. Breast Cancer Res Treat 2011;127:375-84; PMID:20602165; http://dx.doi.org/10.1007/s10549-010-1004-y
60. Andres AC, Reid HH, Zurcher G, Blaschke RJ, Albrecht D, Ziemiecki A. Expression of two novel eph-related receptor protein tyrosine kinases in mammary gland development and carcinogenesis. Oncogene 1994;9:1461-7; PMID:8152808
61. Schmitt F, Nguyen PH, Gupta N, Mayer D. Eph receptor B4 is a regulator of estrogen receptor alpha in breast cancer cells. J Recept Signal Transduct Res 2013;33:244-8; PMID:23725356; http://dx.doi.org/10.3109/10799893.2013.795971
62. Papaxoinis K, Triantafyllou K, Sasco AJ, Nicolopoulou-Stamati P, Ladas SD. Subsite-specific differences of estrogen receptor beta expression in the normal colonic epithelium: implications for carcinogenesis and colorectal cancer epidemiology. Eur J Gastroenterol Hepatol 2010;22:614-9; PMID:20173645; http://dx.doi.org/10.1097/MEG.0b013e328335ef50
63. Thornton MJ. The biological actions of estrogens on skin. Exp Dermatol 2002;11:487-502; PMID:12473056; http://dx.doi.org/10.1034/j.1600-0625.2002.110601.x
64. Miao H, Nickel CH, Cantley LG, Bruggeman LA, Bennardo LN, Wang B. EphA kinase activation regulates HGF-induced epithelial branching morphogenesis. J Cell Biol 2003;162:1281-92; PMID:14517207; http://dx.doi.org/10.1083/jcb.200304018
65. Kaenel P, Antonijevic M, Richter S, Kuchler S, Sutter N, Wotzkow C, Strange R, Andres AC. Deregulated ephrin-B2 signaling in mammary epithelial cells alters the stem cell compartment and interferes with the epithelial differentiation pathway. Int J Oncol 2012;40:357-69; PMID:22020958
66. Weiler S, Rohrbach V, Pulvirenti T, Adams R, Ziemiecki A, Andres AC. Mammary epithelial-specific knockout of the ephrin-B2 gene leads to precocious epithelial cell death at lactation. Dev Growth Differ 2009;51:809-19; PMID:19843150; http://dx.doi.org/10.1111/j.1440-169X.2009.01140.x
67. Kaenel P, Hahnewald S, Wotzkow C, Strange R, Andres AC. Overexpression of EphB4 in the mammary epithelium shifts the differentiation pathway of progenitor cells and promotes branching activity and vascularization. Dev Growth Differ 2014;56:255-75; PMID:24635767; http://dx.doi.org/10.1111/dgd.12126
68. Brantley-Sieders DM, Jiang A, Sarma K, Badu-Nkansah A, Walter DL, Shyr Y, Chen J. Ephephrin profiling in human breast cancer reveals significant associations between expression level and clinical outcome. PLoS One 2011;6:15; http://dx.doi.org/10.1371/journal.pone.0024426
69. Fox BP, Kandpal RP. Invasiveness of breast carcinoma cells and transcript profile: Eph receptors and ephrin ligands as molecular markers of potential diagnostic and prognostic application. Biochem Biophys Res Commun 2004;318:882-92; PMID:15147954; http://dx.doi.org/10.1016/j.bbrc.2004.04.102
70. Zantek ND, Azimi M, Fedor-Chaiken M, Wang B, Brackenbury R, Kinch MS. E-cadherin regulates the function of the EphA2 receptor tyrosine kinase. Cell Growth Differ 1999;10:629-38; PMID:10511313
71. Zelinski DP, Zantek ND, Stewart JC, Irizarry AR, Kinch MS. EphA2 overexpression causes tumorigenesis of mammary epithelial cells. Cancer Res 2001;61:2301-6; PMID:11280802
72. Lu M, Miller KD, Gokmen-Polar Y, Jeng MH, Kinch MS. EphA2 overexpression decreases estrogen dependence and tamoxifen sensitivity. Cancer Res 2003;63:3425-9; PMID:12810680
73. Zhuang G, Brantley-Sieders DM, Vaught D, Yu J, Xie L, Wells S, Jackson D, Muraoka-Cook R, Arteaga C, Chen J. Elevation of receptor tyrosine kinase EphA2 mediates resistance to trastuzumab therapy. Cancer Res 2010;70:299-308; PMID:20028874; http://dx. doi.org/10.1158/0008-5472. CAN-09-1845
74. Fang WB, Ireton RC, Zhuang G, Takahashi T, Reynolds A, Chen J. Overexpression of EPHA2 receptor destabilizes adherens junctions via a RhoA-dependent mechanism. J Cell Sci 2008;121:358-68; PMID:18198190; http://dx.doi.org/10.1242/jcs.017145
75. Hiramoto-Yamaki N, Takeuchi S, Ueda S, Harada K, Fujimoto S, Negishi M, Katoh H. Ephexin4 and EphA2 mediate cell migration through a RhoG-dependent mechanism. J Cell Biol 2010;190:461-77; PMID:20679435; http://dx.doi.org/10.1083/jcb.201005141
76. Miao H, Li DQ, Mukherjee A, Guo H, Petty A, Cutter J, Basilion JP, Sedor J, Wu J, Danielpour D, et al. EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt. Cancer Cell 2009;16:9-20; PMID:19573808; http://dx.doi.org/10.1016/j.ccr.2009.04.009
77. Kawai H, Kobayashi M, Hiramoto-Yamaki N, Harada K, Negishi M, Katoh H. Ephexin4-mediated promotion of cell migration and anoikis resistance is regulated by serine 897 phosphorylation of EphA2. FEBS Open Bio 2013;3:78-82; PMID:23772378; http://dx.doi.org/10.1016/j.fob.2013.01.002
78. Maroulakou IG, Oemler W, Naber SP, Klebba I, Kuperwasser C, Tsichlis PN. Distinct roles of the three Akt isoforms in lactogenic differentiation and involution. J Cell Physiol 2008;217:468-77; PMID:18561256; http://dx. doi.org/10.1002/jcp. 21518
79. Boxer RB, Stairs DB, Dugan KD, Notarfrancesco KL, Portocarrero CP, Keister BA, Belka GK, Cho H, Rathmell JC, Thompson CB, et al. Isoform-specific requirement for Akt1 in the developmental regulation of cellular metabolism during lactation. Cell Metab 2006;4:475-90; PMID:17141631; http://dx.doi.org/10.1016/j.cmet.2006.10.011
80. Chen CC, Boxer RB, Stairs DB, Portocarrero CP, Horton RH, Alvarez JV, Birnbaum MJ, Chodosh LA. Akt is required for Stat5 activation and mammary differentiation. Breast Cancer Res 2010;12:17; http://dx.doi.org/10.1186/bcr2781
81. Haldimann M, Custer D, Munarini N, Stirnimann C, Zurcher G, Rohrbach V, Djonov V, Ziemiecki A, Andres AC. Deregulated ephrin-B2 expression in the mammary gland interferes with the development of both the glandular epithelium and vasculature and promotes metastasis formation. Int J Oncol 2009;35:525-36; PMID:19639173
82. Kaenel P, Schwab C, Mulchi K, Wotzkow C, Andres AC. Preponderance of cells with stem cell characteristics in metastasising mouse mammary tumours induced by deregulated EphB4 and ephrin-B2 expression. Int J Oncol 2011;38:151-60; PMID:21109936
83. Munarini N, Jager R, Abderhalden S, Zuercher G, Rohrbach V, Loercher S, Pfanner-Meyer B, Andres AC, Ziemiecki A. Altered mammary epithelial development, pattern formation and involution in transgenic mice expressing the EphB4 receptor tyrosine kinase. J Cell Sci 2002;115:25-37; PMID:11801721
84. Kumar SR, Singh J, Xia G, Krasnoperov V, Hassanieh L, Ley EJ, Scehnet J, Kumar NG, Hawes D, Press MF, et al. Receptor tyrosine kinase EphB4 is a survival factor in breast cancer. Am J Pathol 2006;169:279-93; PMID:16816380; http://dx.doi.org/10.2353/ajpath.2006.050889
85. Rutkowski R, Mertens-Walker I, Lisle JE, Herington AC, Stephenson SA. Evidence for a dual function of EphB4 as tumor promoter and suppressor regulated by the absence or presence of the ephrin-B2 ligand. Int J Cancer 2012;131:11; http://dx.doi.org/10.1002/ijc.27392
86. Fu DY, Wang ZM, Wang BL, Chen L, Yang WT, Shen ZZ, Huang W, Shao ZM. Frequent epigenetic inactivation of the receptor tyrosine kinase EphA5 by promoter methylation in human breast cancer. Hum Pathol 2010;41:48-58; PMID:19733895; http://dx. doi.org/10.1016/j.humpath.2009.06.007
87. Bonifaci N, Gorski B, Masojc B, Wokolorczyk D, Jakubowska A, Debniak T, Berenguer A, Serra Musach J, Brunet J, Dopazo J, et al. Exploring the link between germline and somatic genetic alterations in breast carcinogenesis. PLoS One 2010;5:0014078; http://dx.doi.org/10.1371/journal.pone.0014078
88. Clevers H, Batlle E. SnapShot: the intestinal crypt. Cell 2013;152:1198; PMID:23452862; http://dx. doi.org/10.1016/j.cell.2013.02.030
89. Clevers H. The intestinal crypt, a prototype stem cell compartment. Cell 2013;154:274-84; PMID:23870119
90. Hafner C, Meyer S, Langmann T, Schmitz G, Bataille F, Hagen I, Becker B, Roesch A, Rogler G, Landthaler M, et al. Ephrin-B2 is differentially expressed in the intestinal epithelium in Crohn's disease and contributes to accelerated epithelial wound healing in vitro. World J Gastroenterol 2005;11:4024-31; PMID:15996027
91. Kosinski C, Li VS, Chan AS, Zhang J, Ho C, Tsui WY, Chan TL, Mifflin RC, Powell DW, Yuen ST, et al. Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors. Proc Natl Acad Sci U S A 2007;104:15418-23; PMID:17881565; http://dx. doi.org/10.1073/pnas.0707210104
92. Holmberg J, Genander M, Halford MM, Anneren C, Sondell M, Chumley MJ, Silvany RE, Henkemeyer M, Frisen J. EphB receptors coordinate migration and proliferation in the intestinal stem cell niche. Cell 2006;125:1151-63; PMID:16777604; http://dx.doi.org/10.1016/j.cell.2006.04.030
93. Batlle E, Henderson JT, Beghtel H, Van Den Born MM, Sancho E, Huls G, Meeldijk J, Robertson J, Van De Wetering M, Pawson T, et al. Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphBephrinB. Cell 2002;111:251-63; PMID:12408869; http://dx. doi.org/10.1016/S0092-8674 (02) 01015-2
94. George MD, Wehkamp J, Kays RJ, Leutenegger CM, Sabir S, Grishina I, Dandekar S, Bevins CL. In vivo gene expression profiling of human intestinal epithelial cells: analysis by laser microdissection of formalin fixed tissues. BMC Genomics 2008;9:209.:10.1186471-2164-9-209; PMID:18457593; http://dx.doi.org/10.1186/1471-2164-9-209
95. Kuhl SJ, Kuhl M. On the role of Wntbeta-catenin signaling in stem cells. Biochim Biophys Acta 2013;2:16
96. Sancho E, Batlle E, Clevers H. Live and let die in the intestinal epithelium. Curr Opin Cell Biol 2003;15:763-70; PMID:14644203; http://dx.doi.org/10.1016/j.ceb.2003.10.012
97. Van De Wetering M, Sancho E, Verweij C, De Lau W, Oving I, Hurlstone A, Van Der Horn K, Batlle E, Coudreuse D, Haramis AP, et al. The β-cateninTCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 2002;111:241-50; PMID:12408868; http://dx.doi.org/10.1016/S0092-8674 (02) 01014-0
98. McConnell BB, Kim SS, Yu K, Ghaleb AM, Takeda N, Manabe I, Nusrat A, Nagai R, Yang VW. Kruppel-like factor 5 is important for maintenance of crypt architecture and barrier function in mouse intestine. Gastroenterology 2011;141:1302-13; PMID:21763241; http://dx. doi.org/10.1053/j.gastro.2011.06.086
99. Beck PL, Rosenberg IM, Xavier RJ, Koh T, Wong JF, Podolsky DK. Transforming growth factor-beta mediates intestinal healing and susceptibility to injury in vitro and in vivo through epithelial cells. Am J Pathol 2003;162:597-608; PMID:12547717; http://dx.doi.org/10.1016/S0002-9440 (10) 63853-9
100. Furukawa K, Sato T, Katsuno T, Nakagawa T, Noguchi Y, Tokumasa A, Yokote K, Yokosuka O, Saito Y. Smad3 contributes to positioning of proliferating cells in colonic crypts by inducing EphB receptor protein expression. Biochem Biophys Res Commun 2011;405:521-6; PMID:21276420; http://dx.doi.org/10.1016/j.bbrc.2011.01.045
101. Owen CR, Yuan L, Basson MD. Smad3 knockout mice exhibit impaired intestinal mucosal healing. Lab Invest 2008;88:1101-9; PMID:18711354; http://dx. doi.org/10.1038/labinvest.2008.77
102. Richmond CA, Breault DT. Regulation of gene expression in the intestinal epithelium. Prog Mol Biol Transl Sci 2010;96:207-29; PMID:21075346; http://dx.doi.org/10.1016/B978-0-12-381280-3.00009-9
103. Solanas G, Cortina C, Sevillano M, Batlle E. Cleavage of E-cadherin by ADAM10 mediates epithelial cell sorting downstream of EphB signalling. Nat Cell Biol 2011;13:1100-7; PMID:21804545; http://dx.doi.org/10.1038/ncb2298
104. Genander M, Halford MM, Xu NJ, Eriksson M, Yu Z, Qiu Z, Martling A, Greicius G, Thakar S, Catchpole T, et al. Dissociation of EphB2 signaling pathways mediating progenitor cell proliferation and tumor suppression. J 2009;139:679-92
105. Tanaka M, Kamata R, Sakai R. EphA2 phosphorylates the cytoplasmic tail of Claudin-4 and mediates paracellular permeability. J Biol Chem 2005;280:42375-82; PMID:16236711; http://dx.doi.org/10.1074/jbc. M503786200
106. Tanaka M, Kamata R, Sakai R. Phosphorylation of ephrin-B1 via the interaction with claudin following cell-cell contact formation. Embo J 2005;24:3700-11; PMID:16211011; http://dx.doi.org/10.1038/sj. emboj.7600831
107. Ogawa K, Takemoto N, Ishii M, Pasquale EB, Nakajima T. Complementary expression and repulsive signaling suggest that EphB receptors and ephrin-B ligands control cell positioning in the gastric epithelium. Histochem Cell Biol 2011;136:617-36; PMID:21959989; http://dx.doi.org/10.1007/s00418-011-0867-2
108. Ogawa K, Saeki N, Igura Y, Hayashi Y. Complementary expression and repulsive signaling suggest that EphB2 and ephrin-B1 are possibly involved in epithelial boundary formation at the squamocolumnar junction in the rodent stomach. Histochem Cell Biol 2013;140:659-75; PMID:23881165; http://dx.doi.org/10.1007/s00418-013-1129-2
109. Liu W, Ahmad SA, Jung YD, Reinmuth N, Fan F, Bucana CD, Ellis LM. Coexpression of ephrin-Bs and their receptors in colon carcinoma. Cancer 2002;94:934-9; PMID:11920461; http://dx.doi.org/10.1002/cncr.10122
110. Herath NI, Boyd AW. The role of Eph receptors and ephrin ligands in colorectal cancer. Int J Cancer 2010;126:2003-11; PMID:20039322; http://dx.doi.org/10.1002ijc.25147
111. Batlle E, Bacani J, Begthel H, Jonkheer S, Gregorieff A, Van De Born M, Malats N, Sancho E, Boon E, Pawson T, et al. EphB receptor activity suppresses colorectal cancer progression. Nature 2005;435:1126-30; PMID:15973414; http://dx.doi.org/10.1038/nature03626
112. Cortina C, Palomo-Ponce S, Iglesias M, Fernandez-Masip JL, Vivancos A, Whissell G, Huma M, Peiro N, Gallego L, Jonkheer S, et al. EphB-ephrin-B interactions suppress colorectal cancer progression by compartmentalizing tumor cells. Nat Genet 2007;39:1376-83; PMID:17906625; http://dx.doi.org/10.1038/ng.2007.11
113. Moser AR, Pitot HC, Dove WF. A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 1990;247:322-4; PMID:2296722; http://dx.doi.org/10.1126/science.2296722
114. Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell 1996;87:159-70; PMID:8861899; http://dx.doi.org/10.1016/S0092-8674 (00) 81333-1
115. Huang J, Xiao D, Li G, Ma J, Chen P, Yuan W, Hou F, Ge J, Zhong M, Tang Y, et al. EphA2 promotes epithelial-mesenchymal transition through the Wntbeta-catenin pathway in gastric cancer cells. Oncogene 2014;33:2737-47. Epub Jun. 10; PMID:23752181; http://dx.doi.org/10.1038/onc.2013.238
116. Wang J, Dong Y, Wang X, Ma H, Sheng Z, Li G, Lu G, Sugimura H, Zhou X. Expression of EphA1 in gastric carcinomas is associated with metastasis and survival. Oncol Rep 2010;24:1577-84; PMID:21042754
117. Yamamoto H, Tei M, Uemura M, Takemasa I, Uemura Y, Murata K, Fukunaga M, Ohue M, Ohnishi T, Ikeda K, et al. Ephrin-A1 mRNA is associated with poor prognosis of colorectal cancer. Int J Oncol 2013;42:549-55; PMID:23258614
118. Shi L, Itoh F, Itoh S, Takahashi S, Yamamoto M, Kato M. Ephrin-A1 promotes the malignant progression of intestinal tumors in Apc (minC) mice. Oncogene 2008;27:3265-73. Epub 2008 Feb. 4; PMID:18246128; http://dx.doi.org/10.1038/sj. onc.1210992
119. Bogan C, Chen J, O'Sullivan MG, Cormier RT. Loss of EphA2 receptor tyrosine kinase reduces ApcMin Ctumorigenesis. Int J Cancer 2009;124:1366-71; PMID:19089910; http://dx.doi.org/10.1002/ijc.24083
120. Cotsarelis G, Sun T, Lavker R. Label-retaining cells reside in the bulge area of pilosebaceous unit: Implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 1990;61:1328-37; http://dx.doi.org/10.1016/0092-8674 (90) 90696-C
121. Simpson CL, Patel DM, Green KJ. Deconstructing the skin: cytoarchitectural determinants of epidermal morphogenesis. Nat Rev Mol Cell Biol 2011;12:565-80; PMID:21860392; http://dx.doi.org/10.1038/nrm3175
122. Hafner C, Becker B, Landthaler M, Vogt T. Expression profile of Eph receptors and ephrin ligands in human skin and downregulation of EphA1 in nonmelanoma skin cancer. Mod Pathol 2006;19:1369-77; PMID:16862074; http://dx.doi.org/10.1038/modpathol.3800660
123. Gordon K, Kochkodan JJ, Blatt H, Lin SY, Kaplan N, Johnston A, Swindell WR, Hoover P, Schlosser BJ, Elder JT, et al. Alteration of the EphA2Ephrin-A signaling axis in psoriatic epidermis. J Invest Dermatol 2013;133:712-22; PMID:23190894; http://dx.doi.org/10.1038/jid.2012.391
124. Truong AB, Kretz M, Ridky TW, Kimmel R, Khavari PA. p63 regulates proliferation and differentiation of developmentally mature keratinocytes. Genes Dev 2006;20:3185-97; PMID:17114587; http://dx.doi.org/10.1101/gad.1463206
125. Sen GL, Boxer LD, Webster DE, Bussat RT, Qu K, Zarnegar BJ, Johnston D, Siprashvili Z, Khavari PA. ZNF750 is a p63 target gene that induces KLF4 to drive terminal epidermal differentiation. Dev Cell 2012;22:669-77; PMID:22364861; http://dx.doi.org/10.1016/j.devcel.2011.12.001
126. Larsen AB, Pedersen MW, Stockhausen MT, Grandal MV, Van Deurs B, Poulsen HS. Activation of the EGFR gene target EphA2 inhibits epidermal growth factor-induced cancer cell motility. Mol Cancer Res 2007;5:283-93; PMID:17374733; http://dx.doi.org/10.1158/1541-7786. MCR-06-0321
127. Banno T, Gazel A, Blumenberg M. Effects of tumor necrosis factor-alpha (TNF alpha) in epidermal keratinocytes revealed using global transcriptional profiling. J Biol Chem 2004;279:32633-42; PMID:15145954; http://dx.doi.org/10.1074/jbc. M400642200
128. Banno T, Gazel A, Blumenberg M. Pathway-specific profiling identifies the NF-kappa B-dependent tumor necrosis factor alpha-regulated genes in epidermal keratinocytes. J Biol Chem 2005;280:18973-80. Epub 2005 Feb. 18; PMID:15722350; http://dx.doi.org/10.1074/jbc. M411758200
129. Zhang G, Njauw CN, Park JM, Naruse C, Asano M, Tsao H. EphA2 is an essential mediator of UV radiation-induced apoptosis. Cancer Res 2008;68:1691-6; PMID:18339848; http://dx.doi.org/10.1158/0008-5472. CAN-07-2372
130. Lavker RM, Sun TT, Oshima H, Barrandon Y, Akiyama M, Ferraris C, Chevalier G, Favier B, Jahoda CA, Dhouailly D, et al. Hair follicle stem cells. J Investig Dermatol Symp Proc 2003;8:28-38; PMID:12894992; http://dx.doi.org/10.1046/j.1523-1747.2003.12169.x
131. Blanpain C, Fuchs E. Epidermal homeostasis: a balancing act of stem cells in the skin. Nat Rev Mol Cell Biol 2009;10:207-17; PMID:19209183; http://dx. doi.org/10.1038/nrm2636
132. Midorikawa T, Chikazawa T, Yoshino T, Takada K, Arase S. Different gene expression profile observed in dermal papilla cells related to androgenic alopecia by DNA macroarray analysis. J Dermatol Sci 2004;36:25-32; PMID:15488702; http://dx.doi.org/10.1016/j.jdermsci.2004.05.001
133. Egawa G, Osawa M, Uemura A, Miyachi Y, Nishikawa S. Transient expression of ephrin b2 in perinatal skin is required for maintenance of keratinocyte homeostasis. J Invest Dermatol 2009;129:2386-95; PMID:19571816; http://dx.doi.org/10.1038/jid.2009.105
134. Tumbar T, Guasch G, Greco V, Blanpain C, Lowry WE, Rendl M, Fuchs E. Defining the epithelial stem cell niche in skin. Science 2004;303:359-63; PMID:14671312; http://dx.doi.org/10.1126/science.1092436
135. Yamada Y, Midorikawa T, Oura H, Yoshino T, Ohdera M, Kubo Y, Arase S. Ephrin-A3 not only increases the density of hair follicles but also accelerates anagen development in neonatal mice. J Dermatol Sci 2008;52:178-85; PMID:18640011; http://dx. doi.org/10.1016/j.jdermsci.2008.05.007
136. Dumesic PA, Scholl FA, Barragan DI, Khavari PA. Erk12 MAP kinases are required for epidermal G2M progression. J Cell Biol 2009;185:409-22; PMID:19414607; http://dx.doi.org/10.1083/jcb.200804038
137. Guo H, Miao H, Gerber L, Singh J, Denning MF, Gilliam AC, Wang B. Disruption of EphA2 receptor tyrosine kinase leads to increased susceptibility to carcinogenesis in mouse skin. Cancer Res 2006;66:7050-8; PMID:16849550; http://dx.doi.org/10.1158/0008-5472. CAN-06-0004
138. Petty A, Myshkin E, Qin H, Guo H, Miao H, Tochtrop GP, Hsieh JT, Page P, Liu L, Lindner DJ, et al. A small molecule agonist of EphA2 receptor tyrosine kinase inhibits tumor cell migration in vitro and prostate cancer metastasis in vivo. PLoS One 2012;7:15; http://dx.doi.org/10.1371/journal.pone.0042120
139. Lema Tome CM, Palma E, Ferluga S, Lowther WT, Hantgan R, Wykosky J, Debinski W. Structural and functional characterization of monomeric EphrinA1 binding site to EphA2 receptor. J Biol Chem 2012;287:14012-22; PMID:22362770; http://dx.doi.org/10.1074/jbc. M111.311670
140. Genander M, Holmberg J, Frisen J. Ephrins negatively regulate cell proliferation in the epidermis and hair follicle. Stem Cells 2010;28:1196-205; PMID:20506314
141. Lin S, Gordon K, Kaplan N, Getsios S. Ligand targeting of EphA2 enhances keratinocyte adhesion and differentiation via desmoglein 1. Mol Biol Cell 2010;21:3902-14; PMID:20861311; http://dx.doi.org/10.1091/mbc. E10-03-0242
142. Getsios S, Simpson CL, Kojima S, Harmon R, Sheu LJ, Dusek RL, Cornwell M, Green KJ. Desmoglein 1-dependent suppression of EGFR signaling promotes epidermal differentiation and morphogenesis. J Cell Biol 2009;185:1243-58; PMID:19546243; http://dx. doi.org/10.1083/jcb.200809044
143. Walsh R, Blumenberg M. Specific and shared targets of ephrin A signaling in epidermal keratinocytes. J Biol Chem 2011;286:9419-28; PMID:21193391; http://dx.doi.org/10.1074/jbc. M110.197087
144. Walsh R, Blumenberg M. Eph-2B, acting as an extracellular ligand, induces differentiation markers in epidermal keratinocytes. J Cell Physiol 2012;227:2330-40; PMID:21809346; http://dx.doi.org/10.1002/jcp. 22968