ROR1, an embryonic protein with an emerging role in cancer biology

Abstract

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a member of the ROR family consisting of ROR1 and ROR2. RORs contain two distinct extracellular cysteinerich domains and one transmembrane domain. Within the intracellular portion, ROR1 possesses a tyrosine kinase domain, two serine/threonine-rich domains and a proline-rich domain. RORs have been studied in the context of embryonic patterning and neurogenesis through a variety of homologs. These physiologic functions are dichotomous based on the requirement of the kinase domain. A growing literature has established ROR1 as a marker for cancer, such as in CLL and other blood malignancies. In addition, ROR1 is critically involved in progression of a number of blood and solid malignancies. ROR1 has been shown to inhibit apoptosis, potentiate EGFR signaling, and induce epithelial-mesenchymal transition (EMT). Importantly, ROR1 is only detectable in embryonic tissue and generally absent in adult tissue, making the protein an ideal drug target for cancer therapy.

Key words： ROR1; embryogenesis; cancer; immunotherapy

References

1 Afzal AR, Rajab A, Fenske CD, Oldridge M, Elanko N, Ternes-Pereira E, Tüysüz B, Murday VA, Patton MA, Wilkie AOM (2000) Recessive Robinow syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2. Nat Genet25: 419-422

2 Al-Shawi R, Ashton SV, Underwood C, Simons JP (2001) Expression of the Ror1 and Ror2 receptor tyrosine kinase genes during mouse development. Dev Genes Evol211: 161-171

3 Barna G, Mihalik R, Timár B, Tömböl J, Csende Z, Sebestyén A, Bödör C, Csernus B, Reiniger L, Peták I (2011) ROR1 expression is not a unique marker of CLL. Hematol Oncol29: 17-21

4 Baskar S, Kwong KY, Hofer T, Levy JM, Kennedy MG, Lee E, Staudt LM, Wilson WH, Wiestner A, Rader C (2008) unique cell surface expression of receptor tyrosine kinase ROR1 in human B-cell chronic lymphocytic leukemia. Clin Cancer Res14: 396-404

5 Baskar S, Wiestner A, Wilson WH, Pastan I, Rader C (2012) Targeting malignant B cells with an immunotoxin against ROR1. mAbs4: 349-361

6 Bicocca VT, Chang BH, Masouleh BK, Muschen M, Loriaux MM, Druker BJ, Tyner JW(2012) Crosstalk between ROR1 and the pre-B Cell receptor promotes survival of t(1;19) acute lymphoblastic leukemia. Cancer Cell22: 656-667

7 Cui B, Zhang S, Chen L, Yu J, Widhopf GF, Fecteau J-F, Rassenti LZ, Kipps TJ (2013) Targeting ROR1 inhibits epithelial-mesenchymal transition and metastasis. Cancer Res73: 3649-3660

8 Daneshmanesh AH, Mikaelsson E, Jeddi-Tehrani M, Bayat AA, Ghods R, Ostadkarampour M, Akhondi M, Lagercrantz S, Larsson C, Österborg A (2008) Ror1, a cell surface receptor tyrosine kinase is expressed in chronic lymphocytic leukemia and may serve as a putative target for therapy. Int J Cancer123: 1190-1195

9 Daneshmanesh AH, Porwit A, Hojjat-Farsangi M, Jeddi-Tehrani M, Tamm KP, Grandér D, Lehmann S, Norin S, Shokri F, Rabbani H (2013) Orphan receptor tyrosine kinases ROR1 and ROR2 in hematological malignancies. Leuk Lymphoma54: 843-850

10 DeChiara TM, Kimble RB, Poueymirou WT, Rojas J, Masiakowski P, Valenzuela DM, Yancopoulos GD (2000) Ror2, encoding a receptor-like tyrosine kinase, is required for cartilage and growth plate development. Nat Genet24: 271-274

11 Forrester WC, Dell M, Perens E, Garriga G (1999) A C. elegans Ror receptor tyrosine kinase regulates cell motility and asymmetric cell division. Nature400: 881-885

12 Forrester WC, Kim C, Garriga G (2004) The Caenorhabditis elegans Ror RTK CAM-1 inhibits EGL-20/Wnt signaling in cell migration. Genetics168: 1951-1962

13 Frank DA, Mahajan S, Ritz J (1997) B lymphocytes from patients with chronic lymphocytic leukemia contain signal transducer and activator of transcription (STAT) 1 and STAT3 constitutively phosphorylated on serine residues. J Clin Investig100: 3140-3148

14 Fukuda T, Chen L, Endo T, Tang L, Lu D, Castro JE, Widhopf GF II, Rassenti LZ, Cantwell MJ, Prussak CE (2008) Antisera induced by infusions of autologous Ad-CD154-leukemia B cells identify ROR1 as an oncofetal antigen and receptor for Wnt5a. Proc Natl Acad Sci USA105: 3047-3052

15 Gentile A, Lazzari L, Benvenuti S, Trusolino L, Comoglio PM (2011) Ror1 is a pseudokinase that is crucial for met-driven tumorigenesis. Cancer Res71: 3132-3141

16 Green JL, Inoue T, Sternberg PW (2007) The C. elegans ROR receptor tyrosine kinase, CAM-1, non-autonomously inhibits the Wnt pathway. Development134: 4053-4062

17 Grumolato L, Liu G, Mong P, Mudbhary R, Biswas R, Arroyave R, Vijayakumar S, Economides AN, Aaronson SA (2010) Canonical and noncanonical Wnts use a common mechanism to activate completely unrelated coreceptors. Genes Dev24: 2517-2530

18 Hanks SK, Quinn AM, Hunter T (1988) The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science241: 42-52

19 Hikasa H, Shibata M, Hiratani I, Taira M (2002) The Xenopus receptor tyrosine kinase Xror2 modulates morphogenetic movements of the axial mesoderm and neuroectoderm via Wnt signaling. Development129: 5227-5239

20 Hojjat-Farsangi M, Ghaemimanesh F, Daneshmanesh AH, Bayat AA, Mahmoudian J, Jeddi-Tehrani M, Rabbani H, Mellstedt H (2013) Inhibition of the receptor tyrosine kinase ROR1 by anti-ROR1 monoclonal antibodies and siRNA induced apoptosis of melanoma cells. PLoS ONE8: e61167

21 Hudecek M, Schmitt TM, Baskar S, Lupo-Stanghellini MT, Nishida T, Yamamoto TN, Bleakley M, Turtle CJ, Chang W-C, Greisman HA (2010) The B-cell tumor-associated antigen ROR1 can be targeted with T cells modified to express a ROR1-specific chimeric antigen receptor. Blood116: 4532-4541

22 Kaucká M, Krejčí P, Plevová K, Pavlová Š, Procházková J, Janovská P, Valnohová J, Kozubík A, Pospíšilová Š, Bryja V (2011) Post-translational modifications regulate signalling by Ror1. Acta Physiol203: 351-362

23 Li P, Harris D, Liu Z, Liu J, Keating M, Estrov Z (2010) Stat3 activates the receptor tyrosine kinase like orphan receptor-1 gene in chronic lymphocytic leukemia cells. PLoS ONE5: e11859

24 MacKeigan JP, Murphy LO, Blenis J (2005) Sensitized RNAi screen of human kinases and phosphatases identifies new regulators of apoptosis and chemoresistance. Nat Cell Biol7: 591-600

25 Masiakowski P, Carroll RD (1992) A novel family of cell surface receptors with tyrosine kinase-like domain. J Biol Chem267: 26181-26190

26 Mathews II, Vanderhoff-Hanaver P, Castellino FJ, Tulinsky A (1996) Crystal structures of the recombinant kringle 1 domain of human plasminogen in complexes with the ligands ϵ-aminocaproic acid and trans-4-(aminomethyl)cyclohexane-1-carboxylic acid†. Biochemistry35: 2567-2576

27 Matsuda T, Nomi M, Ikeya M, Kani S, Oishi I, Terashima T, Takada S, Minami Y (2001) Expression of the receptor tyrosine kinase genes, Ror1 and Ror2, during mouse development. Mech Dev105: 153-156

28 McKay SE, Hislop J, Scott D, Bulloch AGM, Kaczmarek LK, Carew TJ, Sossin WS (2001) Aplysia Ror forms clusters on the surface of identified neuroendocrine cells. Mol Cell Neurosci17: 821-841

29 Mikels AJ, Nusse R (2006) Purified Wnt5a protein activates or inhibits β-catenin-TCF signaling depending on receptor context. PLoS Biol4: e115

30 Mizuno K, Inoue H, Hagiya M, Shimizu S, Nose T, Shimohigashi Y, Nakamura T (1994) Hairpin loop and second kringle domain are essential sites for heparin binding and biological activity of hepatocyte growth factor. J Biol Chem269: 1131-1136

31 Nomi M, Oishi I, Kani S, Suzuki H, Matsuda T, Yoda A, Kitamura M, Itoh K, Takeuchi S, Takeda K (2001) Loss of mRor1 enhances the heart and skeletal abnormalities in mRor2-deficient mice: redundant and pleiotropic functions of mRor1 and mRor2 receptor tyrosine kinases. Mol Cell Biol21: 8329-8335

32 O’Connell MP, Marchbank K, Webster MR, Valiga AA, Kaur A, Vultur A, Li L, Herlyn M, Villanueva J, Liu Q (2013) Hypoxia induces phenotypic plasticity and therapy resistance in melanoma via the tyrosine kinase receptors ROR1 and ROR2. Cancer Discov3: 1378-1393

33 Oishi I, Sugiyama S, Liu Z-J, Yamamura H, Nishida Y, Minami Y (1997) A novel drosophila receptor tyrosine kinase expressed specifically in the nervous system unique structural features and implication in developmental signaling. J Biol Chem272: 11916-11923

34 Oishi I, Takeuchi S, Hashimoto R, Nagabukuro A, Ueda T, Liu Z-J, Hatta T, Akira S, Matsuda Y, Yamamura H (1999) Spatiotemporally regulated expression of receptor tyrosine kinases, mRor1, mRor2, during mouse development: implications in development and function of the nervous system. Genes Cells4: 41-56

35 Oishi I, Suzuki H, Onishi N, Takada R, Kani S, Ohkawara B, Koshida I, Suzuki K, Yamada G, Schwabe GC (2003) The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway. Genes Cells8: 645-654

36 Oldridge MMA, Maringa M, Propping P, Mansour S, Pollitt C, DeChiara TM, Kimble RB, Valenzuela DM, Yancopoulos GD (2000) Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B. Nat Genet24: 275-278

37 Paganoni S, Bernstein J, Ferreira A (2010) Ror1-Ror2 complexes modulate synapse formation in hippocampal neurons. Neuroscience165: 1261-1274

38 Rabbani H, Ostadkarampour M, Danesh Manesh AH, Basiri A, Jeddi-Tehrani M, Forouzesh F (2010) Expression of ROR1 in patients with renal cancer—a potential diagnostic marker. Iran Biomed J14: 77-82

39 Roszmusz E, Patthy A, Trexler M, Patthy L (2001) Localization of disulfide bonds in the frizzled module of Ror1 receptor tyrosine kinase. J Biol Chem276: 18485-18490

40 Stephens RW, Bokman AM, Myohanen HT, Reisberg T, Tapiovaara H, Pedersen N, Groendahl-Hansen J, Llinas M, Vaheri A (1992) Heparin binding to the urokinase kringle domain. Biochemistry31: 7572-7579

41 Stricker S, Verhey Van Wijk N, Witte F, Brieske N, Seidel K, Mundlos S (2006) Cloning and expression pattern of chicken Ror2 and functional characterization of truncating mutations in Brachydactyly type B and Robinow syndrome. Dev Dyn235: 3456-3465

42 Takeuchi S, Takeda K, Oishi I, Nomi M, Ikeya M, Itoh K, Tamura S, Ueda T, Hatta T, Otani H (2000) Mouse Ror2 receptor tyrosine kinase is required for the heart development and limb formation. Genes Cells5: 71-78

43 van Bokhoven H, Celli J, Kayserili H, van Beusekom E, Balci S, Brussel W, Skovby F, Kerr B, Percin EF, Akarsu N (2000) Mutation of the gene encoding the ROR2 tyrosine kinase causes autosomal recessive Robinow syndrome. Nat Genet25: 423-426

44 Wilson C, Goberdhan DC, Steller H (1993) Dror, a potential neurotrophic receptor gene, encodes a Drosophila homolog of the vertebrate Ror family of Trk-related receptor tyrosine kinases. Proc Natl Acad Sci USA90: 7109-7113

45 Yamaguchi T, Yanagisawa K, Sugiyama R, Hosono Y, Shimada Y, Arima C, Kato S, Tomida S, Suzuki M, Osada H (2012) NKX2-1/ TITF1/TTF-1-induced ROR1 Is required to sustain EGFR survival signaling in lung adenocarcinoma. Cancer Cell21: 348-361

46 Yang J, Baskar S, Kwong KY, Kennedy MG, Wiestner A, Rader C (2011) Therapeutic potential and challenges of targeting receptor tyrosine kinase ROR1 with monoclonal antibodies in B-cell malignancies. PLoS ONE6: e21018

47 Zhang S, Chen L, Cui B, Chuang H-Y, Yu J, Wang-Rodriguez J, Tang L, Chen G, Basak GW, Kipps TJ (2012a) ROR1 is expressed in human breast cancer and associated with enhanced tumor-cell growth. PLoS ONE7: e31127

48 Zhang S, Chen L, Wang-Rodriguez J, Zhang L, Cui B, Frankel W, Wu R, Kipps TJ (2012b) The onco-embryonic antigen ROR1 is expressed by a variety of human cancers. Am J Pathol181: 1903-1910