[en] Thymic oxytocin (OT) behaves as a cryptocrine signal targeted at the outer surface of thymic epithelial cell plasma membrane from where OT is able to interact with neurohypophysial peptide receptors expressed by pre-T cells. Immature T cells bear a receptor of the V1 subtype, while OT receptors are predominantly expressed by cytotoxic CD8+ lymphocytes. In both T cell types, neurohypophysial peptide receptors transduce OT via the phosphoinositide pathway. Protein tyrosine phosphorylation is an early event of T cell activation. Western blots of murine pre-T cells (RL12-NP line) proteins probed with anti-phosphotyrosine (PY-20) revealed a great number of proteins the phosphorylation of which increased either with OT or vasopressin treatment. Two were immunoprecipitated with anti-focal adhesion kinase (FAK) mAb 2A7 and were identified one as p125FAK and the other as a coprecipitating 130-kDa protein. The p125FAK is connected to the Ras/MAPK pathway and is also implicated in TCR/CD3 signalling in T cell. Another protein phosphorylated by OT in RL12-NP was identified as paxillin, a 68-kDa protein localised at focal adhesion sites and associated with p 125FAK. These results indicate that phosphorylation of focal adhesion kinase may be induced in pre-T cell by thymic OT.
Schaller MD: The focal adhesion kinase. J Endocrinol 1996;150:1-7.
Schaller MD, Borgman CA, Bradley SC, Cobb BS, Vines RV, Reynolds AB, Parsons JT: pp125FAK, a structurally distinctive protein-tyrosine kinase associated with focal adhesions. Proc Natl Acad Sci USA 1992;89:5192-5196.
Hildebrand JD, Schaller MD, Parsons JT: Identification of sequences required for the efficient localization of the focal adhesion kinase, pp125FAK, to cellular focal adhesions. J Cell Biol 1993;123:993-1005.
Zachary I, Rozengurt E: Focal adhesion kinase (p125FAK): A point of convergence in the action of neuropeptides, integrin, and oncogenes. Cell 1992;71:891-894.
Withney GS, Chan PY, Blake J, Cosand WL, Neubauer MG, Aruffo A, Kanner SB: Human T-lymphocyte and B-lymphocyte express a structurally conserved focal adhesion kinase, pp125(FAK). DNA Cell Biol 1990;12:823-830.
Anderson G, Moore NC, Owen JJ, Jenkinson EJ: Cellular interactions in thymocyte development. Annu Rev Immunol 1996;14:73-99.
Geenen V, Robert F, Martens H, Benhida A, Degiovanni G, Defresne MP, Boniver J, Legros JJ, Martial J, Franchimont P: Biosynthesis and paracrine/cryptocrine actions of 'self' neurohypophysial-related peptides in the thymus. Mol Cell Endocrinol 1991;76:C27-C31.
Martens H, Goxe B, Geenen V: The thymic repertoire of neuroendocrine self-peptides: Physiological implications in T-cell life and death. Immunol Today 1996;17:312-317.
Geenen V, Vandersmissen E, Cormann-Goffin N, Martens H, Legros JJ, Degiovanni G, Benhida A, Martial J, Franchimont P: Membrane translocation and relationship with MHC class I of a human thymic neurophysin-like protein. Thymus 1993;22:55-66.
Vanneste Y, Ntodou Thome A, Vandersmissen E, Charlet C, Franchimont D, Martens H, Schimpff RM, Rostène W, Geenen V: Identification of neurotensin-related peptides in human thymic epithelial cell membranes and relationship with major histocompatibility complex class I molecules. J Neuroimmunol 1997; 76:161-166.
Geenen V, Vandersmissen E, Martens H, Goxe B, Kecha O, Legros JJ, Lefebvre PJ, Benhida A, Rentier-Delrue F, Martial JA: Cellular and molecular aspects of thymic T-cell education to neurohypophysial principles; in Saito T, Kurokawa K, Yoshida S (eds): Neurohypophysis: Recent Progress of Vasopressin and Oxytocin Research. ICS. Amsterdam, Elsevier, 1995, vol 1098, pp 309-319.
Geenen V, Legros JJ, Franchimont P, Baudrihaye MF, Defresne MP, Boniver J: The neuroendocrine thymus: Coexistence of oxytocin and neurophysin in the human thymus. Science 1986;232:508-511.
Martens H, Robert F, Legros JJ, Geenen V, Franchimont P: Expression of functional neurohypophysial peptide receptors by immature and cytotoxic T cell lines. Prog Neuroendocrinimmunol 1992;5:31-39.
Wiemann M, Ehret G: Subcellular localization of immunoreactive oxytocin within thymic epithelial cells of the male mouse. Cell Tissue Res 1993;273:79-87.
Bacon KB, Szabo MC, Yssel H, Bolen JB, Schall TJ: RANTES induces tyrosine kinase activity of stably complexed p125FAK and ZAP-70 in human T cells. J Exp Med 1996; 184:873-882.
Liebermann M, Decleve A, Ricciardi-Castagnoli P, Boniver J, Finn OJ, Kaplan HS: Establishment, characterization and virus expression of cell lines derived from radiation-and virus-induced lymphomas of C57 BL/Ka mice. Int J Cancer 1979;24:168-177.
Kruszynski M, Lammek B, Manning M, Seto J, Haldar J, Sawyer WH: [1-(β-mercapto-β,β-cyclopentamethylenepropionic acid), 2-(O-methyl)tyrosine]arginine vasopressin and [1-(β - mercapto - β,β - cyclopentamethylenepropionic acid)] arginine vasopressin, two highly potent antagonists of the vasopressor response to arginine vasopressin. J Med Chem 1980;23: 364-368.
Burridge K, Turner CE, Romer LH: Tyrosine phosphorylation of paxillin and pp125FAK accompanies cell adhesion to extracellular matrix: A role in cytoskeletal assembly. J Cell Biol 1992;119:893-903.1
Schägger H, von Jagow G: Tricine-sodium sulfate polyacrylamide gel electrophoresis for the separation of proteins in the range from 1 to 100 kDa. Anal Biochem 1987;166:368-379.
Geenen V, Robert F, Fatemi M, Defresne MP, Boniver J, Legros JJ, Franchimont P: Vasopressin and oxytocin: Thymic signals and receptors in T cell ontogeny; in Yoshida S, Share L (eds): Recent Progress in Posterior Pituitary Hormones. ICS. New York, Elsevier, 1988, vol 797, pp 303-310.
Torres BA, Johnson HM: Arginine vasopressin (AVP) replacement of helper cell requirement in IFN gamma production. Evidence for a novel AVP receptor on mouse lymphocytes. J Immunol 1988;140:2179-2183.
Caldwell JD, Walker CA, Noonan LR, Jirikowski GF, Peterson G, Pedersen CA, Mason GA: Changes in thymic oxytocin receptors during early development and in steroid-treated adult rats. Prog Neuroendocrinimmunol 1991; 4:228-233.
Zachary I, Gil J, Lehmann W, Sinett-Smith J, Rozengurt E: Bombesin, vasopressin, and endothelin rapidly stimulate tyrosine phosphorylation in intact Swiss 3T3 cells. Proc Natl Acad Sci USA 1991;88:4577-4581.
Zachary I, Woll PJ, Rozengurt E: A role for neuropeptides in the control of cell proliferation. Dev Biol 1987;124:295-308.
Lipfert L, Halmovich B, Schaller MD, Cobb BS, Parsons JT, Brugge JS: Integrin-dependent phosphorylation and activation of the protein tyrosine kinase pp125FAK in platelets. J Cell Biol 1992;119:905-912.
Zachary I, Sinnett-Smith J, Rozengurt E: Bombesin, vasopressin and endothelin stimulation of tyrosine phosphorylation in Swiss 3T3 cells. J Biol Chem 1992;25:19031-19034.
Zachary I, Sinnett-Smith J, Turner CE, Rozengurt E: Bombesin, vasopressin, and endothelin rapidly stimulate tyrosine phosphorylation of the focal adhesion-associated protein paxillin in Swiss 3T3 cells: Identification of a novel tyrosine kinase as a major substrate. J Biol Chem 1993;268:22060-22065.
Reynolds AB, Kanner SB, Wang H-C, Parsons JT: Stable association of activated pp60src with two tyrosine-phosphorylated cellular proteins. Mol Cell Biol 1989;9:3951-3958.
Wu H, Reynolds AB, Kanner SB, Vines RR, Parsons JT: Identification and characterization of a novel cytoskeleton-associated pp60src substrate. Mol Cell Biol 1991;11:5113-5124.
Kanner SB, Reynolds AB, Wang HC, Vines RR, Parsons JT: The SH2 and SH3 domains of pp60src direct stable association with tyrosine phosphorylated proteins p130 and p110. EMBO J 1991;10:1689-1698.
Sakai R, Iwamatsu A, Hirano N, Ogawa S, Tanaka T, Mano H, Yazaki Y, Hirai H: A novel signalling molecule, p130, forms stable complexes in vivo with v-Crk and v-Src in a tyrosine phosphorylation-dependent manner. EMBO J 1994;13:3748-3756.
Nojima Y, Morino N, Mimura T, Hamasaki K, Furuya H, Sakai R, Sato T, Tachibana K, Morimoto C, Yazaki Y, Hirai H: Integrin-mediated cell adhesion promotes tyrosine phosphorylation of p130Cas, an Src homology 3-containing molecule having multiple Src homology 2-binding motifs. J Biol Chem 1995;270:15398-15402.
Petch LA, Bockholt SM, Bouton A, Parsons JT, Burridge K: Adhesion-induced tyrosine phosphorylation of the p130 src substrate. J Cell Sci 1995;108:1371-1379.
Harte MT, Hildebrand JD, Burnham MR, Bouton AH, Parsons JT: p130Cas, a substrate associated with v-Src and v-Crk, localizes to focal adhesions and binds to focal adhesion kinase. J Biol Chem 1996;271:13649-13655.
Lolait SJ, O'Carroll AM, Mahan LC, Felder CC, Button DC, Young WS 3rd, Mezey E, Brownstein MJ: Extrapituitary expression of the rat V1b vasopressin receptor gene. Proc Natl Acad Sci USA 1995;92:6783-6787.
Sugimoto T, Saito M, Mochizuki S, Tahara A, Watanabe Y, Hashimoto S, Kawashima H: Molecular cloning and functional expression of V1b receptor gene; in Saito T, Kurokawa K, Yoshida S (eds): Neurohypophysis: Recent Progress of Vasopressin and Oxytocin Research. ICS. Amsterdam, Elsevier, 1995, vol 1098, pp 409-413.
Martens H, Malgrange B, Robert F, Charlet-Renard Ch, Heymann D, Godard A, De Groote D, Moonen G, Geenen V: Cytokine production by human thymic epithelial cells: Control by the human recognition of the neurohypophysial self-antigen. Regul Peptides 1996; 67:39-45.
Schlosser SF, Ameida OF, Patchev VK, Yassouridis A, Elands J: Oxytocin-stimulated release of adrenocorticotropin from the rat pituitary is mediated by arginine vasopressin receptors of the V1b subtype. Endocrinology 1994; 135:12058-12063.
Sermasi E, Coote JH: Oxytocin acts at V1 receptors to excite sympathetic preganglionic neurones in neonate rat spinal cord in vitro. Brain Res 1994;647:323-332.
Schlaepfer DB, Hanks SK, Hunter T, Van de Geer P: Integrin-mediated signal transduction linked to ras pathway by GRB2 binding to focal adhesion kinase. Nature 1994;372:786-791.
Chen HC, Guan JL: Association of focal adhesion kinase with its potential substrate phosphatidylinositol 3-kinase. Proc Natl Acad Sci USA 1994;91:10148-10152.
Guinebault C, Payrastre B, Racaud-Sultan C, Mazarguil H, Breton M, Mauco G, Plantavid M, Chap H: Integrin-dependent translocation of phosphoinositide 3-kinase to the cytoskeleton of thrombin-activated platelets involves specific interactions of p85α with actin filaments and focal adhesion kinase. J Cell Biol 1995;129:831-884.
Kanazawa S, Ilic D, Nomura T, Yamamoto T, Aizawa S: Integrin stimulation decreases tyrosine phosphorylation and activity of focal adhesion kinase in thymocytes. Biochem Biophys Res Commun 1995;215:438-445.
Kanner SB, Aruffo A, Chan P-Y: Lymphocyte antigen receptor activation of a focal adhesion kinase-related tyrosine kinase substrate. Proc Natl Acad Sci USA 1994;91:10484-10487.
Maguire JE, Danahey KM, Burkly LC van, Seventer GA: T cell receptor-and β1 integrin-mediated signals synergize to indue tyrosine phosphorylation of focal adhesion kinase (pp125FAK) in human T cells. J Exp Med 1995; 182:2079-2090.
Berg NH, Ostergaard HL: T cell receptor engagement induces tyrosine phosphorylation of FAK and Pyk2 and their association with Lck. J Immunol 1997;159:1753-1757.
Nijima Y, Tachibana K, Sato T, Schlossman SF, Morimoto C: Focal adhesion kinase (pp125FAK) is tyrosine phosphorylated after engagement of α4β1 and α5β1 integrins of human T-lymphoblastic cells. Cell Immunol 1995;161: 8-13.
Haller H, Kuzendorf U, Sachere K, Lindschau C, Walz G, Distler A, Luft FC: T cell adhesion to P-selectin induces tyrosine phosphorylation of pp125 focal adhesion kinase and other substrates. J Immunol 1997;158:1061-1067.
Conroy LA, Alexander DR: The role of intracellular signalling pathways regulating thymocyte and leukemic T cell apoptosis. Leukemia 1996;10:1422-1435.
Crouch DM, Fincham VJ, Frame MC: Targeted proteolysis of the focal adhesion kinase pp125FAK during c-myc-induced apoptosis is suppressed by integrin signalling. Oncogene 1996;12:2689-2696.
Ilic D, Furuta Y, Kanazawa S, Takeda N, Sobue K, Nakatsuji N, Nomura S, Fujimoto J, Okada M, Yamamoto T, Aizawa S: Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature 1995;377:539-544.
Ilic D, Kanazawa S, Furuta Y, Yamamoto T, Aizawa S: Impairment of mobility in endodermal cells by FAK deficiency. Exp Cell Res 1996;222:298-303.
Schaller MD, Hildebrand JD, Shannon JD, Fox JW, Vines RR, Parsons JT: Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2-dependent binding of pp60src. Mol Cell Biol 1994;14:1680-1688.
Weiner TM, Liu ET, Craven RJ, Cance WG: Expression of focal adhesion kinase gene and invasive cancer. Lancet 1993;342:1024-1025.
Weiner TM, Liu ET, Craven RJ, Cance WG: Expression of growth factor receptors, the focal adhesion kinase, and other tyrosine kinases in human soft tissue tumors. Ann Surg Oncol 1994;1:18-27.
Cance WG, Liu ET: Protein kinases in human breast cancer. Breast Cancer Res Treat 1995; 35:105-114.
Owens LV, Xu L, Craven RJ, Dent GA, Weiner TM, Kornberg L, Liu ET, Cance WG: Overexpression of the focal adhesion kinase (p125FAK) in invasive human tumors. Cancer Res 1995;55:2752-2755.
Owens LV, Xu L, Dent GA, Yang X, Sturge GC, Craven RJ, Cance WG: Focal adhesion kinase as a marker of invasive potential in differentiated human thyroid cancer. Ann Surg Oncol 1996;3:100-105.
Xu L, Owens LV, Sturge GC, Yang X, Liu ET, Craven RJ, Cance WG: Attenuation of the expression of the focal adhesion kinase induces apoptosis in tumor cells. Cell Growth Differ 1996;7:413-418.