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DOI: 10.1055/s-2004-830538
J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York
Decreased Expression of G-Protein Coupled Receptor Kinase 2 in Cold Thyroid Nodules
Publication History
Received: December 2, 2003
First decision: February 16, 2004
Accepted: June 28, 2004
Publication Date:
17 March 2005 (online)
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Abstract
G-protein coupled receptor kinases (GRKs) have been shown to regulate the homologous desensitization of different G-protein coupled receptors. We have previously demonstrated that the expression of GRK 3 and 4 is increased in hyperfunctioning thyroid nodules (HTNs) and that GRKs 2, 3, 5 and 6 are able to desensitize the TSHR in vitro. Since cold thyroid nodules (CTNs) and HTNs show different molecular and functional properties, different expression patterns of GRKs in these nodules can be expected. The comparison of GRK expression between CTNs and HTNs could give additional insight into the regulation mechanisms of these nodules. We therefore examined the expression of GRKs in CTNs and analyzed the differences to HTNs. The expression of the different GRKs in CTNs was measured by Western blot followed by chemiluminescence imaging.
We found a decreased expression of GRK 2 in CTNs compared to their surrounding tissues and an increased expression of GRK 3 and 4 in CTNs, which is similar to HTNs. The decreased GRK 2 expression most likely results from reduced cAMP stimulation in CTNs. However, the increased GRK 3 and 4 expression in CTNs remains unclear and requires further investigations.
Key words
GRK - TSH receptor - thyroid - nodule - protein expression
References
- 1 Belfiore A, Rosa G L, Giuffrida D, Regalbuto C, Lupo L, Fiumara A, Ippolito O. The management of thyroid nodules. J Endocrinol Invest. 1995; 18 155-158
- 2 Cideciyan A V, Zhao X, Nielsen L, Khani S C, Jacobson S G, Palczewski K. Null mutation in the rhodopsin kinase gene slows recovery kinetics of rod and cone phototransduction in man. Proc Natl Acad Sci USA. 1998; 95 328-333
- 3 Daaka Y, Pitcher J A, Richardson M, Stoffel R H, Robishaw J D, Lefkowitz R J. Receptor and G betagamma isoform-specific interactions with G protein-coupled receptor kinases. Proc Natl Acad Sci USA. 1997; 94 2180-2185
- 4 Davis B J. Disc electrophoresis. II. Method and application to human serum proteins. Ann New York Acad Sci. 1964; 121 404-427
- 5 Eckhart A D, Duncan S J, Penn R B, Benovic J L, Lefkowitz R J, Koch W J. Hybrid transgenic mice reveal in vivo specificity of G protein-coupled receptor kinases in the heart. Circ Res. 2000; 86 43-50
- 6 Elorza A, Penela P, Sarnago S, Mayor Jr F. MAPK-dependent degradation of G protein-coupled receptor kinase 2. J Biol Chem. 2003; 278 29164-29173
- 7 Freedman N J, Liggett S B, Drachman D E, Pei G, Caron M G, Lefkowitz R J. Phosphorylation and desensitization of the human beta 1-adrenergic receptor. Involvement of G protein-coupled receptor kinases and cAMP-dependent protein kinase. J Biol Chem. 1995; 270 17953-17961
- 8 Gros R, Benovic J L, Tan C M, Feldman R D. G protein-coupled receptor kinase activity is increased in hypertension. J Clin Invest. 1997; 99 2087-2093
- 9 Hara T, Namba H, Takamura N, Yang T T, Nagayama Y, Fukata S, Kuma K, Ishikawa N, Ito K, Yamashita S. Thyrotropin regulates c-Jun N-terminal kinase (JNK) activity through two distinct signal pathways in human thyroid cells. Endocrinology. 1999; 140 1724-1730
- 10 Hedinger C, Wiliams E D, Sobin L H. Histological Typing of Thyroid Tumors. 2nd ed. Berlin, Heidelberg, New York; Springer 1988
- 11 Iaccarino G, Rockman H A, Shotwell K F, Tomhave E D, Koch W J. Myocardial overexpression of GRK3 in transgenic mice: evidence for in vivo selectivity of GRKs. Am J Physiol. 1998; 275 H1298-H1306
- 12 Iacovelli L, Franchetti R, Masini M, De Blasi A. GRK2 and beta-arrestin 1 as negative regulators of thyrotropin receptor-stimulated response. Mol Endocrinol. 1996; 10 1138-1146
- 13 Ishii K, Chen J, Ishii M, Koch W J, Freedman N J, Lefkowitz R J, Coughlin S R. Inhibition of thrombin receptor signaling by a G protein-coupled receptor kinase. Functional specificity among G protein coupled receptor kinases. J Biol Chem. 1994; 269 1125-1130
- 14 Kohout T A, Lefkowitz R J. Regulation of G protein-coupled receptor kinases and arrestins during receptor desensitization. Mol Pharmacol. 2003; 63 9-18
- 15 Krohn K, Emmrich P, Ott N, Paschke R. Increased thyroid epithelial cell proliferation in toxic thyroid nodules. Thyroid. 1999; 9 241-246
- 16 Krohn K, Fuhrer D, Holzapfel H P, Paschke R. Clonal origin of toxic thyroid nodules with constitutively activating thyrotropin receptor mutations. J Clin Endocrinol Metab. 1998; 83 130-134
- 17 Krohn K, Reske A, Ackermann F, Muller A, Paschke R. Ras mutations are rare in solitary cold and toxic thyroid nodules. Clin Endocrinol (Oxf). 2001; 55 241-248
- 18 Krohn K, Stricker I, Emmrich P, Paschke R. Cold thyroid nodules show a marked increase of proliferation markers. Thyroid. 2003; 13 569-575
- 19 Krupnick J G, Benovic J L. The role of receptor kinases and arrestins in G protein-coupled receptor regulation. Annu Rev Pharmacol Toxicol. 1998; 38 289-319
- 20 Laemmli U K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970; 227 680-685
- 21 Lombardi M S, Kavelaars A, Schedlowski M, Bijlsma J W, Okihara K L, Van de Pol M, Ochsmann S, Pawlak C, Schmidt R E, Heijnen C J. Decreased expression and activity of G protein-coupled receptor kinases in peripheral blood mononuclear cells of patients with rheumatoid arthritis. FASEB J. 1999; 13 715-725
- 22 Metaye T, Menet E, Guilhot J, Kraimps J L. Expression and activity of G protein-coupled receptor kinases in differentiated thyroid carcinoma. J Clin Endocrinol Metab. 2002; 87 3279-3286
- 23 Nagayama Y, Tanaka K, Hara T, Namba H, Yamashita S, Taniyama K, Niwa M. Involvement of G protein-coupled receptor kinase 5 in homologous desensitization of the thyrotropin receptor. J Biol Chem. 1996 a; 271 10143-10148
- 24 Nagayama Y, Tanaka K, Namba H, Yamashita S, Niwa M. Expression and regulation of G protein-coupled receptor kinase 5 and beta-arrestin-1 in rat thyroid FRTL5 cells. Thyroid. 1996 b; 6 627-631
- 25 Penela P, Elorza A, Sarnago S, Mayor F J. Beta-arrestin- and c-Src-dependent degradation of G protein-coupled receptor kinase 2. EMBO J. 2001; 20 5129-5138
- 26 Penela P, Ruiz-Gomez A, Castano J G, Mayor Jr F. Degradation of the G protein-coupled receptor kinase 2 by the proteasome pathway. J Biol Chem. 1998; 273 35238-35244
- 27 Peppel K, Boekhoff I, McDonald P, Breer H, Caron M G, Lefkowitz R J. G protein-coupled receptor kinase 3 (GRK3) gene disruption leads to loss of odorant receptor desensitization. J Biol Chem. 1997; 272 25425-25428
- 28 Poertl S, Kirner J, Saller B, Mann K, Hoermann R. T3-release from autonomously functioning thyroid nodules in vitro. Exp Clin Endocrinol Diabetes. 1998; 106 489-493
- 29 Shklyaev S S, Namba H, Mitsutake N, Alipov G, Nagayama Y, Maeda S, Ohtsuru A, Tsubouchi H, Yamashita S. Transient activation of c-Jun NH2-terminal kinase by growth factors influences survival but not apoptosis of human thyrocytes. Thyroid. 2001; 11 629-636
- 30 Tiruppathi C, Yan W, Sandoval R, Naqvi T, Pronin A N, Benovic J L, Malik A B. G protein-coupled receptor kinase-5 regulates thrombin-activated signaling in endothelial cells. Proc Natl Acad Sci USA. 2000; 97 7440-7445
- 31 Voigt C, Holzapfel H, Paschke R. Expression of beta-arrestins in toxic and cold thyroid nodules. FEBS Lett. 2000; 486 208-212
- 32 Voigt C, Holzapfel H P, Meyer S, Paschke R. Increased expression of G-protein coupled receptor kinases 3 and 4 in hyperfunctioning thyroid nodules. J Endocrinol. 2004; 182 173-182
- 33 Wynford-Thomas D, Stringer B M, Harach H R, Williams E D. Control of growth in the rat thyroid - an example of specific desensitization to trophic hormone stimulation. Experientia. 1983; 39 421-423
- 34 Yamamoto S, Sippel K C, Berson E L, Dryja T P. Defects in the rhodopsin kinase gene in the Oguchi form of stationary night blindness. Nat Genet. 1997; 15 175-178
M.D. R. Paschke
III. Medical Department, University of Leipzig
Ph. Rosenthal Str. 27
04103 Leipzig
Germany
Phone: + 493419713200
Fax: + 49 34 19 71 32 09
Email: pasr@medizin.uni-leipzig.de