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Endocrine Reviews 20 (6): 761-787
Copyright © 1999 by The Endocrine Society

The Insulin-Like Growth Factor-Binding Protein (IGFBP) Superfamily1

Vivian Hwa, Youngman Oh and Ron G. Rosenfeld

Department of Pediatrics, Oregon Health Sciences University, Portland, Oregon 97201

I. Introduction
A. Concept of an IGFBP superfamily
B. Superfamily nomenclature
II. IGFBP Family
A. Structure of IGFBPs
B. Correlations between structure and function
C. Biological functions of IGFBPs
D. Genomics of IGFBPs
III. Mac25
A. IGFBP-rP1 (Mac25/TAF/PSF)
IV. CCN Family
A. IGFBP-rP2 (CTGF)
B. IGFBP-rP3 (NovH)
C. IGFBP-rP4 (Cyr61)
D. New members
V. L56
A. IGFBP-rP5 (L56/HtrA)
VI. ESM-1
A. IGFBP-rP6 (endothelial specific molecule-1)
VII. Structural Relationships Within the IGFBP Superfamily
A. Protein domains (modules)
B. Gene structure and correlation with protein domains
VIII. Functional Relationships Within the IGFBP Superfamily
A. IGF binding
B. Insulin binding
C. IGF/insulin-independent actions
IX. Evolutionary Relationships Within the IGFBP Superfamily
A. N-terminal domains
B. C-terminal domains
C. Evolutionary models
X. Summary




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J. Immunol.Home page
D. Nagakubo, T. Murai, T. Tanaka, T. Usui, M. Matsumoto, K. Sekiguchi, and M. Miyasaka
A High Endothelial Venule Secretory Protein, Mac25/Angiomodulin, Interacts with Multiple High Endothelial Venule-Associated Molecules Including Chemokines
J. Immunol., July 15, 2003; 171(2): 553 - 561.
[Abstract] [Full Text] [PDF]


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J. Clin. Endocrinol. Metab.Home page
A. Lopez-Bermejo, J. Khosravi, C. L. Corless, R. G. Krishna, A. Diamandi, U. Bodani, E. M. Kofoed, D. L. Graham, V. Hwa, and R. G. Rosenfeld
Generation of Anti-Insulin-Like Growth Factor-Binding Protein-Related Protein 1 (IGFBP-rP1/MAC25) Monoclonal Antibodies and Immunoassay: Quantification of IGFBP-rP1 in Human Serum and Distribution in Human Fluids and Tissues
J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3401 - 3408.
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J. Biol. Chem.Home page
J. H. Shand, J. Beattie, H. Song, K. Phillips, S. M. Kelly, D. J. Flint, and G. J. Allan
Specific Amino Acid Substitutions Determine the Differential Contribution of the N- and C-terminal Domains of Insulin-like Growth Factor (IGF)-binding Protein-5 in Binding IGF-I
J. Biol. Chem., May 9, 2003; 278(20): 17859 - 17866.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
M. Suzuki, H. Kobayashi, Y. Tanaka, Y. Hirashima, N. Kanayama, Y. Takei, Y. Saga, M. Suzuki, H. Itoh, and T. Terao
Bikunin Target Genes in Ovarian Cancer Cells Identified by Microarray Analysis
J. Biol. Chem., April 18, 2003; 278(17): 14640 - 14646.
[Abstract] [Full Text] [PDF]


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Endocr. Rev.Home page
E. Canalis, A. N. Economides, and E. Gazzerro
Bone Morphogenetic Proteins, Their Antagonists, and the Skeleton
Endocr. Rev., April 1, 2003; 24(2): 218 - 235.
[Abstract] [Full Text] [PDF]


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J. Clin. Endocrinol. Metab.Home page
S. L. Franklin, R. J. Ferry Jr., and P. Cohen
Rapid Insulin-Like Growth Factor (IGF)-Independent Effects of IGF Binding Protein-3 on Endothelial Cell Survival
J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 900 - 907.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Endocrinol. Metab.Home page
E. E. Spangenburg, T. Abraha, T. E. Childs, J. S. Pattison, and F. W. Booth
Skeletal muscle IGF-binding protein-3 and -5 expressions are age, muscle, and load dependent
Am J Physiol Endocrinol Metab, February 1, 2003; 284(2): E340 - E350.
[Abstract] [Full Text] [PDF]


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Cancer Res.Home page
R. J. Levitt and M. Pollak
Insulin-like Growth Factor-I Antagonizes the Antiproliferative Effects of Cyclooxygenase-2 Inhibitors on BxPC-3 Pancreatic Cancer Cells
Cancer Res., December 15, 2002; 62(24): 7372 - 7376.
[Abstract] [Full Text] [PDF]


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Endocr. Rev.Home page
S. M. Firth and R. C. Baxter
Cellular Actions of the Insulin-Like Growth Factor Binding Proteins
Endocr. Rev., December 1, 2002; 23(6): 824 - 854.
[Abstract] [Full Text] [PDF]


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Clin. Cancer Res.Home page
Y. S. Chang, K. Gong, S. Sun, D. Liu, A. K. El-Naggar, F. R. Khuri, W. K. Hong, and H.-Y. Lee
Clinical Significance of Insulin-like Growth Factor-binding Protein-3 Expression in Stage I Non-Small Cell Lung Cancer
Clin. Cancer Res., December 1, 2002; 8(12): 3796 - 3802.
[Abstract] [Full Text] [PDF]


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J. Cell Sci.Home page
C. McCaig, C. M. Perks, and J. M. P. Holly
Intrinsic actions of IGFBP-3 and IGFBP-5 on Hs578T breast cancer epithelial cells: inhibition or accentuation of attachment and survival is dependent upon the presence of fibronectin
J. Cell Sci., November 15, 2002; 115(22): 4293 - 4303.
[Abstract] [Full Text] [PDF]


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J. Clin. Endocrinol. Metab.Home page
I. Y. C. Sun, M. T. Overgaard, C. Oxvig, and L. C. Giudice
Pregnancy-Associated Plasma Protein A Proteolytic Activity Is Associated with the Human Placental Trophoblast Cell Membrane
J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 5235 - 5240.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
R. D. Devlin, Z. Du, V. Buccilli, V. Jorgetti, and E. Canalis
Transgenic Mice Overexpressing Insulin-Like Growth Factor Binding Protein-5 Display Transiently Decreased Osteoblastic Function and Osteopenia
Endocrinology, October 1, 2002; 143(10): 3955 - 3962.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
A. Bachelot, P. Monget, P. Imbert-Bollore, K. Coshigano, J. J. Kopchick, P. A. Kelly, and N. Binart
Growth Hormone Is Required for Ovarian Follicular Growth
Endocrinology, October 1, 2002; 143(10): 4104 - 4112.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Gastrointest. Liver Physiol.Home page
E. J. Kim, P. E. Holthuizen, H. S. Park, Y. L. Ha, K. C. Jung, and J. H. Y. Park
Trans-10,cis-12-conjugated linoleic acid inhibits Caco-2 colon cancer cell growth
Am J Physiol Gastrointest Liver Physiol, August 1, 2002; 283(2): G357 - G367.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
T. J. Maures and C. Duan
Structure, Developmental Expression, and Physiological Regulation of Zebrafish IGF Binding Protein-1
Endocrinology, July 1, 2002; 143(7): 2722 - 2731.
[Abstract] [Full Text] [PDF]


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Cell Growth Differ.Home page
H.-M. P. Wilson, R. S. Birnbaum, M. Poot, L. S. Quinn, and K. Swisshelm
Insulin-like Growth Factor Binding Protein-related Protein 1 Inhibits Proliferation of MCF-7 Breast Cancer Cells via a Senescence-like Mechanism
Cell Growth Differ., May 1, 2002; 13(5): 205 - 213.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
A. Hourvitz, A. Kuwahara, J. D. Hennebold, A. B. Tavares, H. Negishi, T. H. Lee, G. F. Erickson, and E. Y. Adashi
The Regulated Expression of the Pregnancy-Associated Plasma Protein-A in the Rodent Ovary: A Proposed Role in the Development of Dominant Follicles and of Corpora Lutea
Endocrinology, May 1, 2002; 143(5): 1833 - 1844.
[Abstract] [Full Text] [PDF]


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Mol Hum ReprodHome page
J. Liu, V.-M. Kosma, T. Vanttinen, C. Hyden-Granskog, and R. Voutilainen
Gonadotrophins inhibit the expression of insulin-like growth factor binding protein-related protein-2 mRNA in cultured human granulosa-luteal cells
Mol. Hum. Reprod., February 1, 2002; 8(2): 136 - 141.
[Abstract] [Full Text] [PDF]


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Mol. Pathol.Home page
P Vorwerk, H Wex, B Hohmann, K Mohnike, U Schmidt, and U Mittler
Expression of components of the IGF signalling system in childhood acute lymphoblastic leukaemia
Mol. Pathol., February 1, 2002; 55(1): 40 - 45.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
C. H. Lang, G. J. Nystrom, and R. A. Frost
Burn-induced changes in IGF-I and IGF-binding proteins are partially glucocorticoid dependent
Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2002; 282(1): R207 - R215.
[Abstract] [Full Text] [PDF]


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JNCI J Natl Cancer InstHome page
Y. Lu, X. Zi, Y. Zhao, D. Mascarenhas, and M. Pollak
Insulin-Like Growth Factor-I Receptor Signaling and Resistance to Trastuzumab (Herceptin)
J Natl Cancer Inst, December 19, 2001; 93(24): 1852 - 1857.
[Abstract] [Full Text] [PDF]


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Endocr. Rev.Home page
J. Nakae, Y. Kido, and D. Accili
Distinct and Overlapping Functions of Insulin and IGF-I Receptors
Endocr. Rev., December 1, 2001; 22(6): 818 - 835.
[Abstract] [Full Text] [PDF]


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Cancer Res.Home page
A. Hoeflich, R. Reisinger, H. Lahm, W. Kiess, W. F. Blum, H. J. Kolb, M. M. Weber, and E. Wolf
Insulin-like Growth Factor-binding Protein 2 in Tumorigenesis: Protector or Promoter?
Cancer Res., December 1, 2001; 61(24): 8601 - 8610.
[Full Text] [PDF]


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Am. J. Physiol. Endocrinol. Metab.Home page
C. G. Goodyer, R. M. O. Figueiredo, S. Krackovitch, L. De Souza Li, J. A. Manalo, and G. Zogopoulos
Characterization of the growth hormone receptor in human dermal fibroblasts and liver during development
Am J Physiol Endocrinol Metab, December 1, 2001; 281(6): E1213 - E1220.
[Abstract] [Full Text] [PDF]


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Cancer Epidemiol. Biomarkers Prev.Home page
A. Decensi, H. Johansson, R. Miceli, L. Mariani, T. Camerini, E. Cavadini, M. G. Di Mauro, A. Barreca, A. G. Gonzaga, S. Diani, et al.
Long-Term Effects of Fenretinide, a Retinoic Acid Derivative, on the Insulin-like Growth Factor System in Women with Early Breast Cancer
Cancer Epidemiol. Biomarkers Prev., October 1, 2001; 10(10): 1047 - 1053.
[Abstract] [Full Text] [PDF]


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J. Clin. Endocrinol. Metab.Home page
M. W. Elmlinger, I. Mayer, D. Schnabel, B. S. Schuett, D. Diesing, G. Romalo, H. A. Wollmann, W. Weidemann, K.-D. Spindler, M. B. Ranke, et al.
Decreased Expression of IGF-II and Its Binding Protein, IGF-Binding Protein-2, in Genital Skin Fibroblasts of Patients with Complete Androgen Insensitivity Syndrome Compared with Normally Virilized Males
J. Clin. Endocrinol. Metab., October 1, 2001; 86(10): 4741 - 4746.
[Abstract] [Full Text] [PDF]


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J. Clin. Endocrinol. Metab.Home page
C. K. Buckway, E. M. Wilson, M. Ahlsen, P. Bang, Y. Oh, and R. G. Rosenfeld
Mutation of Three Critical Amino Acids of the N-Terminal Domain of IGF-Binding Protein-3 Essential for High Affinity IGF Binding
J. Clin. Endocrinol. Metab., October 1, 2001; 86(10): 4943 - 4950.
[Abstract] [Full Text] [PDF]


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Mol. Pathol.Home page
Z Laron
Insulin-like growth factor 1 (IGF-1): a growth hormone
Mol. Pathol., October 1, 2001; 54(5): 311 - 316.
[Abstract] [Full Text] [PDF]


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Mol. Pathol.Home page
P Vilmos, K Gaudenz, Z Hegedus, and J L Marsh
The Twisted gastrulation family of proteins, together with the IGFBP and CCN families, comprise the TIC superfamily of cysteine rich secreted factors
Mol. Pathol., October 1, 2001; 54(5): 317 - 323.
[Abstract] [Full Text] [PDF]


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J. Clin. Endocrinol. Metab.Home page
E. M. Wilson, Y. Oh, V. Hwa, and R. G. Rosenfeld
Interaction of IGF-Binding Protein-Related Protein 1 with a Novel Protein, Neuroendocrine Differentiation Factor, Results in Neuroendocrine Differentiation of Prostate Cancer Cells
J. Clin. Endocrinol. Metab., September 1, 2001; 86(9): 4504 - 4511.
[Abstract] [Full Text] [PDF]


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Mol. Endocrinol.Home page
T. C. Voss, M. P. Flynn, and D. L. Hurley
IGF-I Causes an Ultrasensitive Reduction in GH mRNA Levels via an Extracellular Mechanism Involving IGF Binding Proteins
Mol. Endocrinol., September 1, 2001; 15(9): 1549 - 1558.
[Abstract] [Full Text] [PDF]


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J. Clin. Endocrinol. Metab.Home page
C. Martinerie, C. Gicquel, A. Louvel, M. Laurent, P. N. Schofield, and Y. Le Bouc
Altered Expression of novH Is Associated with Human Adrenocortical Tumorigenesis
J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3929 - 3940.
[Abstract] [Full Text] [PDF]


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Cancer Res.Home page
T. Nickerson, F. Chang, D. Lorimer, S. P. Smeekens, C. L. Sawyers, and M. Pollak
In Vivo Progression of LAPC-9 and LNCaP Prostate Cancer Models to Androgen Independence Is Associated with Increased Expression of Insulin-like Growth Factor I (IGF-I) and IGF-I Receptor (IGF-IR)
Cancer Res., August 1, 2001; 61(16): 6276 - 6280.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
K. Prelle, M. Stojkovic, K. Boxhammer, J. Motlik, D. Ewald, G. J. Arnold, and E. Wolf
Insulin-Like Growth Factor I (IGF-I) and Long R3IGF-I Differently Affect Development and Messenger Ribonucleic Acid Abundance for IGF-Binding Proteins and Type I IGF Receptors in in Vitro Produced Bovine Embryos
Endocrinology, March 1, 2001; 142(3): 1309 - 1316.
[Abstract] [Full Text] [PDF]


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J. Clin. Endocrinol. Metab.Home page
R. G. Rosenfeld, V. Hwa, and Y. Oh
Nomenclature of the Insulin-Like Growth Factor-Binding Protein Superfamily
J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 946 - 946.
[Full Text]




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