PF00219

Insulin-like growth factor binding protein

Pfam entry
Member databasePfam
Pfam typedomain
Short nameIGFBP
ClanGF_recep_C-rich
Author Finn RD;0000-0001-8626-2148
Sequence Ontology0000417

Description
Imported from IPR000867

This entry represents insulin-like growth factors (IGF-I and IGF-II), which bind with high affinity to specific binding proteins in extracellular fluids
[9, 1, 13]
. These IGF-binding proteins (IGFBP) prolong the half-life of the IGFs and have been shown to either inhibit or stimulate the growth promoting effects of the IGFs on cells culture. They seem to alter the interaction of IGFs with their cell surface receptors. There are at least six different IGFBPs and they are structurally related. The following growth-factor inducible proteins are structurally related to IGFBPs and could function as growth-factor binding proteins
[12, 2]
, mouse protein cyr61 and its probable chicken homologue, protein CEF-10 (both known as CCN family member 1); human connective tissue growth factor (CTGF) and its mouse homologue, protein FISP-12 (both known as CCN family member 2); and vertebrate protein NOV (known as CCN family member 3).

Insulin-like Growth Factor Binding Proteins (IGFBP) are a group of vertebrate secreted proteins, which bind to IGF-I and IGF-II with high affinity and modulate the biological actions of IGFs. The IGFBP family has six distinct subgroups, IGFBP-1 through 6, based on conservation of gene (intron-exon) organisation, structural similarity, and binding affinity for IGFs. Across species, IGFBP-5 exhibits the most sequence conservation, while IGFBP-6 exhibits the least sequence conservation. The IGFBPs contain inhibitor domain homologues, which are related to MEROPS protease inhibitor family I31 (equistatin, clan IX).

All IGFBPs share a common domain architecture (
IPR000867
:
IPR000716
). While the N-terminal (
IPR000867
, IGF binding protein domain), and the C-terminal (
IPR000716
, thyroglobulin type-1 repeat) domains are conserved across vertebrate species, the mid-region is highly variable with respect to protease cleavage sites and phosphorylation and glycosylation sites. IGFBPs contain 16-18 conserved cysteines located in the N-terminal and the C-terminal regions, which form 8-9 disulphide bonds
[11]
.

As demonstrated for human IGFBP-5, the N terminus is the primary binding site for IGF. This region, comprised of Val49, Tyr50, Pro62 and Lys68-Leu75, forms a hydrophobic patch on the surface of the protein
[10]
. The C terminus is also required for high affinity IGF binding, as well as for binding to the extracellular matrix
[7]
and for nuclear translocation
[6, 8]
of IGFBP-3 and -5.

IGFBPs are unusually pleiotropic molecules. Like other binding proteins, IGFBP can prolong the half-life of IGFs via high affinity binding of the ligands. In addition to functioning as simple carrier proteins, serum IGFBPs also serve to regulate the endocrine and paracrine/autocrine actions of IGF by modulating the IGF available to bind to signalling IGF-I receptors
[4, 3]
. Furthermore, IGFBPs can function as growth modulators independent of IGFs. For example, IGFBP-5 stimulates markers of bone formation in osteoblasts lacking functional IGFs
[11]
. The binding of IGFBP to its putative receptor on the cell membrane may stimulate the signalling pathway independent of an IGF receptor, to mediate the effects of IGFBPs in certain target cell types. IGFBP-1 and -2, but not other IGFBPs, contain a C-terminal Arg-Gly-Asp integrin-binding motif. Thus, IGFBP-1 can also stimulate cell migration of CHO and human trophoblast cells through an action mediated by alpha 5 beta 1 integrin
[5]
. Finally, IGFBPs transported into the nucleus (via the nuclear localisation signal) may also exert IGF-independent effects by transcriptional activation of genes.

References
Imported from IPR000867

1.Identification and molecular characterization of insulin-like growth factor binding proteins (IGFBP-1, -2, -3, -4, -5 and -6). Shimasaki S, Ling N. Prog. Growth Factor Res. 3, 243-66, (1991). View articlePMID: 1725860

2.Proviral rearrangements and overexpression of a new cellular gene (nov) in myeloblastosis-associated virus type 1-induced nephroblastomas. Joliot V, Martinerie C, Dambrine G, Plassiart G, Brisac M, Crochet J, Perbal B. Mol. Cell. Biol. 12, 10-21, (1992). View articlePMID: 1309586

3.Specifying the cellular responses to IGF signals: roles of IGF-binding proteins. Duan C. J. Endocrinol. 175, 41-54, (2002). View articlePMID: 12379489

4.IGF-binding proteins are multifunctional and act via IGF-dependent and -independent mechanisms. Mohan S, Baylink DJ. J. Endocrinol. 175, 19-31, (2002). View articlePMID: 12379487

5.Insulin-like growth factor binding protein 1 stimulates cell migration and binds to the alpha 5 beta 1 integrin by means of its Arg-Gly-Asp sequence. Jones JI, Gockerman A, Busby WH Jr, Wright G, Clemmons DR. Proc. Natl. Acad. Sci. U.S.A. 90, 10553-7, (1993). View articlePMID: 7504269

6.Nuclear localization signal in insulin-like growth factor-binding protein type 3. Radulescu RT. Trends Biochem. Sci. 19, 278, (1994). View articlePMID: 7519375

7.Binding of insulin-like growth factor (IGF)-binding protein-5 to smooth-muscle cell extracellular matrix is a major determinant of the cellular response to IGF-I. Parker A, Rees C, Clarke J, Busby WH Jr, Clemmons DR. Mol. Biol. Cell 9, 2383-92, (1998). View articlePMID: 9725901

8.Insulin-like growth factor-binding protein (IGFBP)-3 and IGFBP-5 share a common nuclear transport pathway in T47D human breast carcinoma cells. Schedlich LJ, Young TF, Firth SM, Baxter RC. J. Biol. Chem. 273, 18347-52, (1998). View articlePMID: 9660801

9.Insulin-like growth factor binding proteins. Rechler MM. Vitam. Horm. 47, 1-114, (1993). PMID: 7680510

10.Structure of the IGF-binding domain of the insulin-like growth factor-binding protein-5 (IGFBP-5): implications for IGF and IGF-I receptor interactions. Kalus W, Zweckstetter M, Renner C, Sanchez Y, Georgescu J, Grol M, Demuth D, Schumacher R, Dony C, Lang K, Holak TA. EMBO J. 17, 6558-72, (1998). View articlePMID: 9822601

11.IGF-binding protein-5: flexible player in the IGF system and effector on its own. Schneider MR, Wolf E, Hoeflich A, Lahm H. J. Endocrinol. 172, 423-40, (2002). View articlePMID: 11874691

12.Connective tissue growth factor: a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10. Bradham DM, Igarashi A, Potter RL, Grotendorst GR. J. Cell Biol. 114, 1285-94, (1991). View articlePMID: 1654338

13.Structural and functional analysis of insulin-like growth factors. Clemmons DR. Br. Med. Bull. 45, 465-80, (1989). View articlePMID: 2480830

Wikipedia

This website requires cookies, and the limited processing of your personal data in order to function. By using the site you are agreeing to this as outlined in our Privacy Notice and Terms of Use.