Unraveling insulin-like growth factor binding protein-3 actions in human disease.
The IGF system plays critical roles in somatic growth in an endocrine fashion (somatomedin hypothesis) as well as proliferation and differentiation of normal and malignant cells in a paracrine/autocrine fashion. IGFBP-3 is known to modulate the actions of IGFs in circulation as well as the immediate extracellular environment. Interestingly, apart from the ability to inhibit or enhance IGF actions, IGFBP-3 also exhibits very clear, distinct biological effects independent of the IGF/IGF-I receptor axis. Over the past decade it has become widely appreciated that IGF/IGF-IR-independent actions of IGFBP-3 (antiproliferative and proapoptotic effects) contribute to improving the pathophysiology of a variety of human diseases, such as cancer, diabetes, and malnutrition. Recent studies have implicated interaction of IGFBP-3 with a variety of proteins or signaling cascades critical to cell cycle control and apoptosis; however, the actual mechanism of IGFBP-3 action is still unclear. This review reinforces the concept in support of the IGF/IGF-IR axis-independent actions of IGFBP-3 and delineates potential underlying mechanisms involved and subsequent biological significance, focusing in particular on functional binding partners and the clinical significance of IGFBP-3 in the assessment of cancer risk.
Jogie-Brahim
Sherryline
S
Department of Pathology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia 23298-0662, USA.
Feldman
David
D
Oh
Youngman
Y
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D017124:Conserved Sequence; D015870:Gene Expression; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D009369:Neoplasms / Q000453:epidemiology*; D011110:Polymorphism, Genetic; D011485:Protein Binding; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011956:Receptors, Cell Surface; D012307:Risk Factors; D013002:Somatomedins / Q000378:metabolism*
C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D011956:Receptors, Cell Surface; D013002:Somatomedins; D017526:Receptor, IGF Type 1