IGFBP3

IGFBP3 (Insulin-like Growth Factor Binding Protein 3) is the most abundant insulin-like growth factor (IGF) binding protein in human serum and other biological fluids. It is a key regulator of IGF bioavailability and activity, playing a significant role in growth, development, and metabolism.

Function:

IGFBP3 binds to IGF-I and IGF-II with high affinity, modulating their interaction with cell surface receptors such as the IGF-1 receptor. This binding has several important consequences:

• Inhibition of IGF Action: By sequestering IGFs, IGFBP3 prevents them from binding to their receptors, thus inhibiting IGF-mediated cellular signaling. This inhibitory effect can control cell growth, proliferation, and survival.

• Prolongation of IGF Half-Life: IGFBP3 protects IGFs from degradation and extends their half-life in circulation. This allows IGFs to be transported to target tissues and exert their effects over a longer period.

• IGF-Independent Effects: IGFBP3 can also exert biological effects independent of IGF binding. These IGF-independent actions may involve interactions with cell surface receptors or intracellular signaling pathways.

Structure:

IGFBP3 is a glycoprotein with a molecular weight of approximately 40-45 kDa. It consists of three distinct domains:

• N-terminal Domain: This domain contains the IGF-binding region and is responsible for the high-affinity interaction with IGF-I and IGF-II.

• Central Domain: This domain contains a glycosylation site and is involved in interactions with other proteins, such as the acid-labile subunit (ALS).

• C-terminal Domain: This domain contains a heparin-binding region and may play a role in interactions with the extracellular matrix.

Regulation:

The expression of IGFBP3 is regulated by a variety of factors, including growth hormone (GH), insulin, nutritional status, and age. GH is the primary regulator of IGFBP3 synthesis in the liver.

Clinical Significance:

IGFBP3 levels in serum are often measured to assess growth hormone status and to monitor the effectiveness of growth hormone therapy. Abnormal IGFBP3 levels can be associated with various conditions, including:

• Growth Disorders: Deficiencies or excesses of IGFBP3 can contribute to growth disorders such as short stature or acromegaly.

• Metabolic Disorders: Altered IGFBP3 levels have been observed in metabolic disorders such as diabetes and obesity.

• Cancer: IGFBP3 has been implicated in the development and progression of various cancers, with its role often being complex and context-dependent. It can act as both a tumor suppressor and a tumor promoter depending on the specific cancer type and cellular environment.

Interactions:

IGFBP3 forms a ternary complex with IGF-I or IGF-II and the acid-labile subunit (ALS). This complex is too large to cross the capillary endothelium, which helps to keep IGFs in circulation and prolong their half-life. IGFBP3 can also interact with other proteins, such as proteases, which can cleave IGFBP3 and release IGFs from their bound state. These interactions are crucial for regulating IGF bioavailability and activity.