Cytokines & Cells Online Pathfinder Encyclopaedia
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[Amphiregulin] also abbr. AMR or AREG.
ALTERNATIVE NAMES
CRDGF (colorectum cell-derived growth factor);
KAF (keratinocyte-derived autocrine factor).
See also: individual entries for further information.
SOURCES
Amphiregulin can be isolated from placenta, testes, ovaries, and a number of tumor cell lines.
PROTEIN CHARACTERISTICS
Amphiregulin is an extremely hydrophilic glycoprotein with a length of 84 amino acids. A truncated form of 78 amino acids has been described also. Amphiregulin contains 6 cysteine residues engaged in the formation of disulfide bonds (positions 46/59; 54/70; 72/81) which are essential for its biological activity. The carboxyl-terminal from residues 46 to 84 exhibit striking homology to the EGF family of proteins.
The factor is synthesized as a membrane-bound precursor of 252 amino acids. It contains putative nuclear targeting sequences (NTS; see: signal sequence) and it has been shown recently that nuclear targeting is involved in AR mediated growth responses.
GENE STRUCTURE
The human amphiregulin gene extends over approximately 10.2 kb, comprises six exons, and is located on human chromosome 4q13-21.
RELATED FACTORS
The carboxyterminal amino acids of amphiregulin between positions 46-84 show a strong homology to EGF and contain an EGF-like repeat. Amphiregulin is a member of the EGF family of proteins. A 76 % homology is observed with SDGF (schwannoma-derived growth factor).
RECEPTORS
Amphiregulin binds to the same receptors as EGF and TGF-alpha, albeit with lower affinity. extracellular heparan sulfate glycosaminoglycan (see also: extracellular matrix) has been shown to be essential to AR induced mitogenic signaling by the EGF receptor tyrosine kinase.
BIOLOGICAL ACTIVITIES
Amphiregulin inhibits the growth of various human carcinoma cell lines in vitro. The proliferation of some tumor cell lines and also of fibroblasts and other normal cells is enhanced by amphiregulin. Amphiregulin can functionally replace EGF and TGF-alpha in murine keratinocytes. Amphiregulin has been implicated as an autocrine growth factor for normal human mammary epithelial cells.
Proliferation of immortal and malignant cervical epithelial cells is stimulated by IL1-alpha and TNF-alpha, which act indirectly through autocrine production of amphiregulin. Inui et al (1997) have reported that CD9 in human cultured keratinocytes binds to the membrane-anchored proforms of Amphiregulin. This interaction upregulates its juxtracrine activities as a growth factor.
TRANSGENIC ANIMALS, KNOCK-OUT, AND ANTISENSE STUDIES
Normanno et al (1995) have studied the effects of antisense RNA specific for Amphiregulin in a human colon cancer cell line (GEO) that expresses high levels of AR protein and mRNA. Expression of two different varieties of antisense RNA specific for Amphiregulin inhibits anchorage-dependent growth (40 % growth inhibition) and anchorage-independent growth (up to 80 % inhibition) (see also: Anchorage-dependent cells).
CLINICAL USE AND SIGNIFICANCE
Amphiregulin acts in an autocrine manner on some human, colon carcinomas. There are some indications that amphiregulin mRNA expression is markedly elevated in epidermal biopsies derived from human psoriatic lesions.
Amphiregulin is a major autocrine growth factor for cultured human keratinocytes and probably plays a role in the aberrant growth of keratinocytes in hyperproliferative disorders.
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