Definition
Growth factors are naturally occurring, essential biological mediators that promote cell growth, differentiation, survival and function. Several growth factors including nerve growth factor (NGF), epidermal growth factor (EGF) family, fibroblast growth factor (FGF) family, transforming growth factor beta (TGF-β) family, colony-stimulating factor (CSF) or haematopoietic stem cell factor family, trefoil factor (TFF) family and insulin-like growth factor 1 (IGF1) naturally occur as peptide growth factors (PGFs).

Discovery

NGF was discovered by by Rita Levi-Montalcin around 1950s¹. EGF in mice and human was discovered in the year 1962 and 1975 by Stanley Cohen and Harry Gregory respectively. FGF was found in pituitary extracts by Armelin in 1973². Jansen et al., (1983) reported the nucleotide sequence of a human liver cDNA encoding the complete amino acid sequence of IGF1 ³. In 1986 Sen-Majumdar A et. al, isolated a new peptide growth factor of Mr 34 000 from synctial membranes of human placenta.

Structural Characteristics
PGFs are usually characterized by a relatively low molecular weight of less than 25 kDa. PGFs are classified on the basis of structural homology and disparities into several discrete families. In addition to the structural similarities between peptides within a family, members of a peptide family share a single receptor or a family of receptors, so that functionally they are partially or wholly interchangeable. In addition to these families, a small number of PGFs, seemingly without structural similarities to other growth factors, have been identified within the gastrointestinal tract, including hepatocyte growth factor (HGF) or scatter factor, vascular endothelial cell growth factor (VEGF), and platelet-derived growth factor (PDGF).

Mode of Action
PGFs exert their effects through binding to specific high-affinity cell-surface receptors present on their respective target cells ^{4, 5, 6}. In contrast to classical peptide hormones, peptide growth factors tend to act locally on adjacent cells (paracrine or juxtacrine action), or on the same cell that has expressed the peptide factor (autocrine action) ^{5, 7}. The activation of the receptor bound tyrosine kinases clearly is the principal initiating event for NGF, PDGF, FGF and the other growth factors. These signal transduction pathways are assembled as cascades in which the tyrosine phosphorylations induced by the receptor kinase (following its own autophosphorylations and subsequent association of potential substrates through SH2 domains) lead to activation and subsequent generation of activity. The activation of phospholipase cy(PLCy) leads to the cleavage of phosphoinositides and the production of corresponding inositol phosphates and diacyl glycerides. Each, in turn, can act as an additional signal transducer with the former causing the release of intracellular calcium and with the latter directly activating protein kinase C (PKC),that is induced to associate with the membrane. Similarly, G-protein activating protein (GAP) can be phosphorylated resulting in its activation and the consequent stimulation of Ras protein, a constituent known to be involved in NGF activity.

Functions
Various members of these regulatory peptide families play an important role in the modulation of cell proliferation, cell differentiation, angiogenesis, inflammation, gastrointestinal defense mechanisms, and intestinal wound repair both in vitro and in vivo. Furthermore, they serve as important messengers between the intestinal mucosa and the enteric nervous and immune systems⁸.

The role of growth factors in development has been supported by studies in mouse and other species showing that a range of polypeptide growth factor ligands are produced by the reproductive tract and preimplantation embryo, while many of their receptors can be detected on the embryo surface⁹.

References

1.     Aloe L (2004). Rita Levi-Montalcini: the discovery of nerve growth factor and modern neurobiology. Trends Cell Biol.,14(7):395-399.

2.      Armelin HA (1973). Pituitary Extracts and Steroid Hormones in the Control of 3T3 Cell Growth. PNAS., 70(9): 2702-2706.

3.     Jansen M, van Schaik FM, Ricker AT, Bullock B, Woods DE, Gabbay KH, Nussbaum AL, Sussenbach JS, Van den Brande JL (1983). Sequence of cDNA encoding human insulin-like growth factor I precursor. Nature, 306(5943):609-611.

4.     Green AR (1989). Peptide regulatory factors: multifunctional mediators of cellular growth and differentiation. Lancet, 1(8640):705-707.

5.     Sporn MB, Roberts AB (1992). Autocrine secretion--10 years later.  Ann Intern Med., 117:408-414.

6.     Nathan C, Sporn M (1991). Cytokines in context. J Cell Biol., 113:981-986.

7.     Sporn MB, Roberts AB (1992). Transforming growth factor-β: recent progress and new challenges. J Cell Biol., 119:1017-1021.

8.     Rogler G, Andus T (1998). Cytokines in inflammatory bowel disease. World J Surg., 22:382-389.

9.     Kane MT, Morgan PM, Coonan C (1997). Peptide growth factors and preimplantation development. Hum Reprod Update., 3(2):137-157.