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SIGNALS

GROWTH FACTORS

     In order to ensure proper development and prevent cancer, cell growth must be regulated.  One of the first steps in the promotion of cell growth is the release of signals which promote cell division and differentiation called growth factors.  Many growth factors belong to gene families, having resulted from duplications of ancestral genes.

 

FIBOBLAST GROWTH FACTOR FAMILY

.  About 22 human genes are included in the FGF gene family because of the retention of a conserved region of about 120 amino acids (Storm, 2003).  FGF signals and the Notch pathway are involved in the “segmentation clock” which forms somites along the antero-posterior axis of the embryo (Dubrelle, 2002).

 

FIBOBLAST GROWTH FACTOR 1; FGF1

FGF1 promotes the development of the liver and the growth of endothelia.  The developing liver of an embryonic pig is depicted below.

HEART

FIBOBLAST GROWTH FACTOR 2; FGF2

FGF2 promotes growth in many tissues but is highest in the brain and pituitary.  It has a role in liver development, the development of the endocrine pancreas, and may be a signal to give a “posterior” identity to cells.  It promotes the development of blood vessels.

 

FIBOBLAST GROWTH FACTOR 3; FGF3

FGF3, also known as the oncogene INT2, induces the otic vesicle in ear development.  Mutations have been identified in breast cancers.  Cells of a breast cancer are depicted below.

CANCER

FIBOBLAST GROWTH FACTOR 4; FGF4

FGF4, also known as the oncogene HST, is involved in Wnt and SHH signaling during development and has a special role in tooth and limb development.  Mutations can be involved in stomach cancer.  FGF10, 8, 2 and 4 have important roles in limb development such as the induction of the AER and ZPA (neither of which form in FGF10 mutants) and in the initiation and maintenance of SHH signaling.   Shh, FGF4, and HoxD13 function at the anterior margin of the limb bud, such as that of the embryonic pig in the following image (Manouvrier-Hanu, 1999) 

LIMB

FIBOBLAST GROWTH FACTOR 5; FGF5

FGF5 normally inhibits hair growth.  Mutant mice have abnormally long hair.

 

FIBOBLAST GROWTH FACTOR 6; FGF6

FGF6, also known as the oncogene HST2, is mutated in some leukemia cell lines.  A blood smear of a leukemia patient is depicted below.

LEUKEMIA

FIBOBLAST GROWTH FACTOR 7; FGF7

FGF7, also known as keratinocyte growth factor, is expressed in the epithelia of the skin and lungs.  Mutations in mice cause skin abnormalities.  The human epidermis is depicted below.

SKIN

FIBOBLAST GROWTH FACTOR 8; FGF8

FGF8 has a role in gastrulation and in the development of the brain, limbs, face, and testes.  It is needed with Sonic Hedgehog expression to determine the left-right axis of the body.  Without FGF4 and FGF8, no hindlimbs form in mice and the forelimbs are shorter than normal.  Some mutations cause epithelial and breast cancer (OMIM; Storm, 2003). FGF8 and Wnt3a are involved in establishing the borders of somites (Rida, 2004).  Prolonging the expression of FGF8 results in the elongation of digit phalanges and can produce additional phalanges.  Inhibition of FGF results in the formation of the tip of the digit earlier than would otherwise occur (Sanz-Ezquerro, 2003). Ectopic application of FGF8 can form additional somites in developing chick embryos (Dubrelle, 2002).  Chick embryo somites are depicted below.

SOMITES

FIBOBLAST GROWTH FACTOR 9; FGF9

FGF9 expression is dependent on SHH expression.  Mutations in FGF9 in mice can cause a number of defects ranging from the underdevelopment of testes to sex reversal (in addition to effects in other tissues such as underdevelopment of lungs) (Colvin, 2001).

 

 

FIBOBLAST GROWTH FACTOR 10; FGF10

FGF10 is expressed during brain, lung, and limb development.  Mice without FGF10 do not develop limb buds or lungs (Min, 1998). 

 

FIBOBLAST GROWTH FACTOR 11; FGF11

 

FIBOBLAST GROWTH FACTOR 12; FGF12

FGF12 is expressed in the nervous system.

 

FIBOBLAST GROWTH FACTOR 13;  FGF13

FGF13 mutations may be a factor in mental retardation.

 

FIBOBLAST GROWTH FACTOR 14; FGF14

FGF14 is expressed in the developing and adult CNS.  Mutations cause cerebellar ataxia.  Cells of the developing brain in a pig embryo are depicted below.

LAYERS

FIBOBLAST GROWTH FACTOR 16; FGF16

FGF16 is expressed in brown adipose and its levels decrease after birth.

 

FIBOBLAST GROWTH FACTOR 17; FGF17

 FGF17 is similar to FGF8 and requires the expression of SHH.

 

FIBOBLAST GROWTH FACTOR 18; FGF18

FGF18 functions in lung and bone development.

 

FIBOBLAST GROWTH FACTOR 19; FGF19

FGF19 is expressed in the fetal brain.

 

FIBOBLAST GROWTH FACTOR 20; FGF20

FGF20 is involved in fetal development of the brain, liver, and kidney.  Overxepression can cause some cancers of the gastrointestinal tract.

 

FIBOBLAST GROWTH FACTOR 22; FGF22

FGF22 functions in hair development.  The matrix cells of a hair where growth occurs are depicted below.

HAIR

FIBOBLAST GROWTH FACTOR 23; FGF23

FGF23 has a role in phosphate homeostasis.  Mutations cause hypophosphatemic rickets.

 

The expression of one member of the FGF gene family, KGF (keratinocyte growth factor), is limited to epithelial cells.  From Xenopus through most mammals, there is one copy of the KGF gene.  Multiple copies exist in humans, chimps, gorillas, and orangutans indicating that the amplification of this gene occurred during the evolution of the higher apes (Kelly, 1992).  

A group of proteins once classified as FGFs are now classified as Fibroblast growth factor homologous factors, FHFs, because they are not secreted and do not interact with FGF receptors. They have been modified to bind to interact with the intracellular region of certain sodium channels and Islet-brain2, a neuronal MAP kinase scaffold protein (Goldfarb, 2005).

 

HEPATOCYTE GROWTH FACTOR

HGF induces growth of hepatocytes and is related to plasminogen.  Mutant mice possess underdeveloped livers and die.  A liver lobule is depicted in the following image.

LOBULE

INSULIN

The insulin family of peptide hormones includes IGFs, relaxin, and insulin-like peptides (Hsu, 2003; Kim, 1997).

 

Insulin is a hormone secreted by the Islets of Langerhans in the pancreas which allows cells to take glucose from the blood. It is also anti-inflammatory.  Mutations in the insulin gene can cause hyperproinsulinemia and diabetes.  Hyperproinsulinemia is assocated with low birth weight and an early development of pubic hair.  The cells of a pancreatic islet of Langerhans which secrete insulin are depicted in the image below.

GLOMERULUS

INSULIN-LIKE GROWTH FACTOR 1; IGF1

Animal insulin and insulin-like growth factor (IGF) signaling cascades which regulate metabolism, growth, and lifespan are homologous and largely conserved in animals as diverse as nematodes, flies, and mammals (Luckhart, 2007).

IGF1, also known as somatomedin C, is expressed at higher levels in those with a higher risk of breast cancer before menopause.  Mutations result in growth retardation, mental retardation, and deafness.

 

INSULIN-LIKE GROWTH FACTOR 2; IGF2

IGF1, also known as somatomedin A, may affect variations in body weight.  Imprinting affects its expression since only the paternal copy is expressed.  In may have a role in Wilms tumors. 

 

INSULIN-LIKE GROWTH FACTOR 3; IGF3

IGF3 functions in testicular descent and mutations can cause cryptorchidism.

 

INSULIN-LIKE 3; INSL3

INSL3 is expressed in the Leydig cells of the testis.  Mutations in humans and mice cause cryptorchidism.

 

INSULIN-LIKE 4; INSL4

INSL4 is expressed in the placenta.

 

INSULIN-LIKE 5; INSL5

Insl5 is expressed in the uterus and colon.

 

INSULIN-LIKE 6; INSL6

 

Leydig insulin-like protein is a peptide in the insulin-related gene family produced only in prenatal and postnatal Leydig cells in the testes (Adham, 1993).

 

Insulin-like peptides evolved early in the history of bilaterans. The single insulin-like growth factor in jawless fish had duplicated in early jawed fish (Sherwood, 2005).The insect hormone bombyxin belongs to the insulin gene family (De Loof, 2008).

RELAXIN 1; RLN1

Relaxin 1 is expressed in the ovaries and relaxes the pubic symphysis to facilitate birth.  It is also involved in the timing of birth and mutations of mice cause the failure of nipples to develop during pregnancy.

 

RELAXIN 2; RLN2

 

RELAXIN 3; RLN3

Relaxin 3 is expressed in a variety of tissues including the brain, ovaries, testes, spleen, and thymus.  Cells of the thymus are depicted below.

IMMUNE CELLS

EPIDERMAL GROWTH FACTOR FAMILY

The EGF domain is important for cell adhesion and receptor-ligand interactions.  Many proteins possess multiple EGF domains.  The EGF domain possess about 50 amino acids.  Many proteins such as notch, reelin, agrin, and tenascin possess multiple EGF domains (Nakayama, 1998).  The EGF domain is known in more than 350 genes (Barclay, 2003)

 

EPIDERMAL GROWTH FACTOR; EGF

EGF promotes the growth of epithelia and inhibits gastric acid secretion.

 

EGFL3

 

EGFL4

 

EGFL5

 

EGFL6

 

EGFL6 is expressed in fetal but not in adult tissues.

 

The human genome possesses four proteins known as neuregulins which bind to ErbB receptor tyrosine kinases. Structurally, they possess an EGF-like domain and, depending on how the 20 exons are spliced, may possess an immunoglobulin domain as well. The expression patterns of two of the immunoglobulin-containing isoforms (Types I and IV) of Neuregulin 1 seem to play a role in susceptibility to schizophrenia. The EGF domain interacts with the ErbB3 and ErbB4 receptors, which then interact with ErbB2 ( Harrison, 2006).

 

FAT TUMOR SUPPRESSOR, DROSOPHILA, HOMOLOG OF, 2; FAT2

FAT2 in Drosophila has 2 EGF domains and is a tumor suppressor. 

 

AMPHIREGULIN

Amphiregulin is an autocrine growth factor for astrocytes, Schwann cells, and fibroblasts.

 

LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN 4; LRP4

LDLRP4 possesses 2 EGF domains.

 

TRANSFORMING GROWTH FACTOR a; TGFA

TGFA promotes cell division and is a member of the EGF family.

 

 

 

OTHER GROWTH FACTORS

 

NERVE GROWTH FACTOR, BETA SUBUNIT; NGFB

NGF is a factor which promotes the growth and development of sensory neurons.

 

PLATELET-DERIVED GROWTH FACTOR, ALPHA POLYPEPTIDE; PDGFA

PDGFA is required for normal male reproductive function and production of Leydig cells.

 

PLATELET-DERIVED GROWTH FACTOR, BETA POLYPEPTIDE; PDGFB

PDGFB stimulates vascularization.  Mutations cause meningioma and dermatofibroxarcoma.

 

VASCULAR ENDOTHELIAL GROWTH FACTOR B; VEGFB

VEGFB is a member of a gene family which includes PDGF and PGF.  It is expressed in many tissues and overexpressed in some tumors.

 

VASCULAR ENDOTHELIAL GROWTH FACTOR C; VEGFC

VEGFC is expressed in endothelia.

 

VASCULAR ENDOTHELIAL GROWTH FACTOR; VEGF

VEGF is expressed in endothelial cells and promotes angiogenesis.  Mutations cause diabetic retinopathy.  Below is a sinusoid capillary in the liver of a fetal pig.

FETAL BLOOD

PLACENTAL GROWTH FACTOR; PGF

PGF promotes angiogenesis.

 

CONNECTIVE TISSUE GROWTH FACTOR; CTGF

CTGF has an insulin like motif and is related to PDGF.  It has a role in the development of bones and perhaps in the development of testes.

 

 

 

 

 

FOS-INDUCED GROWTH FACTOR; FIGF