Son of Sevenless
Encyclopedia
In cell signalling, Son of Sevenless (SOS) refers to a set of genes encoding guanine nucleotide exchange factor
s that act on the Ras subfamily of small GTPase
s.
gene in Drosophila melanogaster
in a Ras/MAP kinase pathway
. When sevenless is mutated or otherwise dysfunctional during development of the fly's ultraviolet light-sensitive compound eye, the seventh, central photoreceptor (R7) of each ommatidium
fails to form. Similarly, the mammalian orthologues of Sos, SOS1
and SOS2, function downstream of many growth factor and adhesion receptors.
, and localise them to the membrane resulting in their activation. Ras-GTPases are considered inactive when bound to guanosine diphosphate
(GDP), and active when bound to guanosine triphosphate
(GTP). As the name implies, Ras-GTPases possess intrinsic enzymatic activity that hydrolyses GTP to GDP and phosphate. Thus, upon binding to GTP, the duration of Ras-GTPase activity depends on the rate of hydrolysis. SOS (and other guanine nucleotide exchange factors) act by binding Ras-GTPases and forcing them to release of their bound nucleotide (usually GDP). Once released from SOS, the Ras-GTPase quickly binds fresh guanine nucleotide from the cytosol. Since GTP is roughly ten times more abundant than GDP in the cytosol
, this usually results in Ras activation. The normal rate of Ras catalytic GTPase (GTP hydrolysis) activity can be increased by proteins of the RasGAP family, which bind to Ras and increase its catalytic rate by a factor of one thousand - in effect, increasing the rate at which Ras is inactivated.
and hereditary gingival fibromatosis type 1. Noonan syndrome has also been shown to be caused by mutations in KRAS
and PTPN11
genes. A common feature of these genes is that their products have all been strongly implicated as positive regulators of the Ras/MAP kinase
signal transduction pathway. Therefore it is thought that dysregulation of this pathway during development is responsible for many of the clinical features of this syndrome.
Noonan syndrome
mutations in SOS1 are distributed in clusters positioned throughout the SOS1 coding region. Biochemically, these mutations have been shown to similarly effect aberrant activation of the catalytic domain towards Ras-GTPases. This may be explained because the SOS1 protein adopts an auto-inhibited conformation dependent on multiple domain-to-domain interactions that cooperate to block access of the SOS1 catalytic core to its Ras-GTPase targets. The mutations that cause Noonan syndrome thus appear to perturb intramolecular interactions necessary for SOS1 auto-inhibition. In this way these mutations are thought to create SOS1 allele
s encoding hyper-activated and dysregulated variants of the protein.
Guanine nucleotide exchange factor
Guanine nucleotide exchange factors activate monomeric GTPases by stimulating the release of guanosine diphosphate to allow binding of guanosine triphosphate . A variety of unrelated structural domains have been shown to exhibit guanine nucleotide exchange activity...
s that act on the Ras subfamily of small GTPase
Small GTPase
Small GTPases are a family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate . They are a form of G-proteins found in the cytosol which are homologous to the alpha subunit of heterotrimeric G-proteins, but unlike the alpha subunit of G proteins, a small GTPase can function...
s.
History and name
The gene was so named because the Sos protein that it encoded was found to operate downstream of the sevenlessSevenless
sevenless is a gene in Drosophila melanogaster that encodes a receptor tyrosine kinase protein essential to the development of R7 cells in the Drosophila embryonic eye.The drosophila ommatidium contains 8 distinct retinula or R cells, each of which has a different spectral sensitivity...
gene in Drosophila melanogaster
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
in a Ras/MAP kinase pathway
MAPK/ERK pathway
The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a growth factor binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a...
. When sevenless is mutated or otherwise dysfunctional during development of the fly's ultraviolet light-sensitive compound eye, the seventh, central photoreceptor (R7) of each ommatidium
Ommatidium
The compound eyes of insects, mantis shrimp and millipedes are composed of units called ommatidia . An ommatidium contains a cluster of photoreceptor cells surrounded by support cells and pigment cells. The outer part of the ommatidium is overlaid with a transparent cornea...
fails to form. Similarly, the mammalian orthologues of Sos, SOS1
SOS1
Son of sevenless homolog 1 is a protein that in humans is encoded by the SOS1 gene.Recent studies also show that mutations in Sos1 can cause Noonan syndrome and hereditary gingival fibromatosis type 1. Noonan syndrome has also been shown to be caused by mutations in KRAS and PTPN11 genes...
and SOS2, function downstream of many growth factor and adhesion receptors.
Function
Ras-GTPases act as molecular switches that bind to downstream effectors, such as the protein kinase c-RafC-Raf
RAF proto-oncogene serine/threonine-protein kinase also known as proto-oncogene c-RAF or simply c-Raf is an enzyme that in humans is encoded by the RAF1 gene. The c-Raf protein functions in the MAPK/ERK signal transduction pathway as part of a protein kinase cascade...
, and localise them to the membrane resulting in their activation. Ras-GTPases are considered inactive when bound to guanosine diphosphate
Guanosine diphosphate
Guanosine diphosphate, abbreviated GDP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside guanosine. GDP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase guanine....
(GDP), and active when bound to guanosine triphosphate
Guanosine triphosphate
Guanosine-5'-triphosphate is a purine nucleoside triphosphate. It can act as a substrate for the synthesis of RNA during the transcription process...
(GTP). As the name implies, Ras-GTPases possess intrinsic enzymatic activity that hydrolyses GTP to GDP and phosphate. Thus, upon binding to GTP, the duration of Ras-GTPase activity depends on the rate of hydrolysis. SOS (and other guanine nucleotide exchange factors) act by binding Ras-GTPases and forcing them to release of their bound nucleotide (usually GDP). Once released from SOS, the Ras-GTPase quickly binds fresh guanine nucleotide from the cytosol. Since GTP is roughly ten times more abundant than GDP in the cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
, this usually results in Ras activation. The normal rate of Ras catalytic GTPase (GTP hydrolysis) activity can be increased by proteins of the RasGAP family, which bind to Ras and increase its catalytic rate by a factor of one thousand - in effect, increasing the rate at which Ras is inactivated.
Genetic diseases associated with SOS1
Dominant mutant alleles of SOS1 have recently been found to cause Noonan syndromeNoonan syndrome
Noonan Syndrome is a relatively common autosomal dominant congenital disorder considered to be a type of dwarfism, that affects both males and females equally. It used to be referred to as the male version of Turner's syndrome ; however, the genetic causes of Noonan syndrome and Turner syndrome...
and hereditary gingival fibromatosis type 1. Noonan syndrome has also been shown to be caused by mutations in KRAS
KRAS
GTPase KRas also known as V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog and KRAS, is a protein that in humans is encoded by the KRAS gene. Like other members of the Ras family, the KRAS protein is a GTPase and is an early player in many signal transduction pathways...
and PTPN11
PTPN11
Tyrosine-protein phosphatase non-receptor type 11 also known as protein-tyrosine phosphatase 1D or protein-tyrosine phosphatase 2C is an enzyme that in humans is encoded by the PTPN11 gene. PTPN11 is a protein tyrosine phosphatase Shp2.PTPN11 is a member of the protein tyrosine phosphatase ...
genes. A common feature of these genes is that their products have all been strongly implicated as positive regulators of the Ras/MAP kinase
Mitogen-activated protein kinase
Mitogen-activated protein kinases are serine/threonine-specific protein kinases that respond to extracellular stimuli and regulate various cellular activities, such as gene expression, mitosis, differentiation, proliferation, and cell survival/apoptosis.-Activation:MAP kinases are activated...
signal transduction pathway. Therefore it is thought that dysregulation of this pathway during development is responsible for many of the clinical features of this syndrome.
Noonan syndrome
Noonan syndrome
Noonan Syndrome is a relatively common autosomal dominant congenital disorder considered to be a type of dwarfism, that affects both males and females equally. It used to be referred to as the male version of Turner's syndrome ; however, the genetic causes of Noonan syndrome and Turner syndrome...
mutations in SOS1 are distributed in clusters positioned throughout the SOS1 coding region. Biochemically, these mutations have been shown to similarly effect aberrant activation of the catalytic domain towards Ras-GTPases. This may be explained because the SOS1 protein adopts an auto-inhibited conformation dependent on multiple domain-to-domain interactions that cooperate to block access of the SOS1 catalytic core to its Ras-GTPase targets. The mutations that cause Noonan syndrome thus appear to perturb intramolecular interactions necessary for SOS1 auto-inhibition. In this way these mutations are thought to create SOS1 allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
s encoding hyper-activated and dysregulated variants of the protein.