Spitz is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

fruit flies Fruit fly may refer to: Organisms * Drosophilidae, a family of small flies, including: ** ''Drosophila'', the genus of small fruit flies and vinegar flies ** ''Drosophila melanogaster'' or common fruit fly ** ''Drosophila suzukii'' or Asian fruit ...

which is the major activator of

Epidermal Growth Factor Receptor The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands. The epidermal growth factor recept ...

(EGFR).

Function

Spitz is produced as a

transmembrane protein A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...

in the

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

. There it associates with a cargo receptor called ''Star'' and is trafficked to the Golgi. In the Golgi, Spitz is cleaved by a

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...

called ''Rhomboid'', which releases Spitz to be trafficked to the cell membrane and released out of the cell. From here it can bind EGFR on the surface of other cells, activating the receptor. Alternatively, Spitz can be bound and inactivated by

Argos Argos most often refers to: * Argos, Peloponnese, a city in Argolis, Greece ** Ancient Argos, the ancient city * Argos (retailer), a catalogue retailer operating in the United Kingdom and Ireland Argos or ARGOS may also refer to: Businesses ...

, inhibiting EGFR activation. Spitz is responsible for activating signaling of the ''Drosophila'' epidermal growth factor receptor (DER) and is involved in the development of the embryos, eyes, and wings of fruit flies. Spitz can be sequestered and prevented from binding to DER by the protein Argos (Aos) which then inhibits the epidermal growth factor receptor pathway. Over-expression of epidermal growth factor receptors contribute to human cancers, so the sequestering of activating ligands may be useful in developing ways to diminish EGFR ligands for cancer treatment.

Epidermal Growth Factor Receptor (EGFR) with Spitz protein

Residues binding spitz protein and EGFR (right side)

Residues binding spitz protein and EGFR (left side)

Structure

The protein Spitz is structurally similar to transforming growth factor-α ( TGF-α) and is a homologue of TGF-α, along with other proteins found in ''Drosophila'' such as Gurken and Keren. These proteins are processed by Star, a transmembrane protein, and Rhomboid (Rho), a

. Spitz binds to and regulates the epidermal growth factor receptor.

Epidermal Growth Factor Receptor (EGFR) Binding

EGFR exists as a dimer, and two Spitz proteins bind to the receptor to regulate its function. The dimer is referred to as two subunits: the left hand subunit and the right hand subunit. The binding of the two Spitz proteins on either subunit are not identical, as different

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

residues participate in the binding on either side. On the right hand side, Arg21 and Arg26 of EGFR interact with residues Asn50 and Ile51 of Spitz. On the left hand side, Arg21 and Arg26 of the other part of the dimer interact with Glu53 and Ile51 of another Spitz protein. The Spitz protein can wedge apart the I and III domains of one of the EGFR subunits, subsequently relocating domain I away from domain III and causing new interactions between side chains of the EGFR subunit. Research has shown that there is negative

cooperativity Cooperativity is a phenomenon displayed by systems involving identical or near-identical elements, which act dependently of each other, relative to a hypothetical standard non-interacting system in which the individual elements are acting indepen ...

in the binding of the Spitz ligands to EGFR, where the binding event of the second ligand to the dimer decreases the affinity of the receptors for one another. The specificity,

autophosphorylation Autophosphorylation is a type of post-translational modification of proteins. It is generally defined as the phosphorylation of the kinase by itself. In eukaryotes, this process occurs by the addition of a phosphate group to serine, threonine or ...

, mechanism, and other behaviors of the dimer can change significantly when it is weakened by the double-occupancy of the Spitz proteins.

References

{{Reflist

External links

Spitz
on

FlyBase FlyBase is an online bioinformatics database and the primary repository of genetic and molecular data for the insect family Drosophilidae. For the most extensively studied species and model organism, ''Drosophila melanogaster'', a wide range of ...

, the ''Drosophila'' gene database. Drosophila melanogaster genes