{{Short description|Protein in Drosophila melanogaster}} {{Infobox nonhuman protein | Name = Spitz | Organism = Drosophila melanogaster | image = Spitz protein.png | caption = Spitz protein | width = 150 px | Symbol = SPI | AltSymbols = | EntrezGene = 35253 | RefSeqProtein = NM_057561 | UniProt = Q01083 | PDB = 3LTF | Chromosome = | Arm = | Band = | LocusSupplementaryData = }}

'''Spitz''' is a protein in ''Drosophila'' species which is the major activator of their epidermal growth factor receptor (EGFR).<ref name=Shilo>{{cite journal | vauthors = Shilo BZ | title = Signaling by the Drosophila epidermal growth factor receptor pathway during development | journal = Experimental Cell Research | volume = 284 | issue = 1 | pages = 140–149 | date = March 2003 | pmid = 12648473 | doi = 10.1016/S0014-4827(02)00094-0 }}</ref>

== Function == Spitz is produced as a transmembrane protein in the 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 called ''Rhomboid'', which releases Spitz to be trafficked to the cell membrane and released out of the cell.<ref name=Shilo/> From here it can bind EGFR on the surface of other cells, activating the receptor. Alternatively, Spitz can be bound and inactivated by Argos, inhibiting EGFR activation.<ref name=Klein>{{cite journal | vauthors = Klein DE, Nappi VM, Reeves GT, Shvartsman SY, Lemmon MA | title = Argos inhibits epidermal growth factor receptor signalling by ligand sequestration | journal = Nature | volume = 430 | issue = 7003 | pages = 1040–1044 | date = August 2004 | pmid = 15329724 | doi = 10.1038/nature02840 | bibcode = 2004Natur.430.1040K | s2cid = 4413371 }}</ref>

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.<ref>{{cite journal | vauthors = Jin MH, Sawamoto K, Ito M, Okano H | title = The interaction between the Drosophila secreted protein argos and the epidermal growth factor receptor inhibits dimerization of the receptor and binding of secreted spitz to the receptor | journal = Molecular and Cellular Biology | volume = 20 | issue = 6 | pages = 2098–2107 | date = March 2000 | pmid = 10688656 | pmc = 110826 | doi = 10.1128/MCB.20.6.2098-2107.2000 }}</ref> 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.<ref name="Klein" />thumb|Structure of the complex that forms between the protein Spitz and the epidermal growth factor receptor. The magenta sections are the two spitz proteins

thumb|The interaction of residues R21 and R26 (from the right side of EGFR) with N53 and I51 (from Spitz) in the binding of the Spitz protein to EGFR

thumb|The interaction of residues R21 and R26 (from the left side of EGFR) with E50 and I51 (from Spitz) in the binding of the Spitz protein to the epidermal growth factor receptor

== 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.<ref name=Shilo/> These proteins are processed by Star, a transmembrane protein, and Rhomboid (Rho), a protease. Spitz binds to and regulates the epidermal growth factor receptor.<ref>{{Cite journal |last=Welberg |first=Leonie |date=September 2007 |title=ppERK, sleep & fly |journal=Nature Reviews Neuroscience |language=en |volume=8 |issue=9 |pages=654 |doi=10.1038/nrn2232 |s2cid=38878623 |issn=1471-0048|doi-access=free }}</ref>

== 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.<ref name=":0">{{cite journal | vauthors = Alvarado D, Klein DE, Lemmon MA | title = Structural basis for negative cooperativity in growth factor binding to an EGF receptor | journal = Cell | volume = 142 | issue = 4 | pages = 568–579 | date = August 2010 | pmid = 20723758 | doi = 10.1016/j.cell.2010.07.015 | pmc = 2925043 }}</ref> The binding of the two Spitz proteins on either subunit are not identical, as different amino acid 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.<ref name=":0" /> Research has shown that there is negative cooperativity 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, mechanism, and other behaviors of the dimer can change significantly when it is weakened by the double-occupancy of the Spitz proteins.<ref name=":0" />

== References == {{Reflist}}

== External links == *[http://flybase.org/reports/FBgn0005672.html Spitz] on FlyBase, the ''Drosophila'' gene database.

Category:Drosophila melanogaster genes