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Receptor Family
Netrin    Subfamily2 (Netrin receptors)
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(Summary from Netrin receptors)

Netrin receptors. Netrins are ligands that guide neuronal growth. Interestingly, the same ligand attracts certain neuronal cells but repels others (PUBMED). This is attributable to two receptor types, to which netrin is the ligand. One is known in the human as DCC (deleted in colorectal carcinoma), which have highly conserved orthologs in D. melanogaster (frazzled), zebrafish (PUBMED), rat (PUBMED) and C. elegans (UNC-40). It has an extracellular region with four immunoglobulin domains and six fibronectin III repeats, a single transmembrane domain and a cytoplasmic tail with no known homology. This receptor activation was shown to depend not only on netrin binding but also on heparin binding as a co-ligand to its fifth fibronectin III repeat. The other receptor type is RCM in mammals and UNC-5 in C. elegans. It has an extracellular region with two immunoglobulin domains and two thrombospondin domains, a single transmembrane domain and a cytoplasmic tail without known homology. Cells with DCC are attracted to netrin source, whereas cells with UNC-5 are repelled from it (PUBMED). In D. melanogaster a protein named sina associates with frazzled (DDC and UNC-40 ortholog) following ligand binding. In addition, levels of cyclic nucleotides seem to be critical to neuronal guidance by netrin receptors, but the exact mechanism of regulation is unclear. In the RCM type ligand binding leads a cytoplasmic Src tyrosine kinase to phosphorylate the receptor at multiple tyrosine residues, creating potential binding sites for cytoplasmic signaling proteins (PUBMED). The physiological roles of netrin receptors are in guiding neurons towards and away from the midline, as well as towards developing muscles in D. melanogaster but the latter is uncertain in vertebrates. Thiebault et al (PUBMED) showed that expression of the human UNC5A, UNC5B, or UNC5C is down-regulated in multiple cancers including colorectal, breast, ovary, uterus, stomach, lung, or kidney cancers. Sequencing of UNC5C gene in patients with colorectal tumors revealed the presence of missense mutations. They proposed that loss/reduction of expression may be a crucial mechanism for tumorigenicity because the expression of UNC5H1, UNC5H2, or UNC5H3 inhibits tumor cell anchorage-independent growth and invasion. These hallmarks of malignant transformation can be restored by netrin-1 addition or apoptosis inhibition. UNC5 receptors may represent tumor suppressors that inhibit tumor extension outside the region of netrin-1 availability by inducing apoptosis, also termed anoikis in these circumstances.
Relevant reviews and publications:
9143559, 11677060, 11557102, 11213262, 11533026, 12655055
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