DCC (deleted in colorectal cancer) is a receptor for netrin required for axon guidance [, ]. It also binds a second axon guidance protein, Draxin []. The interactions between these guidance cues and DCC play a key role in the development of the nervous system.DCC belongs to the immunoglobulin superfamily. The protein consists of four N-terminal Ig-like domains []followed by six fibronectin type III domains (FN), a transmembrane segment and the cytosolic portion []. The deletion of DCC has been linked to the propensity of cancerous cells to metastasise [, ]. DCC indeed functions as a tumour suppressor through its ability to trigger tumour cell apoptosis [].
This entry represents the C terminus of eukaryotic neogenin precursor proteins, which contains several potential phosphorylation sites []. Neogenin is a member of the N-CAM family of cell adhesion molecules (and therefore contains multiple copies of and ) and is closely related to the DCC tumour suppressor gene product - these proteins may play an integral role in regulating differentiation programmes and/or cell migration events within many adult and embryonic tissues [].
Neogenin (NEO1) is a multifunctional transmembrane receptor belonging to the immunoglobulin superfamily []. It displays identical secondary structure to DCC (deleted in colorectal cancer), a netrin receptor that is involved in axon guidance and cell survival. Similar to DCC, it is able to transduce signals elicited by netrin []. Netrin-Neogenin interactions result in a chemoattractive axon guidance response []. Neogenin is also a receptor for members of the repulsive guidance molecule (RGM) family, which act as a repulsive axon guidance cue [, , ]. RGM binding to NEO1 activates the bone morphogenetic protein (BMP)-regulated signalling involved in morphogenesis and iron homeostasis [, ].Neogenin has an important role in cancer development [, ].
Cell adhesion molecule DSCAM is a cell adhesion molecule that plays a role in axon guidance, self-avoidance and synaptic formation [, , , , ]. It is a receptor for netrin, acting independently of and in collaboration with DCC []. DSCAM is one of the largest Immunoglobulin (Ig) superfamily CAMs, containing 10 Ig domains and six fibronectin type III (FN) repeats [], and contributes to defects in the central nervous system in Down syndrome patients []. Vertebrate DSCAMs differ from Drosophila Dscam1 in that they lack the extensive alternative splicing that occurs in the insect gene []. Drosophila Dscam2 is also alternatively spliced and plays a crucial role in the development of two visual system neurons, monopolar cells L1 and L2 [].
MyoX, a MyTH-FERM myosin, is a molecular motor that has crucial functions in the transport and/or tethering of integrins in the actin-based extensions known as filopodia, microtubule binding, and in netrin-mediated axon guidance []. It functions as a dimer. MyoX walks on bundles of actin, rather than single filaments, unlike the other unconventional myosins. MyoX is present in organisms ranging from humans to choanoflagellates, but not in Drosophila and Caenorhabditis elegans.MyoX consists of a N-terminal motor/head region, a neck made of 3 IQ motifs, and a tail consisting of a coiled-coil domain, a PEST region, 3 PH domains, a myosin tail homology 4 (MyTH4), and a FERM domain at its very C terminus. The MyoX FERM domain binds to the NPXY motif of several beta-integrins, a key family of cell surface receptors that are involved in cell adhesion and migration. In addition to beta-integrins, the FERM domain binds to the cytoplasmic domains of the netrin receptors DCC (deleted in colorectal cancer) and neogenin []. The FERM domain also forms a supramodule with its MyTH4 domain which binds to the negatively charged E-hook region in the tails of alpha- and beta-tubulin forming a proposed motorized link between actin filaments and microtubules [, ].The FERM domain has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3) []. This entry represents the C-lobe of the MyoX FERM domain.
