Slit2 is a member of the Slit family of large secreted axon guidance molecules that share 65 70% amino acid (aa) identity and are ligands for Robo receptors (1, 2). Similar to other mammalian family members, the 1521 aa, ~200 kDa Slit2 contains a 25 aa signal sequence followed by four groups of leucinerich repeats (22 LRR total), 9 EGFlike sequences and a C terminal cysteine rich domain (2). An ALPS (agrin laminin perlecan slit) domain is found between EGF6 and EGF7 (1, 2). A proteolytic cleavage site occurs between EGF5 and EGF6. A membrane association site just N-terminal to the cleavage site, creates a membrane-bound ~140 kDa N-terminal cleavage product (Slit2 N) that has chemorepellent activity (3). Heparin sulfate is required for interaction of Robo with Slit LRR domains (2, 4). Mature mouse Slit2 shares 98, 97, 97, 97 and 95% aa identity with rat, human, bovine, equine and canine Slit2.
Slit1 and Slit2 (or in some cases Slit3)are expressed in complementary locations during development of the optic and olfactory tracts and the forebrain, and appear to work together to mediate Robo guidance of retinal, olfactory, hippocampal and motor axons (1, 5 9). Deletion of either Slit1 or Slit2 has less effect than deletion of both, which allows axons to wander from tracts and inappropriately cross or recross the midline (7 9).Slit2 also functions outside the nervous system to inhibit migration of leukocytes, endothelial cells and vascular smooth muscle cells toward CXCL12/SDF 1, VEGF165 and PDGF, respectively (3, 10, 11). Slits and Robos are considered candidate tumor suppressor genes because their promotors are frequently hypermethylated in epithelial cancers (12). Loss of Slit2 and Slit3 expression early during tumor progression upregulates a key chemokine signaling axis and generates hyperplastic changes in the epithelium along with desmoplastic changes in the stroma (13).
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