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Slit Structure

Each of the three types of Slit protein have the same basic structure. A major identifying feature of the Slit protein is the four leucine-rich repeat (LRR) domains and the N-terminus. Slits are one of only two protein families that contain multiple LRR domains. These LRRs are followed by six epidermal growth factor-like (EGF) repeats and a laminin G-like β-sandwich domain. After this, invertebrates have one EGF repeat, whereas vertebrates have three EGF repeats. In each case, the EGF is followed by a C-terminal cystine knot (CT) domain. (1)

Slit LRR domains are thought to assist in controlling neurite outgrowth. The domains consist of five to seven LRRs each with disulphite-rich cap segments. Each LRR contains a LXXLXLXXN sequence which is one strand to a parallel β-sheet on the concave face of the LRR domain, while the back side of the domain consists of irregular loops. Each of the four domains of Slit are connected by short "linkers" which attach to the domains via a disulphide bridge, allowing the LRR region of Slit to remain very compact. (1)

It is possible for Slits to be cleaved into fragments of the N-terminal and C-terminal as a result of an assumed proteolytic site between the fifth and sixth EGFs in Drosophila SLIT, Caenorhabditis elegans SLIT, rat SLIT1, rat SLIT3 and human SLIT2. (2)

SOURCES

1) "Interaction of the guidance molecule Slit with cellular receptors" - E. Hohenester, S. Hussain, and J.A. Howitt, 2006

2) "The SLIT-ROBO pathway: a regulator of cell functions with implications for the reproductive system" - Rachel E. Dickinson, W. Colin Duncan, 2010

Function Slit proteins were originally thought to repel neural guidance during development, but further investigation has proved that they have additional important functions. Some of these functions are performed in the vasculature and immune system, and there are implications for the reproductive system as well.(2) Steroid hormones have been found to regulate SLITs and adult cell functions in reproductive tissues. Further, SlITs are expressed during cancer occurring in the reproductive organs such as in the ovary, in the endometrial, in the cervical, and in the prostate. Chemorepellents help to direct growing axons toward the correct regions by directing them away from inappropriate regions. Slit genes, as well as their roundabout receptors, help prevent the wrong types of axons from crossing the midline of the central nervous system during the assembly of the nervous system. Three slit genes, slit 1, slit 2, and slit 3, have been cloned in mammals. When in collagen gel co-cultures, Slit 1 as well as slit 2 have been seen to collapse and repel olfactory axons. Positive effects are also correlated with slits; Slit 2 begins the formation of axon collateral branches through neural growth factor genes of the dorsal root ganglia. (7)

Cancer

Abnormalities or absences in the expression of Slit1, Slit2 and Slit3 are associated with reproductive and hormone dependent cancers, particularly in females. Along with their function in tissue morphogenesis, these genes act as tumor suppressors. Therefore, deletion or lack of expression of these genes is associated with the development of certain tumors, particularly tumors within the epithelium of the ovaries, endometrium, and cervix (all from Dickinson and Duncan). In addition, absence of these genes allows the migration of cancer cells and thus is associated with increased cancer progression and increased metastasis. The role of this gene in cancer is becoming increasingly unraveled but increasingly complex.