Disease relevance of Slk

• At later stages (14.5 dpc), SLK is expressed in the hypothalamus region, all layers of the neural tube, dorsal root ganglion and in the proliferating ependymal layers [1].

High impact information on Slk

• We have demonstrated that a novel Ste20-related kinase, designated SLK, mediates apoptosis and actin stress fiber dissolution through distinct domains generated by caspase 3 cleavage [2].
• Finally, transient transfection of SLK also activated the c-Jun N-terminal kinase signaling pathway [2].
• Cultures expressing the mutant SLK displayed a normal pattern of cyclin D, E, and B expression but failed to down-regulate cyclin A levels, suggesting that they cannot proceed through M phase [3].
• Consistent with microtubule association in exponentially growing cells, our results showed that SLK co-localizes with the mitotic spindle in cells undergoing mitosis [3].
• The Ste20-like kinase SLK is required for cell cycle progression through G2 [3].

Biological context of Slk

• Furthermore, cleavage of SLK released two domains with distinct activities: an activated N-terminal kinase domain that promoted apoptosis and cytoskeletal rearrangements and a C-terminus domain that disassembled actin stress fibers [2].
• We have previously shown that the Ste20-like kinase SLK is a microtubule-associated protein that can regulate actin reorganization during cell adhesion and spreading (Wagner, S., Flood, T. A., O'Reilly, P., Hume, K., and Sabourin, L. A. (2002) J. Biol. Chem. 277, 37685-37692) [3].
• Expression of a kinase-inactive mutant or SLK small interfering RNAs inhibited cell proliferation and resulted in an accumulation of quiescent cells stimulated to re-enter the cell cycle in the G2 phase [3].
• A genomic clone of mSLK was isolated and used for fluorescence in situ hybridization locating the mSLK gene on band D2 of mouse chromosome 19 [4].
• Furthermore, autophosphorylation of the catalytic domain was enhanced in the presence of the C-terminal fragment, which suggests a possible regulatory role for the C-terminal region of mSLK [4].

Anatomical context of Slk

• Using immunofluorescence studies, we report that SLK is redistributed with adhesion components at large podosome-like adhesion sites in fibronectin-stimulated fibroblasts [5].
• Overexpression of active SLK resulted in ectopic spindle assembly and the induction of cell cycle re-entry of Xenopus oocytes, suggesting that SLK is required for progression through G2 upstream of H1 kinase activation [3].
• Furthermore, SLK activity is upregulated during the differentiation of C2C12 myoblasts [6].
• In addition, we have found that SLK localizes presynaptically at neuromuscular junctions and that it is preferentially expressed in types I and IIA myofibers at major myofibrillar striations [6].
• To gain further insight into the role of SLK, we have characterized its activity, expression, and distribution in skeletal muscle and during the in vitro differentiation of C2C12 myoblasts [6].

Associations of Slk with chemical compounds

• We isolated a murine cDNA encoding a novel serine/threonine kinase (referred to as mSLK) ubiquituously expressed during all stages of murine development and in all adult tissues examined [4].
• Proline- and alanine-rich Ste20-related kinase (PASK) is a Ste20-related protein kinase isolated from rat brain [7].

Co-localisations of Slk

• Significantly, endogenous SLK can be colocalized with Rac1 in spreading cells on FN [5].

Regulatory relationships of Slk

• Finally, the overexpression of SLK by adenoviral infection inhibits cell spreading on fibronectin [5].

Other interactions of Slk

• Using microinjection studies, we show that ectopic expression of activated SLK induces the disassembly of actin stress fibers, a process that can be inhibited by dominant negative Rac1 [5].
• Furthermore, the stimulation of adhesion site formation by microtubule-disrupting agents induces the relocalization of SLK with unpolymerized alpha-tubulin to large vinculin-containing adhesion complexes [5].
• Double immunofluorescence studies in exponentially growing or spreading fibroblasts show that SLK is associated with the microtubule network and can be coprecipitated with alpha-tubulin [5].
• The N-terminal fragment of mSLK was able to autophosphorylate on serine and threonine residues, phosphorylate threonine residues on a C-terminal fragment of the molecule, and phosphorylate exogenous substrates myelin basic protein and histone III in vitro [4].
• We have recently cloned and characterized a novel Ste20-like kinase termed SLK (Sabourin et al., Mol. Cel. Biol. 20 (2000) 684) [1].

Analytical, diagnostic and therapeutic context of Slk

• In addition, prolonged overexpression of SLK in cultured fibroblasts resulted in apoptosis as demonstrated by annexin-V and TUNEL staining [8].

References