Kinase Subfamily SLK

Kinase Classification: Group STE: Family STE20: Subfamily SLK

SLK is involved in cell migration, cytoskeletal-membrane interaction, apoptosis and proliferation, across the animal kingdom.

Evolution

SLK is found in all holozoa studied, with two copies in vertebrates, SLK and LOK (STK10).

Domain Structure

SLK have an N-terminal kinase domain, followed by a non-domain region, two PKK domains and another non-domain region. SLK is the only kinase to have PKK (polo kinase kinase) domains. The PKK domains are predicted to form a coiled-coil structure.

Functions

Reviewed in Garland [1] and Al-Zahrani [2].

Of the two human paralogs, SLK is the most widely expressed, while LOK is more selective for hematopoietic tissues [3].

Cytoskeleton

Human SLK and LOK are best known as regulators of the cytoskeleton. Both are known to phosphorylate Ezrin, Moesin and Radixin (ERM), and regulate membrane-cytoskeleton interactions [4, 5]. In osteoclast fusion, SLK activation of moesin is downstream of RhoA and Integrin [6] The Drosophila homolog, Slik (slk, GC4527) activates Drosophila Moesin, the single ERM ortholog [7], to ensure cortical stability during mitosis. In Slik mutant imaginal discs, epithelial integrity fails, due to lack of moesin phosphorylation and increased Rho1 activation [8]. Slik is activated by the FGFR family member breathless in terminal tracheal cells, independent of its canonical ERK signaling function [9].

SLK also phosphorylates focal adhesion adaptor protein paxillin and is involved in focal adhesion turnover and cell motility. [10]. Additional cytoskeletal targets of SLK include dynactin and RhoA [11].

During mitotic interphase, SLK associates with microtubules and the centrosome and is required for proper microtubule arrangement [12]. This may be mediated by SLK phosphorylation of dynactin [13].

SLK can be negatively regulated by phosphorylation by Casein Kinase II, downstream of v-Src in transformed cells [14]. Other upstream regulators include RhoA and FGFR (in Drosophila).

SLK can be cleaved by caspase 3 during apoptosis in myoblasts, creating an N-terminal kinase fragment that promoted apoptosis and cytoskeletal changes, and a C-terminal fragment that induced disassemby of actin stress fibers [15].

SLK and MAPK signaling

Unlike some other STE20 kinases that activate MAPK pathways, there is little evidence for MAPKK targets for SLK, though there are reports that SLK can activate the Jnk pathway [15] and that LOK and Drosophila SLK can inhibit it [16]. LOK was also seen to oppose MEKK1 in activation of a TCR-responsive element in T cells [17]. By contrast, in a kidney injury model, SLK was shown to be an activator of both Jnk and p38 [18].

SLK and cell cycle, apoptosis

LOK was first cloned from Xenopus and named xPlkk1 because it was able to phosphorylate and activate the PLK1 ortholog, Plx1 [19]. Plx1 in turn could phosphorylated xPlkk1/LOK [20]. In mammals LOK was also shown to bind and phosphorylate PLK1, and a dominant negative LOK caused a cell cycle defect [3, 21]. Drosophila Slik was also shown to phosphorylate PLK1 in vitro, but knockdown in S2 cells did not influence polo activation, indicating that it may not be the only regulator of polo function [22]. Since these first publications, no evidence has emerged that SLK is a major regulator of PLK1 or cell cycle.

Drosophila Slik is also required for both to stimulate proliferation and to block apoptosis during imaginal disc development [23]. The anti-apoptotic function acts through the Jnk signaling pathway [16] while the proliferative function acts through raf though apparently not through the canonical ERK pathway, and may be independent of Slik catalytic function [24]. Slik is also known to phosphorylate the integrin anchor Talin at muscle attachment sites in the embryo [25].

Other Functions

The PKK domains/coiled coil regions have been implicated in SLK homodimerization as well as interaction with the nucleoporin, Tpr, and the cytoskeletal protein a-actinin4 [26].

Vertebrate SLK contains a KEAP1-binding "ETGE" motif and is known to bind KEAP1 in a manner that might regulate it's function [27, 28]

Both SLK and LOK have been weakly implicated in cancer. SLK is upregulated in gliomas and required for tissue invasion [29], and is also required for HER2-driven breast cancer cell motility [30]. A number of mutations in LOK that disrupt its anti-apoptotic function have also been seen in peripheral T-cell lymphoma (PTCL) [31].

The C. elegans homolog, gck-4 (C04A11.3) has not been experimentally characterized.

References

All Medline abstracts: PubMed | HubMed

Last updated: Mar 9 2025; GM.

Kinase Subfamily SLK

Evolution

Domain Structure

Functions

Cytoskeleton

SLK and MAPK signaling

SLK and cell cycle, apoptosis

Other Functions

References

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