SLK/LOSK kinase regulates cell motility independently of microtubule organization and Golgi polarization

Fokin, A. I.; Klementeva, Tatiana S.; Nadezhdina, E. S.; Burakov, A. V.

doi:10.1002/cm.21276

Cited by 8 publications

(3 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S1, C to E). Comprehensive literature search further revealed that many of these identified pairs have been reported before (data S2), including the antagonistic interaction between Ste20-like serine/threonine protein kinase (SLK) and ROCK via suppressive phosphorylation of RhoA by SLK (19)(20)(21), the synergistic interaction between fibroblast growth factor receptor 1 (FGFR1)/insulin-like growth factor 1 receptor and MAPK via classical receptor signaling cascade (22)(23)(24)(25)(26), and the antagonistic interaction between Rho GTPase Activating Protein 29 (ARHGAP29) and ROCK (27)(28)(29) via regulators of guanosine triphosphatase activities. Identification of these interaction pairs with literature support indicates that our screen has sufficient power to find important and specific shRNA-drug interactions.…”

Section: Two-hit Screen To Elucidate Signaling Interaction In Cell Mi...mentioning

confidence: 84%

Synthetic dysmobility screen unveils an integrated STK40-YAP-MAPK system driving cell migration

et al. 2021

View full text Add to dashboard Cite

Integrating signals is essential for cell survival, leading to the concept of synthetic lethality. However, how signaling is integrated to control cell migration remains unclear. By conducting a “two-hit” screen, we revealed the synergistic reduction of cell migration when serine-threonine kinase 40 (STK40) and mitogen-activated protein kinase (MAPK) were simultaneously suppressed. Single-cell analyses showed that STK40 knockdown reduced cell motility and coordination by strengthening focal adhesion (FA) complexes. Furthermore, STK40 knockdown reduced the stability of yes-associated protein (YAP) and subsequently decreased YAP transported into the nucleus, while MAPK inhibition further weakened YAP activities in the nucleus to disturb FA remodeling. Together, we unveiled an integrated STK40-YAP-MAPK system regulating cell migration and introduced “synthetic dysmobility” as a novel strategy to collaboratively control cell migration.

show abstract

Section: Two-hit Screen To Elucidate Signaling Interaction In Cell Mi...mentioning

confidence: 84%

Synthetic dysmobility screen unveils an integrated STK40-YAP-MAPK system driving cell migration

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Other effects of SLK in cells include dissolution of actin stress fibers and redistribution to the cell periphery, and loss of cell adhesion [1,10]. Several cytoskeletal proteins have been identified as substrates of SLK, including RhoA [11], ezrin [12,13], paxillin [14], and the p150 Glued dynactin subunit [15,16]. By modulating the cytoskeleton, SLK may control cell motility.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Ste20-like kinase, SLK, activity: Dimerization and activation segment phosphorylation

et al. 2017

View full text Add to dashboard Cite

The Ste20-like kinase, SLK, has diverse cellular functions. SLK mediates organ development, cell cycle progression, cytoskeletal remodeling, cytokinesis, and cell survival. Expression and activity of SLK are enhanced in renal ischemia-reperfusion injury, and overexpression of SLK was shown to induce apoptosis in cultured glomerular epithelial cells (GECs) and renal tubular cells, as well as GEC/podocyte injury in vivo. The SLK protein consists of a N-terminal catalytic domain and an extensive C-terminal domain, which contains coiled-coils. The present study addresses the regulation of SLK activity. Controlled dimerization of the SLK catalytic domain enhanced autophosphorylation of SLK at T183 and S189, which are located in the activation segment. The full-length ectopically- and endogenously-expressed SLK was also autophosphorylated at T183 and S189. Using ezrin as a model SLK substrate (to address exogenous kinase activity), we demonstrate that dimerized SLK 1–373 or full-length SLK can effectively induce activation-specific phosphorylation of ezrin. Mutations in SLK, including T183A, S189A or T193A reduced T183 or S189 autophosphorylation, and showed a greater reduction in ezrin phosphorylation. Mutations in the coiled-coil region of full-length SLK that impair dimerization, in particular I848G, significantly reduced ezrin phosphorylation and tended to reduce autophosphorylation of SLK at T183. In experimental membranous nephropathy in rats, proteinuria and GEC/podocyte injury were associated with increased glomerular SLK activity and ezrin phosphorylation. In conclusion, dimerization via coiled-coils and phosphorylation of T183, S189 and T193 play key roles in the activation and signaling of SLK, and provide targets for novel therapeutic approaches.

show abstract

“…This distinction underscores the regulatory mechanisms that specifically influence actin fiber organization without altering overall protein abundance. Moreover, RhoA, known to be upstream of both SLK and ROCK, plays a pivotal role in the regulatory network affecting the cytoskeleton (4,10,18,23). The interplay between these pathways has been extensively documented, often highlighting the close relationship in regulating cytoskeletal rearrangements (10).…”

Section: The Knockdown Of Slk or Ezrin Resulted In An Increase In Con...mentioning

confidence: 99%

Synthetic dysmobility screening reveals a phosphorylation-independent facet of the SLK-Ezrin-F-actin signaling cascade

Lin,

Wei

et al. 2024

Preprint

View full text Add to dashboard Cite

This study investigates the role of Ste20-like kinase (SLK) in cytoskeletal dynamics, focusing on its interaction with Ezrin and actin remodeling, independent of phosphorylation processes. We utilized HaCaT to explore the effects of SLK and Ezrin knockdown, as well as the application of specific inhibitors on the organization of actin structures. Our findings reveal that both SLK and Ezrin significantly influence the architecture of actin cytoskeletons with differential impacts observed between protein knockdown and dephosphorylation events. Additionally, our results suggest novel, phosphorylation-independent pathways through which Ezrin modulates actin dynamics, potentially indicating alternative, non-enzymatic roles for Ezrin in cytoskeletal integrity.

show abstract

SLK/LOSK kinase regulates cell motility independently of microtubule organization and Golgi polarization

Cited by 8 publications

References 44 publications

Synthetic dysmobility screen unveils an integrated STK40-YAP-MAPK system driving cell migration

Synthetic dysmobility screen unveils an integrated STK40-YAP-MAPK system driving cell migration

Regulation of Ste20-like kinase, SLK, activity: Dimerization and activation segment phosphorylation

Synthetic dysmobility screening reveals a phosphorylation-independent facet of the SLK-Ezrin-F-actin signaling cascade

Contact Info

Product

Resources

About