Rho GTPases regulate PRK2/PKN2 to control entry into mitosis and exit from cytokinesis

Schmidt, Anja; Durgan, Joanne; Magalhaes, Ana; Hall, Alan

doi:10.1038/sj.emboj.7601637

Cited by 99 publications

(84 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…39,40,[44][45][46][47] Our study identifies CDK10/CycM as a key upstream regulator of this biology. Combining our and previous observations, we propose a model in which CDK10/ CycM phosphorylates PKN2 within its RhoA binding domain, thereby promoting RhoA binding and stabilization, which results in actin polymerization and consequent repression of primary cilia formation at cell cycle exit (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…First, PKN2 is known to be phosphorylated in vivo by an unidentified CDK. 40 Second, and directly relevant to the regulation of actin dynamics, PKN2 interacts with RhoA and it makes a positive contribution to various RhoA-regulated processes, including stress fiber formation. 39 Moreover, RhoA inhibition is known to promote ciliogenesis, 22 a result we have confirmed in our assay system (Fig.…”

Section: Identification Of Pkn2 As a Cdk10/cycm Substrate And As A CImentioning

confidence: 99%

See 1 more Smart Citation

STAR syndrome-associated CDK10/Cyclin M regulates actin network architecture and ciliogenesis

et al. 2016

View full text Add to dashboard Cite

CDK10/CycM is a protein kinase deficient in STAR (toe Syndactyly, Telecanthus and Anogenital and Renal malformations) syndrome, which results from mutations in the X-linked FAM58A gene encoding Cyclin M. The biological functions of CDK10/CycM and etiology of STAR syndrome are poorly understood. Here, we report that deficiency of CDK10/Cyclin M promotes assembly and elongation of primary cilia. We establish that this reflects a key role for CDK10/Cyclin M in regulation of actin network organization, which is known to govern ciliogenesis. In an unbiased screen, we identified the RhoA-associated kinase PKN2 as a CDK10/ CycM phosphorylation substrate. We establish that PKN2 is a bone fide regulator of ciliogenesis, acting in a similar manner to CDK10/CycM. We discovered that CDK10/Cyclin M binds and phosphorylates PKN2 on threonines 121 and 124, within PKN2 0 s core RhoA-binding domain. Furthermore, we demonstrate that deficiencies in CDK10/CycM or PKN2, or expression of a non-phosphorylatable version of PKN2, destabilize both the RhoA protein and the actin network architecture. Importantly, we established that ectopic expression of RhoA is sufficient to override the induction of ciliogenesis resulting from CDK10/CycM knockdown, indicating that RhoA regulation is critical for CDK10/CycM's negative effect on ciliogenesis. Finally, we show that kidney sections from a STAR patient display dilated renal tubules and abnormal, elongated cilia. Altogether, these results reveal CDK10/CycM as a key regulator of actin dynamics and a suppressor of ciliogenesis through phosphorylation of PKN2 and promotion of RhoA signaling. Moreover, they suggest that STAR syndrome is a ciliopathy.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Identification Of Pkn2 As a Cdk10/cycm Substrate And As A CImentioning

confidence: 99%

STAR syndrome-associated CDK10/Cyclin M regulates actin network architecture and ciliogenesis

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Mitotic entry was analyzed in synchronized HeLa cells using mitotic marker proteins. 13,15 The mitotic kinase Aurora A is activated by PAK1/2 through phosphorylation at Thr-288. The levels of pT288-Aurora A and its downstream target, the mitotic phosphatase Cdc25, peaked at mitosis entry at 10-12 h (Fig.…”

Section: Delayed Mitotic Entry In Hela Cells Upon Rac1 Glucosylation mentioning

confidence: 99%

“…11 Besides PAK, the Rho/Rac effector PRK2/PKN2 seems to contribute to the regulation of mitotic entry, as its RNAi-mediated depletion resulted in delayed mitotic entry. 13 Although several effector proteins of Rho-GTPases seem to be involved in the regulation of mitotic entry, the upstream Rho-GTPases regulating them have not yet been identified.…”

Section: Introductionmentioning

confidence: 99%

Rac1-dependent recruitment of PAK2 to G₂phase centrosomes and their roles in the regulation of mitotic entry

et al. 2014

View full text Add to dashboard Cite

“…PRKs, as well as the Rho-associated kinases (ROCKs), are considered to be the protein kinases that mediate the phosphorylation events downstream of Rho activation and both can be inhibited by the highly specific protein kinase inhibitor Y27632 (18). The most notable role described for PRK2 is the control of entry into mitosis and exit from cytokinesis (19). In addition, PRK2 phosphorylates the hepatitis C virus (HCV) RNA polymerase (20).…”

mentioning

confidence: 99%

Regulation of the Interaction between Protein Kinase C-related Protein Kinase 2 (PRK2) and Its Upstream Kinase, 3-Phosphoinositide-dependent Protein Kinase 1 (PDK1)

Dettori

Sonzogni

Meyer

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

The members of the AGC kinase family frequently exhibit three conserved phosphorylation sites: the activation loop, the hydrophobic motif (HM), and the zipper (Z)/turn-motif (TM) phosphorylation site. 3-Phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylates the activation loop of numerous AGC kinases, including the protein kinase C-related protein kinases (PRKs). Here we studied the docking interaction between PDK1 and PRK2 and analyzed the mechanisms that regulate this interaction. In vivo labeling of recombinant PRK2 by 32 P i revealed phosphorylation at two sites, the activation loop and the Z/TM in the C-terminal extension. We provide evidence that phosphorylation of the Z/TM site of PRK2 inhibits its interaction with PDK1. Our studies further provide a mechanistic model to explain different steps in the docking interaction and regulation. Interestingly, we found that the mechanism that negatively regulates the docking interaction of PRK2 to the upstream kinase PDK1 is directly linked to the activation mechanism of PRK2 itself. Finally, our results indicate that the mechanisms underlying the regulation of the interaction between PRK2 and PDK1 are specific for PRK2 and do not apply for other AGC kinases.The regulation of protein function by phosphorylation and dephosphorylation is a key mechanism of intracellular signaling pathways in eukaryotic organisms. Protein phosphorylation is catalyzed by protein kinases, which are themselves often regulated by phosphorylation (1). The specificity of protein kinases is essential for their cellular functions. In some groups of protein kinases, the specificity is achieved by means of "docking interactions." Protein kinase docking interactions involve a recognition site on the kinase or a flanking domain that is different from the active site. The most notable example, MAP kinases, uses a docking interaction to specifically recognize substrates, upstream kinases, and phosphatases. Despite the large amount of data on protein kinase docking interactions, e.g. in the MAP kinase field, there is very little information on how these essential interactions are regulated (2-4).3-Phosphoinositide-dependent protein kinase 1 (PDK1) 3 belongs to the AGC family of protein kinases and is the activation loop kinase for several other AGC kinases (5). A key feature of the AGC kinase family members except PDK1 is the presence of a C-terminal extension (CT) to the catalytic core that contains a conserved hydrophobic motif (HM) harboring a phosphorylation site. In many AGC kinases, the HM mediates a docking interaction with PDK1. For example, p90 ribosomal S6 kinase (RSK), p70 S6 kinase (S6K) and serum-and glucocorticoid-induced protein kinase (SGK) interact with PDK1 upon phosphorylation of the HM site (6 -9). The phosphorylated HM binds to a HM-binding pocket in the catalytic core of PDK1 that was originally termed the PIF-binding pocket (6, 10). Besides its role in the docking of substrates to PDK1, the HM/PIF-binding pocket was also identified as a ubiquitous and key regulator...

show abstract

Rho GTPases regulate PRK2/PKN2 to control entry into mitosis and exit from cytokinesis

Cited by 99 publications

References 51 publications

STAR syndrome-associated CDK10/Cyclin M regulates actin network architecture and ciliogenesis

STAR syndrome-associated CDK10/Cyclin M regulates actin network architecture and ciliogenesis

Rac1-dependent recruitment of PAK2 to G₂phase centrosomes and their roles in the regulation of mitotic entry

Regulation of the Interaction between Protein Kinase C-related Protein Kinase 2 (PRK2) and Its Upstream Kinase, 3-Phosphoinositide-dependent Protein Kinase 1 (PDK1)

Contact Info

Product

Resources

About

Rho GTPases regulate PRK2/PKN2 to control entry into mitosis and exit from cytokinesis

Cited by 99 publications

References 51 publications

STAR syndrome-associated CDK10/Cyclin M regulates actin network architecture and ciliogenesis

STAR syndrome-associated CDK10/Cyclin M regulates actin network architecture and ciliogenesis

Rac1-dependent recruitment of PAK2 to G2phase centrosomes and their roles in the regulation of mitotic entry

Regulation of the Interaction between Protein Kinase C-related Protein Kinase 2 (PRK2) and Its Upstream Kinase, 3-Phosphoinositide-dependent Protein Kinase 1 (PDK1)

Contact Info

Product

Resources

About

Rac1-dependent recruitment of PAK2 to G₂phase centrosomes and their roles in the regulation of mitotic entry