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

ABSTRACT: Rho GTPases regulate multiple signal transduction pathways that influence many aspects of cell behaviour, including migration, morphology, polarity and cell cycle. Through their ability to control the assembly and organization of the actin and microtubule cytoskeletons, Rho and Cdc42 make several key contributions during the mitotic phase of the cell cycle, including spindle assembly, spindle positioning, cleavage furrow contraction and abscission. We now report that PRK2/PKN2, a Ser/Thr kinase and Rho/Rac effector protein, is an essential regulator of both entry into mitosis and exit from cytokinesis in HeLa S3 cells. PRK2 is required for abscission of the midbody at the end of the cell division cycle and for phosphorylation and activation of Cdc25B, the phosphatase required for activation of mitotic cyclin/Cdk1 complexes at the G2/M transition. This reveals an additional step in the mammalian cell cycle controlled by Rho GTPases.

SUBMITTER: Schmidt A

PROVIDER: S-EPMC1829391 | biostudies-other | 2007 Mar

REPOSITORIES: biostudies-other

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

Schmidt Anja A Durgan Joanne J Magalhaes Ana A Hall Alan A

The EMBO journal 20070301 6

Rho GTPases regulate multiple signal transduction pathways that influence many aspects of cell behaviour, including migration, morphology, polarity and cell cycle. Through their ability to control the assembly and organization of the actin and microtubule cytoskeletons, Rho and Cdc42 make several key contributions during the mitotic phase of the cell cycle, including spindle assembly, spindle positioning, cleavage furrow contraction and abscission. We now report that PRK2/PKN2, a Ser/Thr kinase ...[more]

PMID: 17332740

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Project description:BackgroundPrevious research demonstrated that small Rho GTPases, modulators of the actin cytoskeleton, are drivers of podocyte foot-process effacement in glomerular diseases, such as FSGS. However, a comprehensive understanding of the regulatory networks of small Rho GTPases in podocytes is lacking.MethodsWe conducted an analysis of podocyte transcriptome and proteome datasets for Rho GTPases; mapped in vivo, podocyte-specific Rho GTPase affinity networks; and examined conditional knockout mice and murine disease models targeting Srgap1. To evaluate podocyte foot-process morphology, we used super-resolution microscopy and electron microscopy; in situ proximity ligation assays were used to determine the subcellular localization of the small GTPase-activating protein SRGAP1. We performed functional analysis of CRISPR/Cas9-generated SRGAP1 knockout podocytes in two-dimensional and three-dimensional cultures and quantitative interaction proteomics.ResultsWe demonstrated SRGAP1 localization to podocyte foot processes in vivo and to cellular protrusions in vitro. Srgap1fl/fl*Six2Cre but not Srgap1fl/fl*hNPHS2Cre knockout mice developed an FSGS-like phenotype at adulthood. Podocyte-specific deletion of Srgap1 by hNPHS2Cre resulted in increased susceptibility to doxorubicin-induced nephropathy. Detailed analysis demonstrated significant effacement of podocyte foot processes. Furthermore, SRGAP1-knockout podocytes showed excessive protrusion formation and disinhibition of the small Rho GTPase machinery in vitro. Evaluation of a SRGAP1-dependent interactome revealed the involvement of SRGAP1 with protrusive and contractile actin networks. Analysis of glomerular biopsy specimens translated these findings toward human disease by displaying a pronounced redistribution of SRGAP1 in FSGS.ConclusionsSRGAP1, a podocyte-specific RhoGAP, controls podocyte foot-process architecture by limiting the activity of protrusive, branched actin networks. Therefore, elucidating the complex regulatory small Rho GTPase affinity network points to novel targets for potentially precise intervention in glomerular diseases.

Dataset Information

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

Publications

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

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