Filamin is essential in actin cytoskeletal assembly mediated by p21-activated kinase 1

  title={Filamin is essential in actin cytoskeletal assembly mediated by p21-activated kinase 1},
  author={Ratna K. Vadlamudi and Feng Li and Liana Adam and Diep N. Nguyen and Yasutaka Ohta and Thomas Peter Stossel and Rakesh Kumar},
  journal={Nature Cell Biology},
The serine/threonine kinase p21-activated kinase 1 (Pak1) controls the actin cytoskeletal and ruffle formation through mechanisms that are independent of GTPase activity. Here we identify filamin FLNa as a Pak1-interacting protein through a yeast two-hybrid screen using the amino terminus of Pak1 as a bait. FLNa is stimulated by physiological signalling molecules to undergo phosphorylation by Pak1 and to interact and colocalize with endogenous Pak1 in membrane ruffles. The ruffle-forming… 

Adapter protein SH2B1beta binds filamin A to regulate prolactin-dependent cytoskeletal reorganization and cell motility.

A model for PRL-dependent regulation of the actin cytoskeleton that integrates the findings with previous studies is proposed and found that in addition to two actin-binding domains, SH2B1β has a FLNa-binding domain that binds directly to repeats 17-23 of FLNa.

p21-Activated Kinase 1 Regulates Microtubule Dynamics by Phosphorylating Tubulin Cofactor B

A novel role for TCoB and Pak1 is revealed in regulating microtubule dynamics through an elusive mechanism that was overexpressed and phosphorylated in breast tumors and revealed a phenotype reminiscent of cells overexpressing Pak1.

Constitutive p21-activated kinase (PAK) activation in breast cancer cells as a result of mislocalization of PAK to focal adhesions.

It is shown that endogenous PAK is constitutively activated in certain breast cancer cell lines and that this activePAK is mislocalized to atypical focal adhesions in the absence of high levels of activated Rho GTPases.

Nuclear Localization and Chromatin Targets of p21-activated Kinase 1*

Investigations provide proof-of-principle evidence that Pak1 could influence the expression of its putative chromatin targets in both a positive and a negative manner, opening new avenues to further the search for nuclear Pak1 functions and identify putative Pak1-interacting nuclear proteins.

Essential role of CIB1 in regulating PAK1 activation and cell migration

It is demonstrated that endogenous CIB1 is required for regulated adhesion-induced PAK1 activation and preferentially induces aPAK1-dependent pathway that can negatively regulate cell migration.

Trihydrophobin 1 Interacts with PAK1 and Regulates ERK/MAPK Activation and Cell Migration*

A model is proposed in which trihydrophobin 1 interacts with PAK1 and specifically restricts the activation of MAPK modules through the upstream region of the MAPK pathway, thereby influencing cell migration.

Ribosomal S6 Kinase (RSK) Regulates Phosphorylation of Filamin A on an Important Regulatory Site

The characterization of the cytoskeletal protein filamin A (FLNa) as a membrane-associated RSK target and substantial evidence that RSK phosphorylates FLNa on Ser2152 in vivo are provided, suggesting a novel role for RSK in the regulation of the actin cytoskeleton.

Biology of the p21-activated kinases.

  • G. Bokoch
  • Biology
    Annual review of biochemistry
  • 2003
A key role is proposed for PAK action in coordinating the dynamics of the actin and microtubule cytoskeletons during directional motility of cells, as well as in other functions requiring cytOSkeletal polarization.

The endocytic adapter E-Syt2 recruits the p21 GTPase activated kinase PAK1 to mediate actin dynamics and FGF signalling

The data suggest that PAK1 interacts with phospholipid membrane domains via E-Syt2, where it may cooperate in the E- Syt2-dependent endocytosis of activated FGFR1 by modulating cortical actin stability.



Localization of p21-Activated Kinase 1 (PAK1) to Pinocytic Vesicles and Cortical Actin Structures in Stimulated Cells

Data indicate a close correlation between the subcellular distribution of endogenous PAK1 and the formation of Rac/Cdc42-dependent cytoskeletal structures and support an active role forPAK1 in regulating cortical actin rearrangements.

A GTPase-independent Mechanism of p21-activated Kinase Activation

The results demonstrate a novel GTPase-independent mechanism of PAK activation and suggest that PAK(s) may be important mediators of the biological effects of sphingolipids.

Expression of constitutively active alpha-PAK reveals effects of the kinase on actin and focal complexes

Transfection shows that in epithelial HeLa cells alpha-PAK is recruited from the cytoplasm to distinct focal complexes by both Cdc42(G 12V) and Rac1(G12V), which themselves colocalize to these sites, which support previous suggestions of a role for PAK downstream of both CDC42 and Rac 1 and indicate that PAK functions include the dissolution of stress fibers and reorganization of focal complexes.

Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics

It is shown that p21-activated kinase (Pak1) phosphorylates LIM-kinase at threonine residue 508 within LIM- Kinase’s activation loop, and increases LIM-Kinase-mediated phosphorylation of the actin-regulatory protein cofilin tenfold in vitro.

Temporal and Spatial Distribution of Activated Pak1 in Fibroblasts

Findings indicate that activated Pak1, and by extension, probably activated Cdc42 or Rac, accumulates at sites of cortical actin remodeling in motile fibroblasts.

Heregulin Regulates Cytoskeletal Reorganization and Cell Migration through the p21-activated Kinase-1 via Phosphatidylinositol-3 Kinase*

A role of PI-3 kinase/PAK1-dependent reorganization of the cortical actin cytoskeleton in HRG-mediated increased cell migration is suggested, and these changes may have significant consequences leading to enhanced invasion by breast cancer cells.

Differential Effects of PAK1-activating Mutations Reveal Activity-dependent and -independent Effects on Cytoskeletal Regulation*

It was found that PAK1 kinase activity was associated with disassembly of focal adhesions and actin stress fibers and that this may require interaction with potential SH3 domain-containing proteins.

Phosphorylation of Actin-binding Protein 280 by Growth Factors Is Mediated by p90 Ribosomal Protein S6 Kinase (*)

It is shown that the p90 ribosomal S6 kinase 2 (RSK2) phosphorylates actin-binding protein (ABP-280) in intact rat 3Y1 fibroblasts and two-dimensional phosphopeptide maps show RSK2 phosphorylated ABP- 280 to be phosphorylation at the same site(s) as those stimulated by growth factors in vivo.

Paxillin LD4 Motif Binds PAK and PIX through a Novel 95-kD Ankyrin Repeat, ARF–GAP Protein: A Role in Cytoskeletal Remodeling

Data implicate paxillin as a mediator of p21 GTPase–regulated actin cytoskeletal reorganization through the recruitment to nascent focal adhesion structures of an active PAK/PIX complex potentially via interactions with p95PKL.