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

Vadlamudi, Ratna K.; Feng, Li; Adam, Liana; Nguyen, Duy; Ohta, Yasutaka; Stossel, Thomas P.; Kumar, Rakesh

doi:10.1038/ncb838

Cited by 287 publications

(284 citation statements)

References 35 publications

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“…This suggests that in vivo, additional factors downstream of Rac1 are required for Op18 phosphorylation. This is consistent with our previous observation that constitutively active Pak1 did not have the same effect on microtubule growth as constitutively active Rac1 (7) and observations of other groups that Pak activity alone is often not sufficient to mediate cytoskeletal changes (46,47). We do not know what additional factors are required for Rac1-mediated Op18 phosphorylation, but our inhibitor studies indicate that PKA and Ca 2ϩ /calmodulindependent protein kinase, which can phosphorylate Op18 at serine 16, are not involved.…”

Section: Pak-dependent Phosphorylation Downstream Of Rac1 Cansupporting

confidence: 81%

Regulation of Microtubule Destabilizing Activity of Op18/Stathmin Downstream of Rac1

Wittmann

Bokoch

Waterman‐Storer

2004

Journal of Biological Chemistry

218

183

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In the leading edge of migrating cells, a subset of microtubules exhibits net growth in a Rac1-and p21-activated kinase-dependent manner. Here, we explore the possibility of whether phosphorylation and inactivation of the microtubule-destabilizing protein Op18/ stathmin could be a mechanism regulating microtubule dynamics downstream of Rac1 and p21-activated kinases. We find that, in vitro, Pak1 phosphorylates Op18/ stathmin specifically at serine 16 and inactivates its catastrophe promoting activity in biochemical and time lapse microscopy microtubule assembly assays. Furthermore, phosphorylation of either serine 16 or 63 is sufficient to inhibit Op18/stathmin in vitro. In cells, the microtubule-destabilizing effect of an excess of Op18/ stathmin can be partially overcome by expression of constitutively active Rac1(Q61L), which is dependent on Pak activity, suggesting that the microtubule cytoskeleton can be regulated through inactivation of Op18/ stathmin downstream of Rac1 and Pak in vivo. However, in vivo, Pak1 activity alone is not sufficient to phosphorylate Op18, indicating that additional pathways downstream of Rac1 are required for Op18 regulation.

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Section: Pak-dependent Phosphorylation Downstream Of Rac1 Cansupporting

confidence: 81%

Regulation of Microtubule Destabilizing Activity of Op18/Stathmin Downstream of Rac1

Wittmann

Bokoch

Waterman‐Storer

2004

Journal of Biological Chemistry

218

183

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“…The PKC binding site at the C terminus of filamin consists of repeat 24, the dimerization site. This repeat is essential for the crosslinking of actin filaments and in addition serves as or is next to the interaction sites for a number of signaling molecules, among which are small GTPases of the Rho family (27), Trio, a Rac1-and Rhoguanine nucleotide exchange factor (GEF) (28), Smads (53), and p21-activated kinase 1 (PAK1) (54). This accumulation of filamin ligands at the C terminus supports the concept that filamin serves as a scaffold allowing cross-talk between different signaling pathways (20).…”

Section: Discussionmentioning

confidence: 99%

The F-actin Cross-linking and Focal Adhesion Protein Filamin A Is a Ligand and in Vivo Substrate for Protein Kinase Cα

Tigges

Koch

Wissing

et al. 2003

Journal of Biological Chemistry

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Filamin A is an established structural component of cell-matrix adhesion sites. In addition, it serves as a scaffold for the subcellular targeting of different signaling molecules. Protein kinase C (PKC) has been found associated with filamin; however, details about this interaction and its significance for cell-matrix adhesiondependent signaling have remained elusive. We performed a yeast two-hybrid analysis using protein kinase C␣ as a bait and identified filamin as a direct binding partner. The interaction was confirmed in transfected HeLa cells, and serial truncation fragments of filamin A were employed to identify two binding sites on filamin. In vitro ligand binding assays revealed a Ca 2؉ and phospholipid-dependent association of the regulatory domain of protein kinase C with these sites. Phosphorylation of filamin was found to be isoform-restricted, leading to phosphate incorporation in the C termini of filamin A and C, but not B. PKC-dependent phosphorylation of filamin was also detected in cells. Our data suggest an intimate interaction between filamin and PKC in cell signaling.

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“…It is especially involved in cell adhesion, spreading and motility, as well as in signaling events (mediated by p21-activating kinase 1) regulating cytoskeletal assembly and cell shape (Vadlamudi et al, 2002). As in MMECs, FLNA is upregulated in human tumor cells (Zhou et al, 2010), while it not defined as oncogenic protein.…”

Section: Angiogenic Proteins Of Mmecs S Berardi Et Almentioning

confidence: 99%

Four proteins governing overangiogenic endothelial cell phenotype in patients with multiple myeloma are plausible therapeutic targets

et al. 2011

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Bone marrow (BM) angiogenesis has an important role in the initiation and progression of multiple myeloma (MM). We looked at novel mechanisms of vessel formation in patients with MM through a comparative proteomic analysis between BM endothelial cells (ECs) of patients with active MM (MMECs) and ECs of patients with monoclonal gammopathy of undetermined significance (MGECs) and of subjects with benign anemia (normal ECs). Four proteins were found overexpressed in MMECs: filamin A, vimentin, a-crystallin B and 14-3-3f/d protein, not yet linked to overangiogenic phenotype. These proteins gave a typical distribution in the BM of MM patients and in MMECs versus MGECs, plausibly according to a different functional state. Their expression was enhanced by vascular endothelial growth factor, fibroblast growth factor 2, hepatocyte growth factor and MM plasma cell conditioned medium in step with enhancement of MMEC angiogenesis. Their silencing RNA knockdown affected critical MMEC angiogenesis-related functions, such as spreading, migration and tubular morphogenesis. A gradual stabilization of 14-3-3f/d protein was observed, with transition from normal ECs to MGECs and MMECs that may be a critical step for the angiogenic switch in MMECs and maintenance of the cell overangiogenic phenotype. These proteins were substantially impacted by anti-MM drugs, such as bortezomib, lenalidomide and panobinostat. Results suggest that these four proteins could be new targets for the antiangiogenic management of MM patients.

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

Cited by 287 publications

References 35 publications

Regulation of Microtubule Destabilizing Activity of Op18/Stathmin Downstream of Rac1

Regulation of Microtubule Destabilizing Activity of Op18/Stathmin Downstream of Rac1

The F-actin Cross-linking and Focal Adhesion Protein Filamin A Is a Ligand and in Vivo Substrate for Protein Kinase Cα

Four proteins governing overangiogenic endothelial cell phenotype in patients with multiple myeloma are plausible therapeutic targets

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